Dr. Fisher discusses the role of renal denervation (RDN) as a therapeutic option to complement medical therapy and lifestyle interventions for patients with uncontrolled hypertension.
heart hospital and BMS. I would like to welcome Dr Naomi fisher. Her talk today is entitled Reynolds renovation. You're for good. Dr fisher is an associate professor of medicine at Harvard Medical School. She did her undergraduate work at Princeton then medical school at the University of pennsylvania. Dr Fisher went on to an internal medicine residency at Mass General, then a fellowship in endocrinology, diabetes and hypertension and a research fellowship in hypertension all at the Brigham and Women's Hospital. She has authored many publications, has been a P. I. On multiple hypertension, reno vascular hemo, dynamic and Ronald Innovation Studies among others. She has garnered international recognition for her work. She has authored standards of care and guidelines, clinical guidelines and as for her teaching, dr fisher is currently the director of hypertension service and hypertension specialty clinic at Brigham and Women's Hospital. She leaves the innovative hypertension program there and is a program director and lecturer at the Harvard catalyst clinical and translational science center. Naomi, we're looking forward to your talk this morning. Welcome. Thank you so much. Good morning everyone. It's a great pleasure to be here today to be with you. Thank you for that kind invitation and a special shout out to one of my two brothers who are either ams Grads dr Eddie fisher a cardiologist in new york. My disclosure, this is a typical response I get when I speak with colleagues. Even cardiologists at an academic center like the Brigham and women's hospital about the work I'm doing and depending on the day I employ some metaphor like Lazarus Rising from the dead or phoenix rising from the ashes as I begin to explain. So I'm going to try to explain here today, telling you the story of rental innovation providing historical and clinical perspective. So you have an up to date context where the field stands. Here's a quick overview of my talk. I'll begin with the clinical context again with some historical perspective and a little bit of physiology. I'll turn to the procedures, the technical aspects for the intervention lists among us with the caveat that I am not one. I will review study results that have been published to date and then speculate about applications and implementation. As we head to the future, hypertension needs no introduction to a cardiology audience. It's a global problem of enormous magnitude. These data are from the global burden of disease program. Critical worldwide resource hypertension sits in the unenviable spot. The single greatest risk factor for death in the world. High blood pressure affects well over a billion people. And that number is rising untreated or uncontrolled. It's the single largest contributor to cardiovascular disease causing stroke, heart failure, coronary artery disease. And a major contributor to kidney disease. And if you look back 30 years, hypertension was on top then and its preeminence has only increased over the decades. Sub optimal blood pressure control is responsible for almost two thirds of cerebrovascular disease and half of the systemic heart disease. So I think we agree with this groundwork, it's a worthy problem to receive our attention and we have a huge problem. We really need help tackling it here. Our data from the N Haines, the National Health and nutrition examination surveys. We were so excited about 15 years ago when there was a dramatic rise in control rates. This period of time until 2014 was statistically steady. No change and alarmingly, control rates are falling. I suspect some of the audience will guess why. And they'll say the rate is lower because of new, lower targets set for hypertension. But that's not the reason all of these in Haines data were collected with the definition of hypertension as less than 1 40 greater than 1 40/90. Quickly, I'll show you what happens if we do apply criteria. From the 2017 guidance and we look at the blood pressure target of 1 30/80. Here's our control rate. A quarter of patients in America are controlled with high blood pressure despite the fact that we have had medications on board for well over half a century. So I think it's important for us to understand why it's so difficult to control hypertension. Many of us have met too many hypertension patients in our clinic. You understand that it's a very complex syndrome with multiple causes and contributors. Note one Fix. It's a silent killer. It would be so much easier for all of us to do our jobs if patients with high blood pressure came in with a cough or severe pain. But almost always they don't. We have decades of inertia paving the way for us where doctors really sat on very, very high blood pressure in the office and attributed to all sorts of things like running up the stairs or being late for an appointment. There are vast numbers of patients that need treatment that it's really testing the limits of our health care system. Our population is getting older and fatter be eating too much salt, drinking too much alcohol. Life is stressful and we're not getting up out of our chairs enough and to change his lifestyle is very, very difficult. In addition chronic conditions that background noise and we have to really focus on it and bring hypertension to the forefront. And so many times your notes will say our notes will say 58 year old with hypertension who presents with chest