Melanie Cole, MS (Host): Welcome to the podcast series from the specialists at Penn Medicine. I'm Melanie Cole and today our discussion focuses on renal denervation. Joining me in this panel today are Dr. Debbie Cohen. She's a Professor of Medicine in the Department of Renal, Electrolyte and Hypertension and she's the Director of the Hypertension Program at the Hospital of the University of Pennsylvania and Dr. Tai Kobayashi. He's the Director of the Cath Lab at the Corporal Michael J. Crescenz Veterans Affairs Medical Center. Doctors, thank you so much for joining us today. This is a great topic.

And Dr. Kobayashi, I'd like to start with you. Renal denervation has been available for some time now. Can you explain a little bit about how it works, the advantages it offers to individuals with resistant hypertension, and the experience for patients who've tried to manage their rising blood pressure without success because there are so many tools in your blood pressure toolbox these days.

Taisei Kobayashi, MD, LCDR, USNR: Thank you so much for having us Melanie. I'd be happy to explain some of this. So renal denervation really originally came from a surgical experience where patients with resistant hypertension underwent surgery in the 1950s. But the concept is still the same now as it was then.

And the idea is, is that several nerves that surround the renal arteries control hypertension and the adrenaline inside the body. And so the concept is if we're able to knock out some of those nerves that surround these kidney arteries, that we could decrease the amount of adrenaline within the body and thereby decrease patient's blood pressures.

And so we've all had patients in the office who's had really difficult side effects from their antihypertensive medications. And that's led to an extremely uncontrolled situation in patients with blood pressures that are out of control.

This is now a newer technology that's paradigm-shifting that we can offer patients that have problems controlling their blood pressure.

Host: Well, thank you for that. So, Dr. Cohen, renal denervation has been studied for at least a decade and Penn Cardiology and Renal Electrolyte and Hypertension took part in several of those trials. Talk about the studies, if you would, and their objectives and how effective this was for lowering blood pressure in resistant hypertension.  

Debbie Cohen, MD: Okay, thank you. Let me give you some history. So, We started right in the beginning when the first trial, the Simplicity HDN3 trial, and we had a lot of excitement about that study and the results, and it turned out to be a negative trial. So it kind of gave the field a negative outlook, however, they went back to the drawing board and really improved the procedure, the catheter, the trial design, and we then participated in a number of different studies.

There are two different devices available, at least FDA-approved commercially in the United States, and one is an ultrasound device and the other is a radiofrequency catheter ablation device, and what happened is we did studies looking at renal denervation in patients either who were not on any medication at all or who were on one to three medications.

The trials differed slightly depending on the device and the protocol. But there was a lot of attention taken to make sure that these trials were done very, very carefully and the protocols were followed 100 percent wherever possible. And thankfully, with all the changes in the approach to new trials, we saw positive results across all the different trials.

This is the SPIRAL-On trial, the SPIRAL-Off trial, as well as the RADIANCE trials. And there was a number of trials in that with on med and off med and the results all showed a benefit of renal denervation with a reduction in blood pressure depending on the group, around 5 to 10 millimeters of systolic blood pressure reduction at either time period of 2 months to 6 months.

And we now have long term data out to three years in many of these studies, showing even more impressive results over time with maintenance of blood pressure reduction with incremental lowering of blood pressure, as well as excellent safety data.

I think that's a summary of everything. I don't know, Tai, if you want to add anything.

Taisei Kobayashi, MD, LCDR, USNR: Yeah, I think that that's a great summary. And I think what clinicians out there need to remember is the gold standard you’re measuring this newer technology against. And I think it's really important for us to remember that in meta-analyses of large blood pressure studies in the past, looking at placebo drug-controlled trials, the average drop in blood pressure with the placebo drug trial was five millimeters of mercury.

And some clinicians out there might say, well, five millimeters is not a lot of difference. But what we also recognize and know now is that in large observational trials, even a small drop, as small as five millimeters of mercury over the course of the patient's lifetime, can drop cardiovascular mortality by 10%.

