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The Latest Renal Denervation Trials: What Have We Learned From Managing High Blood Pressure?

  • Authors: Felix Mahfoud, MD, MA; Ajay J. Kirtane, MD; David E. Kandzari, MD, FACC, FSCAI
  • CME / ABIM MOC Released: 1/27/2023
  • Valid for credit through: 1/27/2024, 11:59 PM EST
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Target Audience and Goal Statement

This activity is intended for cardiologists, internal medicine physicians, and nephrologists.

The goal of this activity is for learners to be better able to understand current medical treatment strategies to lower blood pressure and where renal denervation may potentially play a role for patients who are unable to meet therapeutic goals based on recent clinical trial data.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Results from recent renal denervation trials
  • Demonstrate greater confidence in their ability to
    • Identify patients who may benefit from renal denervation


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  • Felix Mahfoud, MD, MA

    Department of Internal Medicine III​
    Cardiology, Angiology, Intensive Care Medicine​
    Saarland University Hospital​
    Homburg, Germany​
    Harvard-MIT Biomedical Engineering​
    Institute of Medical Engineering and Science​
    Cambridge, Massachusetts


    Felix Mahfoud, MD, MA, has the following relevant financial relationships:
    Consultant or advisor for: Ablative Solutions, Inc.; AstraZeneca Pharmaceuticals LP; Boehringer Ingelheim Pharmaceuticals, Inc.; Inari; Medtronic, Inc.; Merck; ReCor Medical; SERVIER; Terumo Medical Corporation
    Speaker or member of speakers bureau for: Ablative Solutions, Inc.; Amgen, Inc.; AstraZeneca Pharmaceuticals LP; Bayer; Boehringer Ingelheim Pharmaceuticals, Inc.; Inari; Medtronic, Inc.; Merck; ReCor Medical; SERVIER; Terumo Medical Corporation
    Research funding from: Medtronic, Inc.; ReCor Medical

  • Ajay J. Kirtane, MD

    Professor of Medicine​
    Columbia University Medical Center Director of Cardiac Cath Labs​
    New York, New York


    Ajay J. Kirtane, MD, has the following relevant financial relationships:
    Consultant or advisor for: Abbott Vascular; Amgen, Inc.; BIOTRONIK; Bolt Medical; Boston Scientific; Cannon; Chiesi Pharmaceuticals, Inc.; CSI; IMDS; Magenta Medical; Medtronic, Inc.; Merck; Neurotronic; Philips; ReCor Medical; Shockwave Medical; SoniVie
    Speaker or member of speakers bureau for: Abbott Vascular; Amgen, Inc.; BIOTRONIK; Bolt Medical; Boston Scientific; Cannon; Chiesi Pharmaceuticals, Inc.; CSI; Magenta Medical; Medtronic, Inc.; Merck; Neurotronic; Philips; ReCor Medical; Shockwave Medical; SoniVie
    Research funding from: Abbott Vascular; Amgen, Inc.; BIOTRONIK; Bolt Medical; Boston Scientific; Cannon; Chiesi Pharmaceuticals, Inc.; CSI; Magenta Medical; Medtronic, Inc.; Merck; Neurotronic; Philips; ReCor Medical; Shockwave Medical; SoniVie
    Other: Travel Expenses/Meals from: Abbott Vascular; Boston Scientific; Chiesi Pharmaceuticals, Inc.; CSI; Medtronic, Inc.; OpSens; Philips; ReCor Medical; Regeneron Pharmaceuticals, Inc.; Siemens; Zoll Medical Corporation

  • David E. Kandzari, MD, FACC, FSCAI

    Piedmont Heart Institute and Cardiovascular Services​
    Chief Scientific Officer​
    Piedmont Healthcare​
    Interventional Cardiology​
    Piedmont Heart Institute​
    Atlanta, Georgia


    David E. Kandzari, MD, FACC, FSCAI, has the following relevant financial relationships:
    Consultant or advisor for: BIOTRONIK; CSI; Medtronic, Inc.; Terumo Medical Corporation
    Research funding from: Ablative Solutions, Inc.; BIOTRONIK; Boston Scientific; CardioVascular; Medinol; Medtronic, Inc.; OrbusNeich; Teleflex
    Stock options from: Simpson Interventions
    Owns stock (privately owned) in: Crossliner, Inc.


  • George Boutsalis, PhD

    Senior Director, Content Development, Medscape, LLC


    George Boutsalis, PhD, has no relevant financial relationships.

  • Kalanethee Paul-Pletzer, PhD

    Medical Education Director, Medscape, LLC


    Kalanethee Paul-Pletzer, PhD, has no relevant financial relationships.

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    Associate Director, Accreditation and Compliance, Medscape, LLC


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This activity has been peer reviewed and the reviewer has no relevant financial relationships.