pain or cough. And so we really need to bring blood pressure to the front and center. And I have to end with non adherence as a really huge factor. Half of patients in multiple studies stopped their blood pressure medications with them. Within one year. Here's a study of almost 5000 patients with medication, event monitors, automatically recording the date and time of every opening of medication container. You can see what will be perfect adherence here at 100%. Here are patients in the blue who are taking their medications sometimes and here are the patients who are taking it all the time and correctly so that by a year we have half of patients not taking their meds. So we finally have something new to offer. It's clear that we need to offer something new and that's interventional treatment for hypertension. I was asked to speak about this topic today, 99% of the stage is taken up by Catheter based renal renovation with radio frequency and with ultrasound. So I will really focus my talk here. There are other interventional treatments I'll just mention too. There's Ronald innovation with alcohol with the peregrine catheter results from their target BP study. The pivotal trial is expected late this year and there is a backbeat study program which is pacemaker based cardiac neuromodulation. Reno renovation has its roots in the surgical theater. In 1946. Dr. Reginald Smithwick was recruited from the MGH to serve as the chairman of surgery at the BU School of Medicine. He was an innovative surgeon and he is responsible for developing bilateral splanchnic sympathetic. To me it was the only effective treatment for intractable hypertension patients flocked to boston from throughout the world for this operation and colleagues came to witness the procedure. Surgery worked about half the time but it left patients with significant deficits when it came to functionality like being able to stand upright and maintain normal sexual function. The physiology behind sympathetic to me is sound. The goal is to block renal sympathetic nerve activation which is a big contributor to the pathogenesis of hypertension. The procedure is non selective renal renovation targets both the different and the different nerves. That means ablation of the nerves to the judge to governmental apparatus which coordinates green in release, regulates sodium and water retention and responsible for decreased renal flow as well as ablation of different nerves which result in increased central tone. Let's take a quick overview. So from the first procedure to 70 years later when the first real innovation was performed in 2007, we had very exciting data from the simplicity HTN program H. D. N. One and two. I'll briefly share you those results but blood pressure felt 32 points in patients with resistant hypertension. So exciting so much that in 2012 the joint societies in the UK put out a consensus statement recommending that renal innovation should be considered as a component of the nice hypertension treatment guidelines and other algorithms and then simplicity. H. D. N. Three was published in 2014 and a moratorium was placed on Ronald Innovation. So let's dissect what happened here. So After the 70 years passed between the surgical generation, next came some pilot experimental and clinical data following studies and animals and they were quite convincing. HTN one Had that more than 90% of patients had blood pressure for all these 10 points and there's exuberance followed by the simplicity. HTN to trial and you can see here these patients had resistant hypertension. So that means they had to be on at least three medications at full doses, one of which was a diuretic. Our traditional definition of resistant hypertension And the outcome at six months was the office blood pressure fall. And with innovation it fell 32/12 compared to no change in the sham group. And if you think that these blood pressure numbers are too good to be true, I would agree with you. And it turns out that they were. So the next step says what if we added true control and rather than just standard of care, the control group is taken to the cath lab and randomized to a sham procedure with angiogram. And that of course is what happened in the simplicity HTN three trial again for patients with resistant hypertension. Systolic Blood pressure fell significantly at six months. But so too did it fall in the sham procedure at this point Medtronic suspended its regulatory trials and the fields on the brink of extinction. This was a really faulty study which ended up giving the procedure a bad name. The reasons for failure with multifactorial, inadequate entry screening, frequent med changes during the study in the sham group. Probably increased adherence in a sham patients operator and experience and device inadequacy. So lots and lots have been published on what happened there. But let me pick up the story and tell you that we're now in the next chapter. We have improved study design better patient selection. All studies are blinded and controlled. Better physician training and experience. We have improved technology with both ultrasound and frequency and really effective circumferential, real nerve ablation in both arteries. So it's time to go to the Cath lab. Let's talk about procedural details. There are two Catheter systems available. Both are approved in europe, which is way ahead of the US and renal innovation. Thousands of patients have been treated. Both companies are in close talks with the FDA for approval. These are outpatient procedures, patients are in the cath lab and in the hospital