Hello, everyone. Welcome to the American College of Cardiology webinars on renal denervation, the latest data and implications for clinical practice. This webinar is sponsored by the ACC's federal section, by myself, Cretan Mavramadis, and Mladen Vidovich. We are here today to, as the title shows, talk about the latest data and implications for clinical practice with regards to renal denervation. We have three wonderful speakers today. Dr. Michael Fisher, Chandan Devareddy, and Vasilios Papadimitriou. Each one is going to speak on a different topic with regards to hypertension and renal denervation. After each talk, we'll have about a minute or two for a quick one or two questions, which you can enter in the chat, and myself or Dr. Vidovich will read them off. And at the end, after Dr. Papadimitriou's talk, we will have a longer period for questions and answers. Again, you can post your questions in the chat box, and we will read them off. At the very end, there will be a poll with regards to this webinar and your interest in renal denervation, which will be used to plan future programming. Your feedback is greatly appreciated. And again, if you have any problems with WebEx, you may contact James Hahn or Mir Arobo, whose emails are available on this slide or using the chat box. On that, Lon, why don't you introduce our first speaker? So thank you, Creighton, and again, thank you all for attending. And this is, again, a great effort on the American College of Cardiology with the federal section to create this educational program for our members from the Department of Veterans Affairs and Department of Defense. So I'm super happy to present my colleague from Jesse Brown VA in Chicago, where I work as well. He's chief of the renal section, I'm chief of cardiology, so we deal a lot with operations together. But Dr. Fisher is also a NIH-funded scientist and has done actually quite a bit of work about hypertension in the veterans. So without further ado, Michael, please go ahead and give us your overview about hypertension in the VA community. Great. Thank you, Milan, for the kind introduction. Over the next 10 minutes, I'm going to be characterizing the burden of hypertension in the VA community, and I think this will lay the groundwork for the subsequent two speakers who are going to kind of dive into details about renal denervation. Next slide, please. Here are my disclosures, acknowledgments, and disclaimers. Next slide, please. Within the objective of the burden of hypertension in the VA community, I'm going to cover the following three content points. One, define the VA community. Two, describe hypertension among active duty personnel. And three, characterize hypertension and treatment among veterans in the current environment. Next slide, please. So what exactly constitutes the VA community? Well, currently, or as of 2021, there were 1.3 million active duty personnel in the United States. The vast majority of those receive care at DOD or Department of Defense facilities, but they also can use TRICARE insurance to receive such care in the community. Upon honorable discharge, they become veterans, and in 2021, there are about 17 million veterans in the United States. 9 million of those veterans actually enrolled in VA health care, and of those, about 6 million receive care within the VA, which has about 1,300 facilities across the country. Another 2 to 3 million have the VA pay for their care in the community, and some use care in both sectors. But a good proportion, almost half, of veterans don't enroll for VA health care benefits and actually opt for private insurance, Medicare, and Medicaid. These subgroups are important, and the reason why I cover this is they're varied and distinct in terms of their characteristics and their risk factors for hypertension. One key limitation in the current literature, which I'll present today, is that most studies only focus on one of these communities, so it's difficult to get a broad composite of the burden in hypertension in the VA community, but we'll do our best this evening. Next slide, please. So kind of going first to the first content point, the prevalence of hypertension among active duty personnel. This was a study in 2004 of over 15,000 active duty service members in Tacoma, Washington at Fort Lewis. They defined hypertension as indicated here. The demographics are probably not surprising, fairly young, thin, predominantly male, fairly good racial ethnic representation. And what they found was the prevalence of hypertension was 13%, and 2% of service members were actually taking antihypertensive medications. And while this is much lower than that of the general population, it's somewhat surprising since often chronic conditions disqualify you for active service. But it's important to recognize that many people or adults are in active service for years or decades, so it's likely that some of these conditions evolved during the course of active service. Next slide, please. So this histogram compares kind of the prevalence of hypertension in active duty personnel to civilian personnel. As I mentioned previously, the crude rates of hypertension in active duty is much less than the civilian population. So we want to, and one of the reasons why is because active duty population is much younger, and as we all know, advancing age is a large risk factor for hypertension. So here in the histogram, I present age-adjusted prevalence of hypertension, women and men, and what you see that even when you account for age, active duty personnel, both men and women have a much lower prevalence of hypertension than their civilian counterparts. Likely this is because of the other physical stringent requirements to become and continue an active military service. Next slide, please. So turning to the third content point, the prevalence of hypertension among veterans, the data I'm going to present is from the National Health and Nutrition Examination Survey, which is a representative survey of adult Americans, and this was from the period of 2009 to 2012. And based on self-identification to a question about having served in the armed forces, they identified about 1,100 veterans and almost 4,000 non-veterans. They define the hypertension as I've indicated here, the demographics are what you might anticipate. Next slide, please. So this slide shows you a few important things. One, as you go from left to right over these three time periods, oldest to most recent, the prevalence of hypertension, both in those who identified as a veteran and those who did not, who is a non-veteran was increasing over time. And if you look furthest to the right, you see that in those who identified as a veteran, the estimated prevalence, again, this is a representative sample, was over 50%, which is substantial. Number two, it was much higher, almost twice that of the civilian population. And again, one could argue, is that just a function of age? But even when you take account for age, it's still, albeit not meeting statistically