Thanks, Eric. And you'll probably see one or two repeats as the night goes on in terms of slides, but I'll pick up. I'm Ray Townsend again from the University of Pennsylvania in Philadelphia. And again, welcome to folks that are part of our viewing group tonight. I'm going to talk about uncontrolled hypertension and renal denervation and what its responses are and focus on systolic blood pressure responses, because for one thing, it's in the interest of time. And secondly, it's where most of the money is anyway, in terms of outcomes and hypertension. These are my two disclosures. I am part of the Global Exec Committee for Medtronic. You need to know that. I also write part of that, or part of it, co-write the topic of resistant hypertension in UpToData, a kind of popular online medical reference software. Where are we now is part of this talk, and I'm going to use the last slide to tell you what's in the works when it comes to renal denervation. Let me start here at ground zero, which was in April at the ACC meeting in Washington, D.C., where Deepak Bhat presented the results of the first major U.S. foray into renal denervation. And what he showed, in case you forgot, is that there was a 14 millimeter office systolic blood pressure reduction at six months when patients were treated with renal denervation. But unfortunately, what also happened in this trial is that the sham control group had a 12 millimeter office systolic blood pressure reduction, and we were off to the races to figure out A, why, and B, whether CPR or some other life support measure would be adequate to resuscitate renal denervation, because this was a very difficult blow to the whole field itself. But as you just heard from Eric, and let me just show you the global data here, this is from one of the Lancet's World Health Organization studies, and we're going to talk about uncontrolled hypertension, not drug resistant with a certain huge number of systolic blood pressure millimeters involved there, but just uncontrolled, because the control issue is the important one. And there are a lot of people that are still on two, three drugs, but won't take a fourth or a third. And nonetheless, still have the risks for blood pressure. When it comes to women, about 36% are either untreated but still hypertensive or treated but not adequately controlled. And these are diagnosed and not treated or diagnosed and not controlled. And for men, similar type of issue here. So it's about 30-35% or so, folks. And you saw this already, so mercifully, my presentation just got about 20 seconds shorter. Most designs of trials that are evaluating renal denervation as an intervention for hypertension typically have a screening phase here where you document the level of blood pressure. And for the purposes of our uncontrolled aspect here, we're usually looking at office values higher than 149, less than 180, and diastolic higher than 90. One of the lessons from the HTN-3 and other trials is that the widened pulse pressure type of hypertension with the diastolic maybe 70-75 sometimes does not have quite the degree of systolic blood pressure reduction that those with clearly diastolic hypertension do. And the other thing we made sure is to rule out the white coat hypertensive where an ambulatory blood pressure monitor will show values that were clearly in the normal intensive range, despite the office being high. So those are typically incorporated now into trial design. And then there's always a sham control here, courtesy of HTN-3. So at the time of randomization on the table, that's when it's decided whether a person is going to get the real deal of renal denervation or have everything, arteriogram, conscious sedation, the whole work's done, except the actual denervation itself. I'm going to go through some of the data you already know and just make a couple of comments in the interval about this data. And I'm going to concentrate on office systolic blood pressure because that was what Eric showed you in terms of coin of the realm for predicting cardiovascular benefit. I will show you the ABP data conglomerate on one slide. But here's the results of the pivotal off-med trial. So there were, as you can see here, just over 300 people untreated but having blood pressures in the office higher than 150 and willing to go three months out before having a medication added, if needed, to manage their blood pressure. In this particular trial, first author Michael Bohm, there on the right hand side, there was about a nine millimeter office systolic blood pressure reduction and about a seven or so millimeter difference between what you saw in the sham control versus what you saw in the denervation group itself. So this was the off-med trial of Medtronic and the catheter had been re-engineered, so it was no longer a unipolar catheter, it was a quadrupolar catheter shaped in a spiral to ensure circumferential denervations, ablations, would be done because that was one of the many drawbacks we identified from the HTN-3 experience that we had. Now we have one of these transitions like that. I wanted to make sure everybody woke up and said, whoa, what was that? Did I miss something? So the only time it'll happen, but there it is. And in addition to radio frequency energy, one of the other common ways that denervation trials are currently being undertaken is the use of ultrasound. And so these are courtesy of RECOR, the Paradise catheter system, and this is the experience with the equivalent in the ultrasound version of denervation, the SOLO, so with untreated hypertensives higher than 150 in the office. And once again, the degree of systolic blood pressure reduction here is about 10 to 11 millimeters or so. This is a two months post denervation here. But again, it's in that range of about 10 or so, which is auspicious for the field and meaningful in terms of a clinical response. The Radiance Hypertension TRIO study put everybody on triple therapy. So you got a diuretic, an ACE or an ARB, and a calcium channel blocker in a single combination tablet and there were versions of that. So you could have the ACE or you could have the ARB. And then if you were still above the threshold value of 150, you were randomized then again to sham or to ultrasound denervation. And once again, the approximate systolic blood pressure reduction in the office, and you got to look down here, I hope my mouse is showing up, but it's the second line up from the bottom here, is about nine millimeters of mercury for the office systolic blood pressure reduction, roughly two months. And I apologize, but