for a total of just a few hours. They're currently femoral access. But radial artery access is under very close development. So the first technology, as you've heard was with radio frequency Reynold innovation and the simplicity studies were done with the flex catheter, single electrode catheter and the most recent set of studies were done with the spiral catheter. And you can see what happens here is that we're really punk Tate separate discrete lesions that were used for ablation. The simplicity catheters, multi electrode and you can see looking down the barrel here, that vessel contact allows simultaneous ablation with four electrodes. And if you look along the length of the transducer. There's really a circumferential ablation and the procedure has been done in 20,000 times 7000 patients treated. So are very, very robust literature. Set. A quick review of the an atomic scheme is really instructive. You'll see that there are fewer nerves surrounding the renal arteries in the distal segments compared with the proximal and middle segments. But the mean distance from the lumen decreases as you move distantly. Radio frequency energy is delivered by most casters, reaching only about 2-3 mm in the peri vascular tissue so Destruction of renal nerves could be incomplete using radio frequency ablation in the main renal arteries, where sympathetic fibers can be found. 8 9 10 Distance from the Lumen. So treating side branches with could improve renal renovation because the renal nerves are closer to the internal layer in the distal part of the renal artery in the side branches. So the spiral catheter. This flexible, flexible catheter allowing branch treatment is used Both in the mains and then the branches. A typical ablation lasts 45 seconds to be considered successful. 62nd goal Main treatment for patients and in their largest study to date was 2.2 main renal arteries per patient and And six branch arteries for a total of 47 abrasions. The newer kid on the block is the ultrasound renal renovation system. This is the paradise ultrasound ablation catheter developed by record medical, there is ultrasonic heating with the arterial wall prevented by water cooling through a balloon. So you can see the ring of a blade of ultrasound energy. The nerve targeting. With ultrasound is up to really up to 89 targeting about 6-7 mm of death, sparing The internal one millim for endothelial sparing With circumferential ablation that will target about 80% of the nerves. The paradise treatment system strategy is very different. There are truly circumferential ablation zones. The ultrasound emissions are delivered only along the main renal artery. Each emission is about seven seconds in duration. After we screen patients for study and they are met regimen is adjusted. They're either taken off of all medications or their medications are stabilized for a month Before catheterization patients undergo a 24 hour ambulatory blood pressure monitor if their blood pressure qualifies. The next step is imaging with a cT angiogram or an M. R. Angiogram. Before study here's a picture from my most recent patient who is currently awaiting procedure. It's a three D volume rendering of a CT angiogram and you can see the beautiful pictures that we get and they're sent out to two independent radiologists and a customized ablation map is provided that guides therapy. We have catheters available to treat arterial arteries diameters ranging from 3 to 8 mm and you can see that it's recommended here for example that this is the first ablation, then pull back for the 2nd 3rd before exiting. So I'm going to turn now to review all of the published studies. There haven't been many But there have been five and I'll start with the one that I was personally involved with. I've been involved in the radiance program. And this first study radiance HtN solo treated patients with mild to moderate hypertension Who were on 01 or two meds. So you'll recall that the field was really developed for resistant hypertension. That's what the first surgeries were done for. That's what the simplicity program was done for. But the FDA requested in this renewal of studies looking at patients off medications for safety measures had to be withdrawn for at least a month. And then as I told you, patients had to be hypertensive by ambulatory blood pressure monitoring before randomization. So we're not a blading anybody with white coat hypertension nor anybody with isolated systolic hypertension. All patients had to have combined systolic and diastolic hypertension. And I showed you that imaging is done for a vessel anatomy and to rule out artery stenosis and tumors. And then randomization happens on the table after the angiogram. Sometimes the angiogram picks up some abnormalities in the reno vasculature and our and our cardiologist dr Patrick discerns that is not an appropriate candidate. The renal renovation Total was about five 5.4 to be precise emissions with a total ablation time per patient of 40 seconds with this technique and including angiography. The average total procedure time was just over an hour, 72 minutes for Ronald Innovation Group in 38 minutes for the sham. I can quickly show you what the demographics look like for our first study patients in their mid-50s. The demographics mirror what we have here for our population in Boston. Most patients were overweight, bordering on obese and had preserved renal function. Common exclusions are renal artery stenosis, renal artery aneurism. We've picked up a few real carcinomas. Any aortic stents and causes of secondary hypertension