significance, still higher among veterans than non-veterans. And this is likely due to other socio-demographic and clinical risk factors in a very vulnerable veteran population. Next slide, please. So that was veterans overall. What about veterans who specifically rely on the VA for their healthcare? This was a study done around 2000 of almost 400,000 veterans at medical centers in the southeastern United States. They had the following criteria, which were quite detailed for what indicated the individual at hypertension. The demographics, again, predominantly male, middle to late 50s. And what they found was that, again, slightly over half met criteria for hypertension. Obviously, these criteria are slightly different than the prior study, but there's thematic consistency in that about half or a little bit more than half of veterans meet criteria for hypertension. Next slide, please. What about resistant hypertension? So among all those who have hypertension, a big clinical concern is resistant hypertension because of the negative health consequences associated with it. And this study done in the VA in Northern California around 2010 of about 18,000 adults receiving care, veterans receiving care there, examined the prevalence of resistant hypertension, which they defined as blood pressure over 140, over 90 on three or more medications or controlled on four or more medications, including a thiazide diuretic, a pretty standard deposition of resistant hypertension. And what they found was that 9% of veterans had resistant hypertension or 13% of those with hypertension, they found almost two thirds of veterans had hypertension in this population. So quite substantial. The second question I think is how does it compare to the civilian population as kind of a framework? And it was actually quite close. It was 8.9% in the civilian population. So while hypertension overall is more common in veterans, perhaps resistant hypertension or these severe groupings of hypertension is somewhat similar. Next slide, please. So the other clinical concern is how well is hypertension controlled? And the guidelines for what define controlled are always changing. In this study, they defined it as having a blood pressure less than 140 over 90. And they looked at half a million hypertensive patients in 15 VA centers between 2000 and also in 2010. So if we look at the histogram, the left slide is 2000, the right is 2010. They compared it to the civilian population. That's an orange, which is, again, drawn from the NHANES survey, a representative sample. And what you see is that in both groups, the good news is that the control of hypertension improved over this 10-year period. The other consistent theme, which was even becoming more pronounced in 2010, is that control of hypertension was better among veterans, specifically those receiving care at the VA. And in 2010, by this definition, it was more than two-thirds having control of their hypertension. So improving and better than in the civilian population. Next slide, please. Lastly, we want to consider treatment and specifically medication use for hypertension in those receiving care in the VA. And this study was over a million and a half veterans. They used a national VA database for all medications with veterans of hypertension. And they looked at what was the burden in 2006 with medications. And you can see here, almost 80% of veterans of hypertension were receiving at least two medications. Almost half were taking at least three antihypertensive medications. And moreover, what's the secular trend? Well, if you look over the six-year period from 2000 to 2006, it was only getting worse. Going from 22% to 26% on three drugs. And more than three antihypertensive drugs almost doubled, going from 12% to 18%. So medication burden is worsening over time. That may, in part, explain the improving control. But the trade-off is increasing pill burden for our patients. Next slide, please. Oh, so there's just one last slide, I think, that may have come off as my summary slide, which I'll just quickly just kind of hit the high main points, which are, number one, hypertension is very common in the veteran population. And it is getting more common over time, affecting more than half of veterans. It's less in the active duty population. But still, I think, higher than one might think, considering the physical requirements to get into that. And while control of hypertension is improving in the veteran population, and more so than among civilians, the medication burdening is increasing. And therefore, as we think about the next two talks, we need to explore other avenues, both for treating hypertension, evaluating secondary causes of hypertension, and thinking of ways best to provide patient-centered care for this important chronic condition. And I'll stop there. Yeah, Michael, this is actually terrific. And I think, again, we're very grateful that we got a nephrologist speaking to a cardiologist, because I think, as it'll become evident, as you mentioned, from the subsequent talks, it'll take a village. It'll take probably comprehensive care, like probably resistant hypertension clinics to put these programs together. So, Cretan, would you like to introduce our next speaker? You're muted. Cretan, you're muted. Sorry about that. Yeah, I just had one quick question for you, Dr. Fisher. Do you have a feeling for how much of this hypertension is just isolated systolic hypertension versus both systolic and diastolic? Has that come about in the paper? In your practice? It's a great question. I think, generally, in elderly populations, I'm thinking specifically of veteran populations, we see a lot more high systolic, low diastolic, isolated systolic hypertension. That's what I've observed in my clinical practice. That's what I've observed not in data I've presented here, but in research I've done. Unfortunately, and you probably noted from, yeah, I think it's been a couple of years and you probably noted from, yeah, I presented the best studies I could find, their definitions did not tease apart those two components. And I think it's unfortunate that wasn't done because it has a lot of relevance to our approach of that. So, in summary, I think oftentimes we are seeing isolated systolic hypertension in geriatric populations. Well, thank you, Dr. Fisher. So, I would like to introduce our next speaker at this point. It's Chandan Devareddy, who is at the Emory University School of Medicine in Atlanta. He has been a long-time clinical trialist in the area of renal denervation. And I know firsthand from hearing from him in the past that he has been involved in a lot of studies, and I bet you he is going to be able to enlighten us in where the clinical trial data has led us so far. Chandan? Thanks, Ketan. It's a pleasure to be here. We have a heavy load to carry for the next 15 minutes, so hopefully everyone's got their seatbelts on and we're going to take you through a whirlwind of data, which is a good thing. Ten years ago, the