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The Latest Renal Denervation Trials: What Have We Learned From Managing High Blood Pressure?

Authors: Felix Mahfoud, MD, MA; Ajay J. Kirtane, MD; David E. Kandzari, MD, FACC, FSCAIFaculty and Disclosures

CME / ABIM MOC Released: 1/27/2023

Valid for credit through: 1/27/2024, 11:59 PM EST


Activity Transcript

Felix Mahfoud, MD, MA: Hello, and welcome. My name is Felix Mahfoud, here from Saarland University Hospital in Homburg, Germany. Welcome to this program, which is entitled, "The Latest Renal Denervation Trials. What Have We Learned From Managing High Blood Pressure?" Joining me today are 2 great experts in the field and close friends, Ajay Kirtane, who is a professor of medicine at Columbia University Medical Center, director of cardiac cath labs in New York. Hi, Ajay.

Ajay J Kirtane, MD: Thanks for having me.

Dr Mahfoud: And David Kandzari, who's chief of Piedmont Heart Institute and Cardiovascular Services and chief scientific officer at Piedmont Healthcare and Piedmont Heart Institute. Welcome, David.

David E. Kandzari, MD, FACC, FSCAI: Thank you. Good to be with both of you.

Dr Mahfoud: In this program today, we will review the impact of the recent On-Med trials in renal denervation and how these trials may fit into the totality of evidence and what we can learn from these trials and how to integrate probably renal denervation in the armamentarium of effective antihypertensive approaches.

There's absolutely no question that hypertension represents an unmet clinical need. We know that high systolic blood pressure remains the leading modifiable risk factor globally, accounting for approximately 11 million deaths in 2021. We also know that about a third of the world adult population suffers from hypertension. And it has nicely been described by various publications that indeed the blood pressure control rates remain poor, despite the availability of many safe and effective antihypertensive drugs to lower blood pressure and also improve outcomes. We will discuss that in a second. These drugs are widely available. These drugs are cheap in almost all regions in the world, but patients do not adhere to what we prescribe in the vast majority of cases. And this is also something that we will discuss later during this session. One out of 4 women and 1 out of 5 men indeed remain uncontrolled despite the availability of lifestyle modification and antihypertensive drugs. So indeed, there is a huge population of patients in need for novel approaches to get their blood pressure controlled.

We've talked already about the existing options and have just briefly mentioned lifestyle modification and antihypertensive drugs. But before we discuss renal denervation, I think it's important to also revisit the benefits of antihypertensive drugs. And I'd like to ask you, Ajay, in brief, what is the importance of antihypertensive agents, and what have we learned in the past about these drugs?

Dr Kirtane: Well, thanks, Felix. I think you set the stage perfectly. And to me, it's just remarkable that hypertension represents a huge opportunity. There're so many things in medicine where when people are diagnosed, they have end-organ failure, they have irreversible cancer, other things like that, and then you're sort of way behind the 8 ball because these things have already manifested themselves with end-organ damage. And for me, hypertension is an opportunity because if you have a patient in the office with elevated blood pressure, perhaps at a younger age, these changes that lead to end-organ damage haven't happened yet. So, this is a key opportunity to intervene.

And we have drugs that are very, very effective at intervening to prevent things like heart failure, atrial fibrillation, stroke, coronary artery disease, and all the other manifestations that can occur. We know that drugs are generic, lifestyle modification is easy, and with these implemented, we can see reductions on the order of 10% in terms of reductions in major adverse cardiovascular events, perhaps even higher for stroke-type events, heart failure events. We can see these reductions with minimal changes in blood pressure. Two to 5 mm Hg across a population, if you drop the blood pressure, you'll reduce these events to that extent. And given how frequent and prevalent these other disease states are, we know that if we were to intervene earlier, that would be super effective. The problem though is that it's hard to implement these changes. Even if we know that medicines are cheap and generic, it's just hard to get patients to take them. We also know that if we reduce blood pressure more and more, we get lower and lower reductions or more and more reductions in terms of adverse events. So, it's a true unmet need in my book, and I think it's important to emphasize all of those things even before considering renal denervation.

Dr Mahfoud: Ajay, when you talk about blood pressure lowering, you have to keep blood pressure targets in mind, too, right? So, what do guidelines recommend these days? Where should patients be targeted to?

Dr Kirtane: In general, we're targeting lower and lower, so less than 130 systolic, less than 85 diastolic. We do know from the SPRINT trial that there can be some side effects with aggressive lowering to those levels, but we still do know that we can reduce cardiovascular events with those types of targets. But what becomes challenging is that when you look at those targets, it becomes harder to achieve those with single therapies. And that's why the effectiveness of combination blood pressure medications or even combining diet, exercise, lifestyle modification with drugs and perhaps other therapies as well might be needed in order to get people to those levels.