you know it's not like they collude in these trial designs. The Radiance trials are typically two months before the endpoint. The Medtronic ones are three or six months before they call it for the endpoint. So a little bit of nuances of how trials are done across companies, but nonetheless, the point is that there's usually a blood pressure reduction that is more significant in the intervention compared to the sham control group. And this is the pilot for the OnMed, and as you see on my last slide, OnMed is still recruiting. It's not quite done. We're hoping to be done by the end of this year, but courtesy of the coronavirus, etc., that slowed everybody's recruitment down. Same idea here, but instead of no therapy, you're on one to three antihypertensive meds and still at that 150 to 180 office, higher than 140 on ambulatory and greater than 90 for diastolic so that we are really treating patients with with bona fide diastolic and systolic hypertension resistant now to meds, but one to three meds, not four or more, that kind of thing, or the five or even six the way some of the older trials were. And once again, you're seeing about a nine millimeter office systolic blood pressure reduction, and this is at six months, not three, the way the OffMed was, now we're at six months here, but the same idea, and that's our co-host up there is a picture you saw in the introductions to tonight's webinar. This is the ambulatory blood pressure monitor data. If you can say six to eight millimeters, you've got everything I need to tell you on this particular slide. Same studies I just covered, and six to eight millimeters of 24 hour or daytime in the case of the RADIANCE trial is about what you see in terms of ambulatory blood pressure reduction. But in general, the amount of sham systolic blood pressure reduction over 24 hours is typically in the range of one, maybe two, and in the rare exception, like the HTN TRIO, it was three millimeters, but it's typically smaller, often close to one to two millimeters because ABPM is a little more robust than the office levels are to the placebo or sham effect. What you may not have seen is this. This is the global simplicity registry data and what it is doing around the world, and there are many countries involved that are contributing patients to this, is bear in mind that the radio frequency ablation catheter, the original RDN catheter using unipolar was approved in many countries around the world, so people received this therapy in a lot of places. And Medtronic organized a system, courtesy, especially under the leadership of people like Felix Mahfoud up here in the right hand corner, but also others in Germany that spearheaded a lot of this effort, to enroll patients who had this done clinically in a forward manner. And you'll see, if you look down in the middle lower left part of the slide, that the baseline systolic blood pressure in these folks was 166 millimeters of mercury. And they're often on three, four, or five medications, and you can see the numbers involved here. The goal was to enroll 3,000 patients to follow for at least three, preferably five years. And I want to just point your attention again to the one year time point under office BP, where you see that 14.1, which is almost identical with the degree of reduction that was seen in HTN3, a quote, failed unquote trial. So when you look at the benefit, if that hadn't been done, and these people just kept at their same blood pressure level and did not have the 14 millimeter office systolic blood pressure reduction, you can imagine from what Eric showed you with the cardiovascular consequences of that might have been. And this is the kind of phenomenon set in a different way that really supports that. Again, not BP trialists here, but other ways of, I'm sorry, BP trialists. Okay, so what Eric showed you, I'm showing you in a different fashion. He showed you the little circles with all the names of the hypertension trials. This is the actual benefit that you would see with a five or 10 millimeter systolic office blood pressure reduction over time. And instead of cost effectiveness analysis in this field, what you're going to see, I believe, are more and more presentations like this. It was done at PCR earlier this year in May. And so this kind of phenomenon where you have, if you have a 10 millimeter office pressure reduction, you will see a major CBD reduction in the range of 20%. And that's the magnitude that we're seeing from the intervention trials to date using ultrasound and using radiofrequency ablation. I would be remiss if I didn't say there's also an ablative way to put alcohol, absolute ethanol, in the space around the kidney artery and denervate that way. Ablative solutions is the company doing that. But there's just not enough data in the current space to show you any results from them, except for their one trial that I'm aware of that was drug resistant hypertension, where it had the old, like the HTN1 and 2 values, 25 millimeters of systolic blood pressure reduction. So let me close here with two comments. One is adherence. You heard that from Eric. It's a problem. But you're not having to take a pill each day when you've been denervated. And as far as we know, the results, courtesy of the Global Simplicity Registry, among other places, have been robust out to about three plus years at this point. So we think the effects of denervation last about three years. And then the duration of the response within an individual over time is the last thing I'll show you. And especially for the early morning hours on the left hand side of the slide of the panel, where it says RDN, on your left hand side there's good nighttime reduction, as well as full daytime reduction with RDN. So I will close on that comment. And I will use my last slide. Oh, back up a slide. Can I go back? Okay, let me tell you what's up. So there are three studies in progress, and I will technically actually close with this. The OnMed trial from Medtronic is still ongoing. Hopefully we'll recruit by the end of the year. Radiance2 is a stage two hypertension trial, up to two meds, that's being done in the US and Europe. It's ongoing. We're waiting. And the REQUIRE trial is an Asian study, Japan and Korea. It's done. We're waiting for the results, which we understand will be out in October. So I now am truly done. And I will now turn it over to Dr. Block to talk about patient pathways for hypertension care.

uncontrolled hypertension

renal denervation

systolic blood pressure responses

controlling hypertension

renal denervation trial