question was, would there be any data in this field? And now we've got quite a bit. Next slide. Next slide. These are my disclosures. Next slide. So, in the early days of renal denervation, you would have lots of background slides kind of explaining the underlying physiology and whatnot. Because of the time constraints, we'll kind of keep that to a minimum here. This will be my one background slide just demonstrating that there's an active relationship between the sympathetic nervous system and the control of renal function in terms of cellular retention, overall renal blood flow, the renal angiotensin-aldosterone axis. And this has a very profound effect in hypertensive mediated organ damage and potentially in organ systems far beyond the kidneys and the vasculature. Trying to intervene on this has been the question, and that's some of the data that we're going to review this evening. Next slide. Currently, there are three approaches percutaneously in a minimally invasive fashion to try to affect and modulate sympathetic function as mediated through renal nerves coming off the vasculature. The first on the left is a radiofrequency-based system that emits frequency energy to try to silence nerve traffic in the nerves that lie just outside the renal arteries. That's been the longest-standing device that's been in clinical testing so far. In the center of this cartoon is an ultrasound-based system, which is a balloon-based device with rotational ultrasound, somewhat newer on the stage but with a fairly extensive data set behind it at this point. And the newest is on the right, which is an alcohol-mediated renal denervation, not through alcohol ingestion, which would be the opposite of what we want, but actually through direct microneedle perfusion of pure ethanol that diffuses into the tissue around the renal arteries and, in effect, kills renal nerves through chemical denervation. We have short-term safety data, and there's trials that are actually just finished and rolling out to randomization recently. Next slide. I'm sorry. The big question that we're going to now discuss is whether these work. So, this is a very interesting graphic that shows the timeline of this adventure since 2010. Everything above the blue arrow are clinical trials that have been tested with a randomized sham-controlled design. You can see that's the majority of data in this field. The three trials below the blue arrow are randomized control trials that did not involve a sham procedure arm. All the trials listed that are in green print are trials that met their pre-specified endpoints. The red trials, or the red letters, are trials that did not meet pre-specified endpoints. You can see their early experience had trials that did not meet this. Trials that then reset sort of the thinking of how to assess these patients, how to truly manage medications and achieve a standardized sort of platform on which to compare these patients are more sort of what we define as the modern era, moving from 2017 onwards. The trials in gray, actually, several of these have reported data, the majority of which have met pre-specified endpoints, the last being the target trials, which are chemical denervation. Next slide, please. We'll first discuss the radio frequency catheter, which is the spiral catheter. This is designed and manufactured by Medtronic. This, in its current iteration, is a multi-electrode catheter that has four electrodes and circumferential pattern 90 degrees apart that deliver a 60-second radio frequency energy treatment. This is completely percutaneous, the same size catheters that one would receive if undergoing a cardiac catheterization. The way the catheter appears angiographically is on the right. You can see on a perpendicular view that the electrodes are 90 degrees apart, which then space the treatments in different directions so you don't get an overdose, and these are delivered both in the main renal artery as well as in the branches of the renal artery just outside the renal pelvis. Next slide, please. These trials have been tested in what's called the Spiral HTN Clinical Program. This has involved now over 4,000 patients with some of these trials and registries that now actually have a decent amount of long-term data that we can review. We won't be able to review all of these trials in detail, again, given the time constraints, but we'll try to hit some of the high points. Next slide, please. You'll see a recurring theme as we go through the trial and study design of these clinical trials across even different sponsors and platforms. The Spiral HTN trial tried to look at these trials in two varying fashions. One pathway was to try to really demonstrate the proof of concept, that if you could take a patient and remove their underlying medication so that there was very little room for confounding, that it was just a patient, their blood pressure, and this treatment, could you show a difference between patients who underwent true renal denervation and patients who received a sham-controlled procedure? Patients had to demonstrate that they were hypertensive and then were taken off their medications if they were on any to begin with. They were monitored over a safety check, and then two weeks later underwent a 24-hour ambulatory blood pressure monitor, which in all these trials you will see was demonstrated as the true standard of measurement of blood pressure, both at baseline and in follow-up endpoints. Patients had drug testing to demonstrate that they were compliant or non-compliant, as it were, and then they were randomized between the sham control and the renal denervation procedure. In this off-med spiral program, patients had their primary endpoint at three months and then were unblinded at six months. Between three months and six months, they could begin medications if they met pre-specified endpoints of meeting requirements for blood pressure over 140 and starting medications. Next slide, please. The other pathway was the on-med pathway. These were patients that would be typically described more as resistant and requiring medications, and despite those medications not being adequately controlled. In the Medtronic version of these trials, patients had to be on one, two, or three medicines of the four classes listed on the left, thiazide, calcium channel blockers, ACE, ARB, or beta blockers. Patients underwent an observation period over a period of two to four weeks, and then at the second visit, underwent drug testing, 24-hour ambulatory blood pressure monitoring, and had to be on stable medicines during this phase. If patients either had a blood pressure that was too low or too high outside those pre-specified endpoints, they were screen failed, but if they met criteria, they were then randomized between a sham procedure or renal denervation, similar to the off-med cohort described in the prior slide, but now the primary endpoint was at six months on stable medications during this period. Next slide, please. Just to kind of give you a flavor