Talking Tall Rounds® Renal Denervation for Uncontrolled Hypertension

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Welcome to Cardiac Consult, brought to you by the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute at Cleveland Clinic. This podcast will explore the latest innovations, medical and surgical treatments, diagnostic testing, research, technology and practice improvements.

Dr. Khaled Ziada:

I'm Khaled Ziada, one of the intervention cardiologists. It's my pleasure to introduce the session for the Tall Rounds today for renal denervation for uncontrolled hypertension. This has been a long journey from conception to innovation and research, and now finally this technology is available for patients. There seems to be also horizons of further innovation in this space. Today we're going to cover a number of topics related to renal denervation.

Dr. Luke Laffin:

Great. Thank you very much, Dr. Ziada, for the moderating and ability to speak here. Great case, Vince, really illustrative of just a pretty typical case that we've done here at Cleveland Clinic. Over the next about 10 minutes, I'm going to take the opportunity to talk a little bit about the science behind renal denervation and some noteworthy clinical trials. But first, let's talk about what do the guidelines say in terms of renal denervation in the United States, but also in Europe? It is now actually in the blood pressure guidelines that we can do renal denervation. It's a 2B recommendation as of August of 2025, when the most recent AHA/ACC multi-society blood pressure guidelines came out. I'll highlight some things that it said specifically. The guidelines were a little bit less enthusiastic, although still a 2B recommendation. They recommend it in carefully selected patients with an office systolic blood pressure greater than 140 and a diastolic blood pressure greater than 90, and a GFR greater than 40, who have resistant hypertension despite optimal treatment. Resistant hypertension, as you may remember, is three drugs and still uncontrolled. The guidelines went a little bit further and specified that patients should also get a trial of spironolactone because of the high incidence of primary aldosteronism before they go forward for renal denervation. We could argue that maybe that was a little bit too far and outside of the evidence that we have for renal denervation so far, and really, it should be used as an adjunct treatment to blood pressure medications and lifestyle modification. That, the adjunct treatment component of it, is very in line with, actually, the regulatory or FDA labeling that we see, which was quite a broad label. They didn't put restrictions on “you have to do it in resistant hypertension” or anything like that. You can see on the bottom right-hand corner some issues with patient selection for renal denervation, and we'll highlight later a few contraindications, but things like renal artery aneurysms, stented renal arteries, known renal artery stenosis, any neurogenic orthostatic hypotension, those would be patients where we wouldn't try to pursue this. Now, what do the European guidelines say? Well, they're not that different. Also, a class 2B recommendation, and really should be performed at a high-volume center, and despite a three-drug combo, like with a thiazide or a thiazide-type diuretic in uncontrolled hypertension. They also make reference to patient preference. This could be a discussion or very well should be a discussion with patients, whether they would like to have a one-time procedure to try and help lower blood pressure beyond just taking a daily medicine. That was the European Society of Cardiology. The European Society of Hypertension is pretty similar in terms of what they recommend. So, how does this work? Well, essentially, we don't know the specific pathophysiology, but what we do know is that there are multiple pathways by which renal denervation can directly and indirectly result in reduced sympathetic nerve activity. Why is that important? Well, if you get an increase in renal sympathetic nerve activity, what you're going to see is the following: you're going to see increased renin secretion, which can lead to elevated blood pressure; you're going to get increased proximal tubular sodium reabsorption within the kidney; and then you're going to also get increased afferent arterial resistance. What all those lead to is right at the bottom of that picture, which is increased blood pressure. So, there's a very good reason why renal denervation may work and does work to lower blood pressure. This is an example of some of the preclinical data, really just looking at an obesity model of hypertension, and what happens if you stimulate the baroreflex. You get an acute drop in blood pressure, you let it recover, and then you do renal denervation. This was a surgical sympathetic denervation. You see, again, an acute lowering of blood pressure. Now, Dr. Nanjundappa is going to go into a little bit more of the specifics about the different devices and how we do the procedure. I think the ones that I'm going to focus on are the top two on the right, which is the Spyral catheter, which is radiofrequency ablation. We'll also