Can see baseline blood pressure is about 155 over 100. So the primary efficacy endpoint in the HtN Solo was a change in daytime ambulatory blood pressure at two months. So there's a turn away from office blood pressures and towards ambulatory blood pressures. And you can see here a fall of 8.5 millimeters of mercury with some fall in the sham group. For a between group difference of 6.5 millimeters. If we take a look at the per protocol instead of intention to treat, you can see that the between group differences over eight of mercury. And that's because 13 patients in the Sham group had to receive rescue medications before the primary outcome and some of the data were missing and they were considered a zero change. So the difference here was about 8.5 millimeters of mercury. That's with ambulatory pressure. I don't know how many of you are familiar with reading 24 ambulatory blood pressure monitors. But in lots of studies, it turns out that it's about two thirds of the value that drop in ambulatory is about two thirds of the value of a drop in office blood pressure. Office blood pressure here fell 11,000,011 points of mercury. Another way to look at the success is how many patients could achieve control without needing medications. So, a few months down the road, we had one quarter of patients Who reached their goal, blood pressure off of all medications compared to 3% of patients with Sam. So it's only a quarter. I think we'd all hoped it would be a lot higher. But it's still vastly improved consistently across studies. We've come to recognize that there's a significant variability of response. Here's a waterfall plot which depicts individual responses for Reynold innovation from the HTN Solo cohort. The renal renovation on the top and the sham procedure on the bottom and again the daytime ambulatory blood pressure. So if we call response, the percent of patients who had more than five millimeter decrease again in Ambito re pressure. We have a response in about 2/3 of patients. And I would say that in all of the studies that have been published, this number is between 2/3 and 3/4 the sham group. It's a third of patients responded. Clearly these patients really weren't responding to sham procedure, but this is reflective of all the noise we have in the system. For example, when we repeat an ambulatory blood pressure monitor in patients a month later, there is necessarily some noise. So we're really imperfectly measuring what's going on among patients who respond. And I often explain it to patients like this if you are going to respond. The fallen daytime ambulatory pressure was 14. So the fallen offers pressure is really in the high teens. It's a very different statistics. So I'll take a few minutes now to review the five randomized sham controlled trials that have demonstrated efficacy of renal renovation And the endpoint here is 24 hour ambulatory systolic blood pressure. So spiral HTN replaced the simplicity HTN program from Medtronic. The spiral program began with two 80 patient pilot studies, proof of concept studies. The off med pilot and the HTN on Med pilot. You can see here the p values and the ends for these studies. The off med pilot paralleled the solo study. I just showed you with ultrasound except they have a three month follow up instead of a two and you can see the difference in blood pressure minus 5.5 compared to 2.5 essentially. No change in the sham group. They Off med group went on to publish their pivotal trial in 331 patients And the delta I have to say it was a little bit disappointingly only a bit over four of mercury. They were announced last year. The on med studies now is the second request from the FDA is to focus on patients with hypertension who are taking medications. The spiral on med pilot was dramatically positive patients were on 123 drugs with stable doses for up to six weeks. They were maintained on their drugs through the primary endpoint. This was a six month endpoint like the simplicity And you can see the difference of falling blood pressure of nine points compared to 1.6. The spiral on med pivotal trial was awaited was to have been presented at TC T in november and I'll tell you about that in a little bit turning to the radiance data set. I already explained to you the solo this was our patients off Meds. The radiance trio trial was published last year. That's the only study that has really looked at patients with true resistant hypertension. We took our patients with resistant hypertension, stopped all their medications and put them on a combined triple pill. Usually X forged H C T with angiotensin receptor blockade casting channel blocker and diuretic was difficult enrollment. One of the most important things we learned is over one third of the patients with very high blood pressure didn't pass because when we put the inventory blood pressure monitor on them after they took the triple pill for a month. Their blood pressure was beautifully controlled. We had a positive result from the trio study I showed you here on the previous slide, the 24 hour blood pressure Changes and they ranged between five and 9 mm of mercury here. The office blood pressure. These are blood pressure changes That Mimic parallel what you see in most blood pressure trials before now and changes again about 10 of mercury about the amount of blood pressure full you'd expect to see with the pill. Is this enough? Is it worth it? We know that Reynolds renovation reduces blood pressure in the range that reduces cardiovascular outcomes. So let's look at these two meta analyses. I think you're probably