of who these patients were, if you look at the patients in the on-med cohort, they were significantly hypertensive, blood pressure over 160 on office, and almost 150 on 24-hour monitoring. Next slide, please. As far as the medicines, you can see here, the patients were pretty much split between one, two, or three classes, the majority of whom were taking an ACE or an ARB, and then next commonly was a calcium channel blocker. Next slide, please. The procedure with the spiral catheter, typically, success rate was highly successful, almost 100%. This required treatment both in the main arteries as well as an average of six branches treated. A total of 47 ablations performed overall. Catheter time was just over 50 minutes. Generally, a very reproducible procedure. Next slide, please. This slide is a nice slide that shows across these different study pathways. The two bars on the left are the off-med pathways, and the two bar graphs on the right are the on-med pathways. The bar graphs on the top are measured with 24-hour blood pressure monitoring, and the bar graphs on the bottom are office blood pressure measurements. The bars in blue are patients who received renal denervation and show the depth of blood pressure drop after treatment. The gray bar are patients that underwent a sham procedure. There was some blood pressure lowering, but you can see across the board in different study pathways in different types of patients, the blood pressure lowering achieved by renal denervation was fairly consistent. You see a drop anywhere from about You see a drop anywhere from about five to as much as nine millimeters of mercury in a 24-hour blood pressure measurement. Generally, what's felt to be clinically significant is a number greater than five. Blood pressure drops in the sham cohort, although present, were generally slight, most parts statistically significant. The on-med full cohort did have a fairly profound drop in blood pressure drop in the sham procedure, and in going through those patients, there was found to be somewhat inconsistencies in patients coming off or changing their medications while they were in full stream into the trial and in their monitoring. But overall, blood pressure drops with renal denervation were fairly consistent. Next slide, please. The nice thing about renal denervation, and you'll see this across these different study platforms, is that the effect encountered afterwards is consistent, 24 hours a day, daytime, nighttime. The dark line are blood pressure measurements of over a 24-hour period at baseline, and the light blue line on the bottom is the blood pressure seen at the primary endpoint. In this case, this is long-term data in the on-med pilot three years out. You can see there's a much more stark difference between baseline to three years in the graph on the left in patients who underwent renal denervation compared to patients who underwent the sham procedure, and you can see at three years afterwards, there was not as stark a difference. These are patients who their providers were allowed to manage their medicines, change doses, but despite best efforts at medical management, there was a significant difference in patients who had undergone renal denervation. Next slide, please. When looking at long-term data, these are, again, these different study pathways, the off-med on the left, on-med in the middle, and actually a long-term European registry of patients who had received commercial denervation outside the United States. You can see that not only was blood pressure lowered after renal denervation at the initial time points, which are the bars on the left, but in the same color coding as you move forward to the right, and the on-med, in terms of randomized data, out to three years, blood pressure was sustained in its drop after renal denervation, if not further lowered over time, and this has been an interesting phenomenon that's been seen across multiple studies that the renal denervation effect is sustained and, if anything, further lowered. Next slide, please. As I mentioned, there has been a registry outside the United States. These are patients who had commercial experience. These were over 2,500 patients and did show significant reductions in patients in multiple high-risk subgroups. Next slide. Safety has also been another large concern, but in the renal denervation studies across the board, safety performance has been excellent. There was one vascular event across the entire off-med and on-med study experience of 253 patients, greatly improving the pre-specified performance goal. Next slide, please. The next method of renal denervation I'd like to review is with the ultrasound system. This is also catheter-based, slightly larger profile catheter, but similar to what patients may experience if they're undergoing a coronary angioplasty. This balloon-based system is advanced over a wire into the renal arteries, and a rotational ultrasound element spins and delivers a very short duration of ultrasound heat energy, which then denervates the targeted depth of approximately 3 to 5 millimeters around the renal arteries. Next slide, please. This treatment is very short. It's only a seven-second sonication and only requires two to three treatments in each of the main renal arteries and possibly side branches if required. Next slide, please. Next slide. The renal artery as seen here with a catheter is outlined. Next slide. The balloon is inflated with a contrast injection to make sure that there's no contrast leaking around the balloon. Next slide. That's a graphic of where the balloon is located. Next slide. At this point, the balloon is brought back for an additional treatment, and that would actually be the duration of treatment for seven seconds each in the renal artery, in this case, the left renal artery. Next slide. The ReCorp company, which is the sponsor of this device and this trial system, has outlined these trials as the RADIANCE-HTN Clinical Trial Program, very similar in philosophy and in their approach as the Medtronic Spiral HTN Program. Next slide, please. They also approached this with an off-med and an on-med cohort. Their off-med was called SOLO, and then subsequent design was called RADIANCE-II. Their on-med cohort was called the TRIO patients. The big difference with their on-med cohort was that they put these patients on a fixed three-drug combination pill that all patients had to take in order to qualify to participate in this clinical trial program. Another large difference was that their endpoint was a little bit shorter at two months and used a daytime ambulatory systolic blood pressure endpoint as opposed to a 24-hour ambulatory blood pressure endpoint. Next slide, please. In looking at their trial results combined here in one slide, again, a very consistent drop in blood pressure in the daytime ambulatory blood pressure monitor measurement at two months, at 8 millimeters mercury in very different types of patients, but across three different trial programs. In the sham