And so even small blood pressure differences can manifest large differences for patient outcomes. Furthermore, looking at these really strict trials, like the SPRINT trial, for example, when the study ended, it has been seen that drugs can do just as well as procedurally-based strategies for hypertension.

The question really is, is once these patients came off of trial, what happened to their blood pressure? And what ended up happening in these trials was that patient's blood pressures rebounded to pre study levels. And so what we found is that the cardiovascular mortality drop that we originally saw in the SPRINT trial, went away.

This is a technology that offers a more durable result that mirrors some of the placebo drug trials we've had in the past.

Host: That is so interesting and Dr. Cohen, why don't you tell us the current status of renal denervation and the FDA approval of the devices used for this and Penn's role in these studies and while we're discussing Penn, what makes Penn's multidisciplinary approach to refractory hypertension unlike that of any other hospital systems in the region? 

Debbie Cohen, MD: The current status of renal denervation is that in November ’23, we had approval of both the ultrasound device that's marketed by Recall and the radio frequency ablation device by Medtronic. We participated in all the different trials, so we have vast experience with both techniques, so that already, I think gives us a huge advantage. Currently, we are enrolling in post-market trials for patients who meets criteria for renal denervation, and it's also commercially available. But to really summarize is that we now have data out to three years and actually in observational renal denervation studies, there's data out to 8 to 10 years. And what we've shown is that over time, you get an incremental increase in the reduction in blood pressure. So, initially you're seeing 5 to 10 millimeters of systolic blood pressure reduction, but over time, across the board, actually, in both techniques, the studies are showing somewhere between 17 to 20 millimeters reduction in systolic blood pressure and it's maintained over time and, all the studies have shown reduction in medication. So, I think that this is durable. The safety data is excellent. We have, ourselves at Penn had no serious adverse events at all.

And the only issue with renal denervation, which I think should be addressed, is that it works in about 75 to 80 percent of patients. And despite really looking at the data in multiple different ways, we haven't really been able to determine which patients respond best to renal denervation, and that is the one issue that needs further research and work going forward.

However, the one factor we do know is that the higher your starting blood pressure, the more likely you are to have a greater decrease in blood pressure overall. But overall, I feel comfortable recommending this to appropriate patients. I have no safety issues, with the caution that we cannot guarantee that it's going to be effective in every single patient. However, it's effective in probably about 80 percent of patients.

Taisei Kobayashi, MD, LCDR, USNR: And I think that one of the unique things about how our program works is that we are a true multidisciplinary team. And while the current technology is currently focusing on renal denervation and procedural-based strategies for hypertension, what makes Penn unique is that we're built upon Debbie's program to make sure that all of this is really meant to target a hypertensive population and to decrease cardiovascular risk for patients long term. One of the things that makes Penn unique is that we're able to deliver comprehensive hypertension care.

And that's the real key, is that renal denervation is within its nascency and is becoming a more mature product. And I think that's what's unique about Penn is that we're not looking just to get the next patient on the table. We're looking to allow you to have comprehensive care of hypertension for your patients.

This technology has the ability to treat a plethora of patients, and we have the ability now, and we're standing at a precipice, to be able to decrease cardiovascular disease in a population basis. This has the possibility of decreasing strokes and heart attacks by 10 to 20 percent over the patient's lifetime.

As far as the FDA and what their language has been on the approvals of the devices, it's been very broad. And what I mean by that is that if you look at both of the devices that are currently FDA approved, they basically are open to any patient that has uncontrolled hypertension, despite lifestyle and medication changes. And that's a pretty broad patient group that the device is approved for by the FDA. What makes this challenging is that we're still looking at what CMS's guidance is on who they will cover moving forward, and that determination is currently ongoing with national coverage decisions, but we should be able to figure that out in the next coming months, and then we should follow with private payers soon after to figure out what their coverage plan will be for this groundbreaking technology.