Dr Mahfoud: David, along the lines of the SPRINT trial, which represents one of the most important recent trials in blood pressure research. I guess, there was a paper published end of last year where they looked into the very long-term outcomes of SPRINT. Can you review the trial's outcome, and what does that mean for managing patients with high blood pressure?

Dr Kandzari: Certainly. So, the SPRINT trial was landmark and revised guidelines and advanced the motivation for more-intensive blood pressure lowering, as you both well recognize. A 20-mm Hg reduction in blood pressure translates to significant reductions in mortality itself. And yet with medications, it raises the issues of medication adherence, compliance, and sustainability with medications. That even though was simple antihypertensive medications that blood pressure could be effectively and significantly reduced, it was not sustained, the benefits were not sustained over long-term follow-up. And therefore, it mitigated much of the clinical advantage in terms of a survival benefit, in terms of an advantage of reducing the risks for major adverse events that may include stroke, myocardial infarction, or heart failure, that a lot of this potential benefit was lost over time with likely waning adherence to medications.

Dr Mahfoud: When you see patients in any practice who have uncontrolled high blood pressure, how often do you suspect that these patients are nonadherent to what you've prescribed?

Dr Kandzari: To be sure, it is in clinical practice an unknown, simply given that we don't routinely perform blood or urine testing for metabolites of their antihypertensives, as we've done in clinical trials. But in some selected instances of short-term treatment-resistant hypertension clinics, when this has been performed in the past, historically, these rates of nonadherence to medications have approached 50%, and indeed, in clinical trials involving renal denervation therapy, that we'll soon discuss, and involving strict adherence to prescribed antihypertensive medications. And moreover, even with the patient's acknowledgment or awareness of the purpose for drug adherence testing of blood or urine samples, still, the rates of drug nonadherence have approached on average 40%. And what's highly remarkable, too, is that nonadherence is very dynamic, meaning that at selected time points, patients may be taking all, let's say, 3 of their antihypertensive medications and yet at another time, none of them, and perhaps at another time, 2 or 1 of those 3 antihypertensive medications.

Dr Kirtane: And Felix, I just want to make 1 point in that regard, and it is just . . . it's not to be punitive to patients, it's not to look down on them. This is just practical clinical life. When people have side effects to a variety of things, they might blame their antihypertensives. And because blood pressure is not something that people feel, it's pretty common for folks to just not want to take their medications in that way. And so, I think we have to work together collaboratively with our patients rather than sort of say, "I'm the doctor, you're the patient, you must do what I say," because frankly, that doesn't work in real life.

Dr Kandzari: Well, to expand on that, too, these are, of course, in clinical trials, highly motivated individuals, right? They're willing to enlist themselves in a trial of uncertain outcome and uncertain procedure, at least at the time to do something about their blood pressure. So, they're highly motivated. And I would expand the statement to say that it's not simply limited to antihypertensive medications alone, of course, whether it's drugs for long-term conditions such as diabetes or cardiovascular disease, hyperlipidemia or others, this is real challenge. And a survey of a thousand individuals taking medications for a variety of conditions were once asked, "What proportion of your life would you give up to avoid taking a single daily pill?" And a third of the study population would give up some time period, even in a small group, up to 2 years of their lives to avoid taking a single daily pill. So, it's by all means, not specific to antihypertensive medications.

Dr Mahfoud: Is it fair to say that we generally underestimated the importance of nonadherence to chronic pharmacological therapy in the past? Would you agree to that statement?

Dr Kirtane: Yeah, I certainly would. I think that the adherence data from the denervation trials alone is a lesson in and of itself. And I think it's one that should be humbling. It's one that should in inspire us not to blame our patients, but to become better doctors, better communicators, to explain and understand what the barriers are, and then also to seek other alternative therapies or other ways of motivating patients, because ultimately, it's about reducing their blood pressure.

Dr Mahfoud: That is also an important point of our discussion today. So, we are seeking alternative approaches to lower blood pressure that do not require daily intake of antihypertensive agents, and among those, renal denervation is an interesting approach to lower blood pressure. David, can you briefly review the pathophysiology behind renal denervation? What are we targeting? What are we looking for? And what are we doing by renal denervation?

Dr Kandzari: Certainly. The recognition that the renal efferent and afferent nerves mediate hypertension, and particularly with the focus on the renal efferent nerves that result in renin release; changes in renal blood flow, sodium retention that led to a neurohormonal cascade and elevations and the sympathetic signature of the body is interestingly not new science. And in fact, in the 1930s through 1950s, surgeons would perform surgical renal sympathectomy where they would surgically sever the renal efferent and afferent nerves that arborize or spiral around the adventitial layer of the renal arteries in an effort to reduce blood pressure. And indeed, in case-controlled studies, not only was blood pressure effectively lowered, but in some instances, it may have a survival advantage, as we've seen with many other therapies by reducing blood pressure.