procedure arm, again, there was a drop, but statistically significantly lower in patients who received the rotational ultrasound renal denervation with what they call the paradise balloon through this RADIANCE trial program. Next slide, please. Patients here, in terms of the types of patients, similar. Office blood pressure was about 154 millimeters mercury systolic, similar between the sham patients and the denervation patients. Approximately 30 percent of patients were female. Next slide, please. When you pool all the data together, off-med, on-med, RADIANCE-2, you can see here that there was an average drop of 8.5 millimeters by the ambulatory systolic blood pressure measurement at two months, an average of 3 millimeters in the sham procedure group, and this was statistically significant when pooling all patients together. Next slide, please. Similar to that graph I showed you in the spiral HTN patients, you can see here that when looking across 24 hours, there was a bigger difference in drop between the baseline, which is the top line, and then the hashed line, which is below, when you compare denervation on the left and the sham procedure arm on the right. This was statistically significant and does demonstrate that the effect of renal denervation occurs throughout the day and night, is independent of having to take a medicine, or of the individual form of kinetics that may occur with specific types of medications. Next slide, please. Safety, again, excellent. Minimal events in both the denervation and sham arms, demonstrating an excellent safety profile for the system. Next slide, please. Next slide, please. This is just an interesting slide that shows there is a significant amount of variation in patients between patients in the same study. Each line on these graphs are individual patients showing their blood pressure either dropping to the left of the graphs or rising on the right of the graphs at the time of the endpoint at two months. Some patients saw profound differences in blood pressure, as much as 20 to 30, even 40 millimeters mercury drops after receiving therapy. And there were a few patients in the sham arm that also may have seen some blood pressure drop. But the differences in patients who achieved as much as five or even over 10 millimeters in an ambulatory blood pressure measurement was much more commonly seen in patients who underwent renal denervation as opposed to a sham procedure. Next slide, please. This just shows that in their trial system, they have long-term data out to as long as three years. And in these patients, the blood pressure drop has been sustained, and again, if not further lowered over time. Next slide, please. This graph shows these different trials against each other, both in the Medtronic Spiral HTN trial program and the two bar graphs on the right, the Radiance HTN, which is the ultrasound program. And again, almost demonstrating a class effect of, and this is again in office blood pressures as opposed to ambulatory blood pressure measurements, of about 10 millimeters mercury in the office setting after undergoing denervation, as opposed to about a two to three millimeter drop in patients in the sham procedure arm across these different trial programs, and even with different catheter based denervation systems. Next slide, please. That last trial program that I mentioned, which is the Target BP program, this is looking at an alcohol injection, this is looking at an alcohol injection through microneedles delivered inside the renal arteries. Their trials have just closed to enrollment, and they're hoping to potentially report results later this year. Next slide, please. And as you can see here, their trial program and framework is very similar in terms of screening patients, randomization, and in this case, a three month endpoint with six months on blinding between a sham procedure and renal denervation. So we look forward to seeing their results later this year. Next slide, please. I know that was a lot of information. Hopefully there'll be a decent discussion. I've gone a few minutes over, but in conclusion, I do feel that there are now prospectively powered sham controlled, randomized controlled trials that validate a blood pressure lowering effect with renal denervation. Depending on, you know, how you look at this, these appear to be statistically significant and clinically relevant. There is no significant safety events across these different trials of different devices, and it demonstrates that the effect of renal denervation is always on after patients undergo this procedure, independent of the need to take a pill or a different medication. Moving forward, as we design and think about strategies of lowering blood pressure across communities of hypertension patients, such as seen in the veteran system, renal denervation may serve as a powerful adjunct therapy in our approach to patients to try to maximize our ability to get them to goal. Thank you for your attention and look forward to the discussion. Hey, Chandan, this is absolutely terrific. As you said, like, you know, a lot to chew, a lot to digest, and I think this is why it's great to have you here because you've been involved in these trials. And then, Kriten, can you introduce our next speaker? Absolutely, Mladen. Thank you, Chandan. Our next speaker is also an experienced doctor with regards to taking care of hypertension and in renal denervation, Dr. Vasilios Papadimitriou. He's a professor of medicine at Georgetown University and based also at the Washington, D.C. VA. I know for years he's been running renal, I'm sorry, hypertension programs and doing renal denervation. Dr. Papadimitriou, you have about 10 to 12 minutes to kind of wrap it up and tell us, put it all together for us. Well, thank you very much, Kriten, and thank you, everybody. It's a pleasure to be here, and I try to go over my slides quickly or as fast as I can. Next slide, please. Obviously, I'm going to talk about the two topics that were described earlier, but I cannot do any other way but start from this slide that shows the beginning of hypertension, the beginning of it all. The CSPPRO program that started in the VA back in the 1940s and the hypertension program that started in 1962 by the man who has been my boss for 15 years before he died, Edward D. Fries. He's the one who did the famous VA cooperative studies, the one in severe hypertension and one in moderate hypertension, that actually put the hypertension on the map and gave us all the tools and information and the data to proceed and try to control hypertension across the country and around the world. The first study, of course, was in severe hypertension and showed in a brief period of time, in 18 months, that the treatment of patients had only one event and control patients had 21. The study was stopped and never repeated again, and we all treat severe hypertension today. The second study was in mild to moderate hypertension, included 380 patients, randomized to placebo or active