familiar with them and they demonstrate that the reduction of cardiovascular disease outcomes with a five millimeter or a 10 millimeter lowering and office blood pressure well within the range of renal renovation is significant in the shorter blue bars. You can see that a five millimeter fall resulted in a 10% reduction in cardiovascular events and the 10 millimeter fall, which is really what we see with innovation In a separate meta analysis correlates with a 20% fall and the risk reduction was even greater with stroke and with heart failure, patients can take or not take their pills will work only if they're swallowed. But with Reynold Innovation, many like to emphasize that the effect is always on Here are two studies from the off med program demonstrating 24-hour blood pressure monitoring on the same study. And and then the same study two or three months later. So take a look at Ronald innovation here at baseline. And then at three months, the fall in blood pressure and sham no fall. And the same with the radiance htN Solo at time zero and two months later. And across the time, across the 24 hour time circadian rhythm there's blood pressure falls. So we know that nocturnal hypertension is particularly associated with increased cardiovascular risk. So it's heartening to see this result. So where do we stand? Let's take a bird's eye view of where these clinical studies have brought us to date. We have five independent Shem controlled randomized clinical trials of renal innovation that are positive. We know that Ronald Innovation significantly lowers blood pressure in patients on and off medications And office blood pressure falls about 10 points mercury. I'll review the basics. I've already shared with you the data demonstrating efficacy that's been demonstrated across the board again in patients with mild to moderate hypertension. True resistant hypertension patients on meds and off meds with diabetes without diabetes. Different races. Both genders. Let's turn to safety. And I will tell you now that experts are confident about the safety of the procedure with the data that we've collected to date from a vascular standpoint Renal artery stenosis following renovation is rare with an incidence of less than .5%. Most of the events occur within a year at a median of 5.5 months. Post procedure, you can see the meta analysis from Ray Townsend Pen, one of the PS and the medtronic data. Looking at the vast numbers of patients and patient follow up. We similarly have very, very rare incidences of renal artery stenosis with the ultrasound catheter. And we now have follow up out to three years with the registry Michelle show you. In addition data have failed to support any concerns about accelerating renal function decline after Ronald innovation. So Felix Mahfoud demonstrates here the fall in G fr Over three years. In the global simplicity registry In patients both with seek with intact and impaired renal function. CKGF far greater than 60 GF. Are less than 60. You can see that there's an expected decline that we would see in patients who have severe hypertension over several years. A similar meta analysis of all comers with already and showed no significant change after. I mean, follow up of nine months, similar data, you can look at all the zeros and a one here for renal artery angioplasty with the solo data with ultrasound, there was a patient with osteoporosis that unfortunately would have met criteria for exclusion but wasn't recognized randomization underwent stent placement in the stenosis was not at the site of a prior ultrasound emission. So we'll be happy when we gather more data from registries will help provide more numbers. But we can move on now from efficacy and safety to durability. And I'd like to share that durability has been shown in clinical trials out to one year. You expect the publication of 12 month follow up data shortly. They have been submitted And in registry data out to three years. It's a little bit difficult to look at blood pressure changes that happen after the primary endpoint. But here in spiral on met the primary endpoint at six months with no hypertensive medications allowed up until that point. That's when escape crate unless escaped criteria are met. You can see here looking at Ronald innovation as opposed to sham for 24 hour systolic and diastolic blood pressure. And for office and it's six months the blood pressure group differences persisted and the group differences persisted at six months. In radiant solo you can see sham blood pressure's in the blue bars and mental reservation in the green and the fall in blood pressure that persists. Now here our primary endpoint was at two months. So we're delivering medications to patients. It's very difficult to examine these data and to know what really is the effect of mental innovation. What's the effect of medications after the primary outcome timepoint passes. But nonetheless, we're happy to see a persistence of blood pressure fall. Most important we have data from the global simplicity registry which is the largest and the longest duration investigation of renal innovation. It's prospective open label all comer so these are patients with uncontrolled hypertension or other conditions associated with increased sympathetic activity who were treated with simplicity system and you can see here with by the numbers the vast majority were treated with the single electrode, simplicity flex catheter and the more recent ones with the spiral catheter. And these are the number of patients that are eligible to date. These patients are all in