talk about the PARADISE catheter, which is ultrasound-based renal denervation. I won't touch as much on the bottom right-hand corner, which is an alcohol-mediated renal denervation, but that's also been in clinical trials, although it's not FDA-approved at this point. That's an injection of ethanol in the perivascular space. Again, bilateral renal arteries. Many of you who've been around for a while and following this space know that the real first iteration of this was the SYMPLICITY flex catheter. It was just a straight catheter. This was going to cure hypertension. It was a series of trials, SYMPLICITY HTN-1 through SYMPLICITY HTN-3. The first two were non-randomized. Well, first was non-randomized with no control. The second was randomized with no sham. You're seeing 25-30 millimeter mercury blood pressure reductions. But many of us may remember about 12 years ago or so, the results of SYMPLICITY HTN-3 were quite underwhelming, and actually it was a negative trial. Randomized sham-controlled renal denervation in almost 300 patients did not lower office blood pressure any differently than placebo. There are lots of reasons why that may be the case, and there have been chapters and chapters written about this with patient selection bias, maybe some medications after randomization, and technically suboptimal renal ablation. What that did was lead to an FDA circulatory device panel meeting to discuss. Really, what should the next generation of RDN trials look like? And that's what's led to the now PIVOTAL trials and ultimately regulatory approval. It led to this Spyral catheter, which is a multi-electrode radiofrequency renal denervation. It was studied in patients who were not on medications, sham-controlled, involving just over 300 patients, looking at blood pressure reduction on an ambulatory basis. On placebo-subtracted, you're looking at about five millimeters of mercury over that 24-hour period in the patients who were not on medications. You look at office, typically we'll see greater office blood pressure reduction than ambulatory reduction, and we see this here, about seven to eight millimeters of mercury. A little bit different for the on-med. These were patients on three drugs. It was pretty promising in terms of their pilot data. Their expansion cohort, not as much. Technically, radiofrequency renal denervation on their primary endpoint didn't hit for resistant hypertension in terms of a difference with sham, although that didn't impact their label ultimately by the FDA. But they did see significant office blood pressure reduction. Importantly, I think one question we always get asked is how safe it is. You can see there's a lot of zeros here. It's a very safe procedure, the radiofrequency denervation. Here was a little bit of just an overview. I won't spend a lot of time with this, but in 2023, it went before a circulatory system device advisory panel with the FDA and ultimately was approved for commercial use in November of 2023. When we look at the ultrasound catheter or PARADISE catheter, I won't break it down by individual trial, but they had a very similar structure in that there was patients that were not on any drugs or were withdrawn from drugs before renal denervation to take away some of the adherence and drug effect, really know what the pure impact of renal denervation was, but then also in patients taking three medicines. You can see very similar blood pressure reduction here on a placebo-subtracted basis, about six to eight millimeters of mercury in general. Again, a lot of zeros on here, and this is combined amongst their PIVOTAL trials in terms of just a few little things like a vascular complication as we would expect, but that was only in one participant. Very, very safe procedure. Again, also this catheter, a subsequent day went through a FDA panel and was approved as well a little bit earlier than the Spyral catheter. And so that's really an overview of what we see. I mean, I think when we look at the clinical trial data in general, the way that I would put an overview on it is blood pressure reduction, it's not going to bring someone from 180 to 150 or to controlled. It shouldn't be looked at like that. It also shouldn't be looked at as a Hail Mary in the patient taking six, seven drugs because those were not the persons that were studied. In patients taking no medicines, it was worth about one blood pressure medicine worth of lowering. That's what about five to eight millimeters of mercury gets you. Then, in patients with resistant hypertension, the ultrasound denervation data are better, but in general, we see about an, again, six to eight millimeter mercury reduction in terms of office blood pressure. One other thing that I'll just touch on it's really important in these folks, even if it's not ambulatory blood pressure monitoring, it's some degree of out-of-office blood pressure monitoring, and that can be home blood pressure monitoring. It's easy to do, just to under rule out those patients that have a white coat effect because we know up to 40% of people have very different in-office and out-of-office blood pressures. So thank you for your time.

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