therapy, and it also showed dramatic reductions in events, 75% reduction in the composite endpoint, 70% reduction in deaths. Progression to severe hypertension was eliminated. There was zero progression in the treated patients. There was dramatic reduction in heart failure and stroke, and the study showed that for the first time, under-intensive therapy is safe and effective in reducing blood pressure and cardiovascular events in patients with hypertension. Next slide, please. So, those studies set the background for diagnosis and treatment control of hypertension across the VA hospitals and continue for the next 70 years and continue as of today. I have on this slide data that we collected from 6.5 million patients in 162 of VA hospitals, and they show the improvement in blood pressure control from the year 2000 as of 2014, and in the year 2000, a goal was set to control at least 50% of hypertension across the nation and the VA, of course, by 50%. In the VA, the results have always been better, and as you can see here on the top slide, the control rates achieved by year 2010 were 76%, although there was some flattening of the curves and some decline in the subsequent years, and that was noted in all the ethnic groups, in whites, in Hispanics, and in Blacks, and you can see on the lower part that Blacks always lag behind a little bit by a few percentage points in hypertension control. There are many reasons for that, and we can discuss them, but I'm not going to go into that for the time being. The next slide, please. So, this blood pressure control through the years resulted, I think, contributed to the changes or prevention of morbid events mortality, and again, you see this data from 8 million patients and 3,160,000 hypertensives, and you can see that the lowest mortality was noted in patients with systolic 120 to 140 overall, and that was true for the five years of follow-up and the 10 years of follow-up. The lowest mortality was seen in the range of blood pressure that we'll consider normal today, and that's the target of our treatment and of our programs today. Next slide. So, compared to the national data, the previous figure I mentioned, the enhanced data is the survey that we usually consider. The enhanced data showed results much lower than the VA data, and in the year 2017 to 18, I could find these numbers. Our data from the VA showed a control rate of about 76, 75 percent overall, and in blacks, it was less, about 71 percent, but the enhanced data showed much lower control rate. So, we have been doing better and will continue to do better than the national surveys. Next slide. In the recent years with COVID, hypertension treatment and control has also been affected, and I'll try to summarize some data in the year 2020 to 2023 from our hospital, but I assume that they are similar in other VA hospitals. And you can see with the onset of COVID, the control rates went from 76% to down to 38%. In the year 2021, there was mild improvement, but not quite back to the levels of the pre-COVID era. And you see in 22 and 23, the control rates climbed gradually up to 58%. And the last data I have seen a couple of months ago show the 59% control rates overall in our hypertensive population. Still much lower than the pre-COVID era, but we're making progress. We need to refocus, resettle, and try to treat and control more patients and get back to the pre-COVID results we had. Next slide. So the question is, what do we do at the VA that is different from the community around us, from other institutions and the private practice? Certainly, we try to implement a series of things that can affect blood pressure. And first, we try to get patients involved and improve compliance, because that's the main reason why blood pressure is not controlled. We implemented telehealth, we get nurses to call the patients and instruct them how to check their blood pressure correctly and how to take their medication correctly. They do that two, three times a week, and that's very, very helpful. It gets the patient engaged. And of course, we give to every patient a blood pressure monitor to check his blood pressure every day and record it. And when we contact them, they have to read us the numbers they get. We make sure that they check their blood pressure correctly. And that helped tremendously in improvement of blood pressure control. In our VA, now we expanded the hypertension clinics. We used to have one clinic a week. Now we have five clinics a week. We have three expert physicians that are interested in hypertension that see patients five different days. Two are remote and three are in person. And we can see about 60 to 70 patients a week in our VA. One thing we do, and I think it's very helpful in improving hypertension control, is to give the patients frequent appointments and stay in touch with them as much as possible. That's very helpful because it makes patients compliant, makes them take their pills, and certainly improves hypertension control. We also try to get primary care physicians engaged. And we do seminars with them, we team up with them. And actually, we print lists of patients that are not controlled, and we send them to them periodically to point out that they need to do a little better job in controlling the hypertension. And that works. And obviously, we try to help for all those patients that are difficult, they're complex, and they need complicated regimens. We also provide tutorials and lectures to the primary care physicians in their morning reports on how to manage hypertension, what's the proper regimen. And we do make a point to tell them that including if they read it. Aria, did you take a bath after the pool? Was that? Okay. And obviously, we have our guidelines that we distribute to the patients and we try to make them adhere to those. Next slide. This is the VADO guidelines that detail the diagnosis and treatment of hypertension. They are published periodically. The champions of those guidelines have been Dr. Bill Cushman and Dan Berlovich for years now when they published the latest version. These are very helpful. They're not very different from the national guidelines, but they detail the approach of management and control of hypertension. They are very helpful. I recommend it to anybody who wants to read a little more. Next slide. This is one patient that has recorded blood pressures through the years for 20 years, and this is very helpful in CPRS that we have in our fingertips, the blood pressure over a long period of time. And you can see there is a marked variability, which is not unusual in patients with hypertension at the VA. The blood pressure coverage from 119 all the way to 180 from visit to visit. This visit to visit variability is very common and is not due to biologic changes in the blood pressure. Yes, this may contribute to some, but the main reason is compliance of the patients. And seeing them frequently and seeing them in a short period of time improve compliance and help us control these patients much