europe. My Children, europe got a huge head start on Ronald innovation. The the program was approved. Has ce mark already for a long time and many patients are treated commercially significant blood pressure reductions have been sustained out 23 years. So you can see whether you're looking at changes in office blood pressure or changes in 24 hour ambulatory blood pressure that the blood pressure changes continue even strengthen again, not randomized, not controlled open label single arms. Just looking at everybody who's had a rental renovation. What happened to them? I think I already showed you what happened to their kidney function the decline just as expected. Okay, we're turning the corner now. I'm going to spend a little bit more time on what questions that we still have and what to expect. And I hope to leave plenty of time for discussion at the end. What's still left? We're trying hard to understand the heterogeneity of response. Why do some patients respond by dropping their blood pressure? 15 or 20 points and some don't respond at all. The last two questions here are being pursued to try to explain this range of responsiveness. The first measures of procedural efficacy, measures of efficacy have been elusive if you're the operator and you're in the cath lab and you're delivering energy, you sure would like to know if it's working. Are the nerves really a bladed? For example with cryo ablation, it's easy to see the oblate ID zone. Here is a renal cell carcinoma on cT scan on the right before cry ablation procedure. Then during ablation you see a hipaa dense ice ball. It's extending from one of the cryo probes and it's extending I think you can see even beyond the limits of the team. There is nothing analogous for Reynold innovation. Not acutely nor months later to potential pathways to assess procedural embassy are being examined. Micro neuro graffiti which is sympathetic nerve recording and neurochemical measures which are based on the norepinephrine spillover technique. Neither is advanced yet to be in use. So we are searching we're also searching and analyzing data sets to look for predictors of response. Wouldn't it be great to know who's going to respond well and who's not going to respond. So we know who to bring into the cath lab. I wish I could tell you. We had great results on this question as well. Lots have been proposed one study showed that patients with baseline blood pressure that was higher and indication of high sympathetic nerve activity had a better response hasn't been replicated baseline blood pressure. Sorry, baseline heart rate showed an increased response in a subset baseline blood pressure has been shown in multiple studies. The higher your blood pressure, the more it will fall abdominal obesity plas Marine in in Valdosta Rhone. Again, we had hopes this analysis again by the in the Medtronic simplicity study tested the hypothesis that hormones that were relevant to the mechanism of action. Specifically an activated renown angiotensin. L Doctorow's system would predict greater blood pressure responsiveness. They divided patients in the spiral hTN off study by er a cut off. This was something used by John Lara decades ago. This Piara of less than .65 and greater and found that higher baseline reading activity was associated with a greater fall in recent activity. We perform the same study with data from the ultrasound study. My mentor taught me. We're not supposed to want, you're not supposed to want to result in clinical research but I really wanted this to be true. However, in our hands, Renan and Valdosta known concentrations did not predict the blood pressure response to rental. Innovation. We divided patients by media and bringing concentration and they were significant on both sides with a negative interaction term. So at this point I would say evidence does not appear appear to be sufficiently robust to allow measurements of Renan especially in non standardized conditions to predict the response to deprivation and individual patients and unfortunately that's the study across the the story across the board studies have either been negative or positive, lacking confirmation to assure us. So currently there are no widely accepted features that will reliably predict who will respond and who will not, what results should we be on the lookout for in the next year or two. Okay. The ahmed pilot was published. The on med pivotal study was to have been presented to T. C. T. In november. But there was an announcement in october the data safety monitoring board found insufficient data to close the study with the 1st 130 patients. So the trial continues The second half of this year. We should see a result in 260 patients. The solo study that I first showed you again was also a pilot. We have a pivotal study undergoing now called radiance to We're nearly up to 200 patients and that should be closed and we hope for publication. This year. The trio study you'll remember was a study of patients with resistant hypertension and I'm honored to be the national P. I. Of the study with my colleague Ajay Courtney at Columbia. There is the granting of the Kappa Continued access protocol. So it's non randomized. We have patients now with resistant hypertension who can come to centers and have your renovation performed without randomization in order to collect safety and efficacy data in patients. What about outcome studies? I'm trying to anticipate a question that's often asked. We need outcome studies in a perfect world but the cost is likely to be very prohibitive. It's highly unlikely blood pressure