Host: I want to give you each a chance for a final thought, and Dr. Kobayashi, as far as the FDA-approved devices, how do you make the decision on which one to use? Are there differences?

Taisei Kobayashi, MD, LCDR, USNR: The only data that we have that compares the two FDA-approved devices was a randomized control trial looking at both the devices compared against each other and what I can tell you is at 12 months the performance of one versus the other did not matter in regards to dropping blood pressure, and safety events were no different between the two.

I'm happy to report that no matter where you go, and no matter which device we use, and from a proceduralist perspective, there are going to be some differences between the two devices. And there may be anatomical differences that you may want to consider one versus the other, but the way you should be describing this to your patient is it really doesn't matter how you get renal denervation if your cardiologists, and your nephrologists, and your multidisciplinary hypertension team think that you're an appropriate candidate.

But if you are a candidate, you should really consider it. And coming down the future, I think some of the trials that we'll be looking into and new innovation may make this even faster. It may make it even less invasive with shorter recovery times than it already is. And the next portion of this is to even go beyond hypertension by itself.

We may start looking into other secondary diagnoses that drive cardiovascular mortality higher, things like diabetes, things like stroke. And so some of these populations are yet to be studied and we're really looking forward to being part of those trials soon.

Host: Thank you so much, Dr. Kobayashi and Dr. Cohen, last word to you. Tell us your view, what you want the key message to be for other providers, the takeaways from this podcast, the indications, are they going to change, clinical trials, and what do you hope happens for the world of refractory hypertension? 

Debbie Cohen, MD: So I think a few things. Firstly, I think it's very important to make sure that the appropriate patients get access to renal denervation. And I think it's also important that the patients that are not really appropriate are not referred for renal denervation.

Because I think there's some ethics involved here, so I want to just stress that I think patients that are appropriate are patients that do have resistant hypertension, requiring three or more drugs with poor blood pressure control, patients that truly have medication intolerances, and then also, patients that just will not take their medication for different reasons.

So, patients with true compliance issues, with adherence to their medication, these are the patients that are appropriate. Now, what we do at Penn and, you know, what we encourage other people to do is that we screen patients for secondary causes of hypertension, particularly primary aldosteronism, because that is treatable with either medication or surgery.

And these people will not respond to renal denervation. And I think that they make up a part of that 20 percent who don't respond. So I think it's really important that people get a thorough evaluation before they go forward with the procedure. And if it's appropriate, then I highly endorse it.

In the future, I would like to see trials focusing particularly on people with chronic kidney disease because people with chronic kidney disease have more severe difficult-to-treat hypertension. So that would be a group that would really benefit from this procedure.

And the trials so far have excluded patients with a GFR of less than 40 cc's per minute. So, we have done patients with stage three CKD and above, but we'd really like to see how effective it is in people with more severe chronic kidney disease.

Another thing that I think is exciting that Tai has sort of alluded to, but there's new devices, new procedures with a radial approach to renal denervation with ultrasound device that is apparently quicker, and that's one of the studies we're going to be starting soon at Penn and then the other thing I wanted to say about resistant hypertension overall is that there's actually a ton of drugs being actively studied right now coming down the pike, including injectable agents, aldosterone synthase inhibitors, dual endothelin receptor antagonists. So we have a lot of exciting new things to offer our patients with resistant hypertension.

So that's why also Penn is unique because we give our patients the ability to have access to these trials. And I do think that in a year or two, we'll be having a lot more options accessible to patients for treatment of resistant hypertension.

Host: Thank you both so much for such an informative and enlightening discussion today. And I hope you will join us again as things progress. And thank you again. To refer your patient to Dr. Cohen or Dr. Kobayashi at Penn Medicine, please call our 24-7 provider only line at 877-937-PENN. Or you can submit your referral via our secure online referral form by visiting our website at pennmedicine.org/referyourpatient. That concludes this episode from the specialists at Penn Medicine. I'm Melanie Cole. Thanks so much for joining us today.