better. Next slide, please. Telehealth also helps, and the nurses are doing a great job in making the patient check their blood pressure and record them. They send these numbers and then they register in the patient's chart, and we review them carefully whenever we contemplate revising the regimen of the patient. And it's very helpful to see blood pressure reports over a longer period of time. And it's not just one office blood pressure that is dictating the change in our regimen. Next slide. Obviously, the measurement of blood pressure depends on the device we use, and there are devices that are non-reliable. Of course, we don't use the method of Siebenhals anymore. It's 200 years old or 300 years old, and we don't use the mercury manometer. It's dangerous, although it's very accurate. But we replace those with the automated manometers, and we prefer the Omron series and have been using that for a long period of time. Although lately, we tested and we adopted the Philips device that's very reliable and very reproducible, and I think we will replace all our automated manometers with the Philips series of devices. Next slide. Now, coming to renal denervation, a lot has been said, and I'm just going to touch on a few things. The idea here was to interrupt the renal nerves, the renal, the fibers in the renal arteries, and that did disrupt the communication of the brain with the kidney and the kidney with the brain. Next, we need to click on this. And the procedure one is successful and interrupts the…next slide…the renal fibers can't work. The next is a built-up slide. Please click on the next one. Yeah, it works as a diuretic or a RAS blocker and works on the heart as a beta blocker. Next. And it works on the periphery as a vasodilator. So, this was the promise of renal denervation. Next, to work as a diuretic and a RAS blocker. And the next as a vasodilator. And certainly, it's like a polypill that contains three different pills. And this promise obviously got a lot of us excited many years ago. A lot of studies have been done and a lot of studies have been designed. And we have today a lot of data that we can rely our decisions on. Next. So, the promise of the renal denervation and other devices that have been used for the treatment of hypertension is that possibly they can cure hypertension with one intervention. They can limit or eliminate the use of drugs. They can help improve hypertension control. And obviously, this procedure is only one time. And if it works, you get rid of everything else and the patient is cured. However, this has not materialized, and we're going to see why in the next few slides. Next slide, please. So, I'll spend the next five minutes or so to describe to you what we've done. We have seen this slide before. We used three sources of energy to achieve renal denervation. The frequency devices, the ultrasound devices, and obviously, the three needles that can inject a small amount of alcohol in the dentition of the renal artery to interrupt the renal fibers. The purpose is to achieve a circumferential disruption of the renal fibers and disrupt the communication of the brain with the kidney. The next slide. And this is a summary of the uncontrolled studies, 12 studies that were done early on, and they showed dramatic results. And they actually got a lot of us excited about the procedure. And on average, the reduction in systolic blood pressure of these 12 trials that included about 481 patients was 21 millimeters of mercury. There was a great variability, however, in the response from 7 millimeters to 32 millimeters of mercury. And this is something that we know that, yeah, the inconsistency of results. And that introduces some skepticism about the reproducibility of the results. The next slide. And of course, we have the studies that utilize the ambulatory blood pressure monitoring, which is a much more reliable method of assessing blood pressure changes. And there are nine studies that use that method, and they showed in aggregate 7.8 millimeters of mercury reduction in blood pressure. The next slide shows the nine registries that have been published data. The largest one was the European registry that had 2,200 patients. And in aggregate, they showed a 17 millimeter of mercury reduction in systolic blood pressure. And these data obviously are impressive and very satisfactory and kept the enthusiasm going for some time in the field. The next slide. However, in hypertension, you cannot do studies without controls. And the FDA, when they reviewed this data, they were not happy, and they requested data with sham control trials. Next slide. The next slide. So, we entered the new era of renal denervation, and these are the three devices that were used to carry out sham control trials, the spiral multi-electrode radiofrequency catheter, the PARADISE ultrasound renal denervation system, and the alcohol-mediated renal denervation system of Jim Fischel that is using three needles to inject alcohol in the adventitious of the renal artery. Next slide. This last system is injecting 0.6 ml of alcohol in the adventitious of the renal artery, and the uncontrolled studies early on showed a substantial reduction in systolic blood pressure by office measurements and by ABPM, similar to the previous studies. But because they had no controls, obviously, the company and the sponsor of this device and these studies proceeded to do sham control studies as with the other devices. Next. So, the two studies of the sham control sites that are going on is the TARGET-BP on and the TARGET-BP off medication. They're in progress, and from what I hear, they have been completed. Actually, we are part of one of these studies, but we have difficulty in identifying patients. And this is one of the things that I'm going to discuss a little bit at the last few slides of this presentation. Next slide. So, you have seen this slide before that shows the six sham control studies from the Simplicity Hypertension 3 to the ultrasound studies that consistently showed reduction in systolic blood pressure much better with renal denervation as compared to sham control. And that was true for the office blood pressure and the ABPM. The next slide. And these are very good results. And the 24-hour blood pressure monitoring showed a clear separation of the curves in the renal denervation group and not so clear in the sham control. Next slide. This is a summer slide that shows the absolute sham control subtracted results of these six studies. And the office blood pressure was reduced on an average of 60 millimeters of mercury. And the ABPM was six millimeters and the office blood pressure was reduced in absolute terms by seven millimeters of mercury. And these are definitely clinically relevant results. These reductions in blood pressure result in substantial improvement in cardiovascular events, about a 15 to 16 percent reduction in mortality, 21 percent reduction in cardiovascular events, and 30 to 40 percent reduction in heart failure and stroke. However, these