reduction has been considered a validated surrogate endpoint which is mechanism agnostic. That means no matter what modality. We used to lower blood pressure. This translation to lower rates of cardiovascular outcomes and the outcome isn't dependent directly on any particular causal pathway. Hence the FDA has approved. That's the surrogate endpoint of systolic blood pressure is enough. It can stand in for these clinical outcomes and clinical trials can be conducted more rapidly and in smaller populations. We need implementation studies as we move to the cath lab. In addition to randomized trials, we need to ensure that interventions are performed to stan standard, especially as we widen the scope and the numbers of interventional ists who are performing the procedure and we need to ensure that appropriate candidates are referred to optimize efficacy and utilization. And that's my last chapter of the talk here. Before we break for questions, I want to talk about the appropriate candidates who should be offered. Raynald innovation. Let's remember that Ronald innovation was developed to treat patients with true resistant hypertension. And when I presented this data and my work originally to my colleagues, everyone said, yeah, this makes a lot of sense for patients with resistant hypertension. After all, they're failing three drugs, they have the most severe hypertension. It turns out this is a small subset of patients. We have many, many more patients that cannot do not will not take their medications but don't have resistant hypertension that need to be treated. So the current thinking is we treat patients who have confirmed uncontrolled hypertension despite maximally tolerated medications without secondary cause. And I think the more forward way of thinking is that we'll treat not just hypertension, but also other diseases that are characterized by increased sympathetic tone, like heart failure, like chronic and end stage renal disease, atrial fibrillation and obstructive sleep apnea. We have guidelines. We sat together and formulated consensus statement co sponsored by Sky in the National Kidney Foundation to put forward what patients may be considered for Ronald Innovation. The Europeans are ahead of us Again, they have a guideline statement published In 2021 and here, we are with our consensus roundtable saying that patients should be considered if they have persistent uncontrolled hypertension despite being prescribed therapy and you'll notice it's not Being prescribed. three drives. We need confirmation of hypertension with out of office blood pressures and that means we're ruling out white coat hypertension. We have to exclude patients who have secondary causes of hypertension. We're gonna be treated more effectively and have a condition that needs to be taken care of should probably prioritize patients have elevated cardiovascular risk, maybe those who have had event organ damage. And the critical piece of shared decision making is really new and important, having intensive discussions with patients on risks and benefits, taking into account patient preference. So an FDA panel recognized that patient preference is really important. We have to assess what patients want providers payers. The FDA all parties are coming to appreciate the importance of patient preference. And studies in this domain are underway. It's a growing field which is really critically important. And it turns out that patients and doctors want different things. What influences the doctor to refer in this study by Rollin Schmieder is if you have a patient who's on more medications or a patient was higher blood pressure, but patients decisions turns out to be independent of the number of medications they're taking. They're really concerned about side effects to medications is in prime player. So there are universal themes that bridge all of the consensus statements. And again, the universal patient consideration is among the themes. So basically, we're talking about hypertensive patients who are confirmed to have primary hypertension, higher risk and we listen to the patient voice and here I'll close I think I'm safe in concluding with the obvious that innovation is mandated with the poor state of hypertension control, incredibly prevalent problem. And we're just doing a worse and worse job as the years go by, it seems. And that's despite the fact that we have treatments, we have lifestyle suggestions to make to patients, have them lose weight, have them stop drinking, have them exercise. But we know if it's possible, it's often possible just in the short run and the recidivism rate is so high and it's often just impossible altogether, medications are a second option. Despite the fact that we have multiple classes of drugs, dozens of particular drugs to use their use is limited. And again, we all are faced with so many patients who I can't I won't just don't take their medications. And I've shared with you data to say that even patients who do take their medications, often half of them stopped taking them by the time you're out a year. So we really do need some innovative therapy for blood pressure because many patients just won't take minutes. Renal renovation is a proven safe and effective treatment that will lower blood pressure and reduce risk. Further. Clinical studies should reassure us about the safety. They should solidify efficacy reports, they should expand our patient populations, measure procedural efficacy and study predictors of response focusing on patient preference.
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