numbers are much smaller than we have seen in the early on trials, the uncontrolled trials. And this is probably responsible for the change in the attitude of the community and the private practice physicians. Next slide. So, from these sham control studies, we can conclude that renal denervation works. And the overall effect on office and 24-hour blood pressure is clinically relevant, although it is small. The rate of evidence is low, but the procedure is safe. And it changes our approach of renal denervation. Instead of trying to promote it or place it as a longstanding procedure, I think renal denervation will find its place as an adjunct therapy to drug therapy in the future and in the populations at large. Next slide. So, attacking the renal nerves is not easy. These fibers are distributed, you know, unevenly around the renal artery. And choosing how to disrupt them is complicated. Early on, we were burning in the proximal part of the renal artery, but this didn't work well. We realized later that in the distal part of the renal artery in the branches, the fibers are closer to the lumen. And for travascular procedures, it's easier to transmit thermal energy in the distal part of the renal artery in the branches. And this was done in the second-generation radiofrequency studies that Medtronic did. And it did work much better. There are data showing that burning into the branches works better than burning in the main renal artery. Next slide. The clinical consideration we learned from these clinical trials, obviously, that is that, you know, controlling blood pressure in large populations is not easy. I think it's a limitation that the inclusion criteria in the studies require combined hypertension, systolic and diastolic, because these patients are not that common in our population. I know from my experience that the patients that I screened, I screened 1,500 patients to find a handful of patients that qualified for the studies. So, the studies, the way they were done, are not representative of the VA population. And certainly, we need more data in patients with isolated systolic hypertension, that is elevated systolic and normal diastolic blood pressure, either off medication or even on two or three medications. It is understandable that in patients that have combined hypertension, and they take three medications, after you put them on medication, the diastolic may decrease down to 70 or 80, and the systolic may remain to 140, 150. So, they qualify as on-treatment ISH patients. And we need to clarify our information on these patients, because right now, they will be excluded from treatment if we follow the inclusion criteria that was followed in the clinical trials. However, many of those patients had combined hypertension before they were placed on therapy, and we need to get together and decide how to approach these patients and how to manage them. Certainly, a lot of them will be candidates for renal denervation, even though they have elevated systolic and diastolic below 90. We need definitely more data in these kind of patients, and it's difficult to, we realized from the studies that were done, that it's difficult to discontinue or even decrease the number of medications needed to achieve blood pressure control. Renal denervation may contribute to a certain extent to blood pressure control, but it will not normalize the blood pressure in most patients who start with moderate severe hypertension. If a patient has a systolic of 175 and a diastolic of 92, renal denervation may bring it down to 160, but it will rarely bring it down to 130 or 132. So, we need combination with drug therapy and adrenal denervation as an adjunct therapy to improve hypertension control. Next slide. So, this was included in the European guidelines, the most recent version of those, and they agree that the optimal medical therapy of renal denervation is probably the most appropriate approach for treatment. Renal denervation alone only is seen, it will work in rare patients and should be done only in rare patients that refuse to take any medication and they have elevated blood pressure. Renal denervation may reduce to a certain extent blood pressure in these patients, but optimally they should be on medical therapy when they receive renal denervation. Unfortunately, once in a while, we get these patients that refuse to take any medication because they think they affect their lifestyle, they affect their well-being, and they don't take them. Even when we prescribe them, we recognize that they don't take them when they go home. The patient should be well informed about the potentials of the results, what kind of blood pressure reduction we expect, and we should negotiate with them and make them understand what we expect and what they should expect from renal denervation when it is added to optimal medical therapy. Decision-making should include well-informed hypertension experts too, and this is up to us to educate them and provide all the data available and the most correct information. Next slide. I believe it's my last slide. Next slide. Yeah, so renal denervation as a therapy for hypertension is these days at the crossroad, and certainly devices and procedures will be approved by the FDA. All the data have been submitted. I haven't heard that the panel has met yet, but when they meet, the data are good enough. I've been on that panel for several years, and I know the thinking. The devices will be approved. Maybe they will be approved with restrictions, and they will become available at some point in the near future. So, the next tab. I like to paraphrase what Hillary Clinton said at one time, that this is our chance to change the management of hypertension for the better. Thank you very much. Well, thank you so much, Vasilis. That was a wonderful summary of your vision of the data and your experience at the VA. It's 8-11 or so. I think we've run out of time, unfortunately, to have a discussion, but I think we've heard a lot of wonderful food for thought today. Yes, I just want to thank everybody for attending. I saw we were running a little bit over time, but we'll be following up with an email for a little survey because we're thinking of doing an in-person meeting at some point to actually get some hands on, get some experts on, and then actually get the VA community together to see if we can learn more about this technology once it's approved. So, there is polling questions that we can answer for those of us who remain online here. James or Mir, tell us what to do. We see polling questions in the chat or in the polling area. Hopefully, everybody has a polling box open, and if you'd be so kind as to answer those two questions, I think we can wrap things up for the evening. These are easy questions. CME credit. I already answered them, yeah. All right. Well, so we're planning to do it in a nice warm place somewhere. I hope I'll see you soon in person, guys, in a warm place. Exactly.

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