And this particular procedure, though, understandably fell out of favor given its complexity and risk as a generational cascade of antihypertensives was introduced, targeting many different mechanisms of the neurohormonal cascade or vasodilatory effects for lowering blood pressure. But approximately 20 years ago, scientists revisited a less-invasive and perhaps more-specific method with catheter-based renal denervation, in that instance using radiofrequency energy delivery. And as we'll soon discuss to date, we now have a wealth of data with regard to both radiofrequency energy delivery as well as intravascular ultrasound delivery to mediate renal nerve denervation through a catheter based, a very safe approach to this, and now exploring new ways with drug delivery in the perivascular space, as well.

Dr Mahfoud: This approach was investigated in registries, in observational studies, but also in randomized clinical controlled trials. And the first sham-controlled, clinical trial indeed was SYMPLICITY HTN-3. And I don't want to spend too much time on discussing this trial, but I want to highlight that we have learned a lot from this 535-patient study where patients with severely uncontrolled hypertension were randomized to receive sham or renal denervation in a 2-to-1 fashion. And the trial was neutral in a nutshell. There was a significant reduction in both blood pressure readings, ambulatory and office, but the difference between the renal denervation group and the sham group was not statistically significant. So, it lowered blood pressure, but in almost an equivalent amount in those patients who received the active treatment, renal denervation, and sham.

But there were more lessons to be learned from this study. And David, you were one of the investigators in these studies. What are the key learnings that we took away from HTN-3 to design and to conduct novel trials in renal denervation? And what are for you the most important aspects that these trials provided us?

Dr Kandzari: Yeah, I think that's a great introduction to where we have come today with a new generation of renal denervation trials, Felix, because the SYMPLICITY HTN-3 study is one that we learned from in terms of how we conduct a new phase of clinical trials with renal denervation therapy. And, as we'll soon discuss, it's one that we still continue to learn some of the lessons of long-term follow-up of device-based therapies for hypertension. But more specifically, in the HTN-3 study and learning from it, we understood that there were a number of potential confounders.

One of them was the reliance on changing endpoints. So specifically, the reliance on the office blood pressure and its variability and to focus at least equally as much—and now as a primary endpoint for most studies—on ambulatory blood pressure, which is still limited in its accuracy, but at least can provide a more accurate perspective of the hypertension burden for an individual at least over a 24-hour period and may be less variable than the office blood pressure.

Secondly, we revisited the patient population in whom we were studying. And specifically, the HTN-3 study had a very polarized patient population with an average blood pressure of more than 180 mm Hg for the systolic blood pressure, taking an average of at least 5 antihypertensive medications at their maximally prescribed doses. And this introduced a number of issues as we've discussed earlier in this program with regard to drug adherence and changing medications frequently. And this involved changes in clinical trial conduct to simplify the medicine regimen and revisit a patient population with still uncontrolled hypertension, but what we might describe as moderate uncontrolled hypertension taking 1 to 3 antihypertensive medications.

And the last component of this is that we also learned a great deal with regard to the science of renal denervation therapy, as well. Given the understandable enthusiasm from early single-arm studies of quite substantial reductions in blood pressure with a variety of renal denervation technologies, the expectations were that this study would be an easily predictable result and a very successful one with regard to the procedure itself. And in some ways, no pun intended, we oversimplified the procedure itself. It wasn't so simple. As we've learned that the renal artery anatomy and the location of the renal artery nerves may be in different locations than what we initially had assumed. And we performed the procedure in a different way, at least with radiofrequency energy delivery, with a greater focus more towards distal branches and the distal components of the renal vasculature where the renal efferent and afferent nerves may be a more approachable therapy target, at least for that specific therapy of radiofrequency energy delivery.

Dr Mahfoud: And then, the 2 different sets of clinical trials were conducted and are published now, the on-med and off-med studies. Off-med means that these patients were not receiving any concomitant antihypertensive drugs. The patients were either drug naive or have been washed out.

And I'd like you, Ajay, just to review what the outcomes of these studies are, and what do they mean, I mean, not so much from a clinical perspective but probably more from proof-of-principle perspective.

Dr Kirtane: I would just want to echo David's points about what we learned from HTN-3. And if you look back historically at that time, there was unbridled enthusiasm for renal denervation. And the idea that we could just simply treat everybody, as David said, was not right. I think that what we needed to really do is refine these studies. And so, this study, HTN-3, allowed us to design all of these future studies.

And Felix, you were also involved and David as well and many others, and the idea was, is to take away medicines first. We wanted to see, does renal denervation work in terms of lowering blood pressure compared to sham, because HTN-3 had called us into question. And unequivocally across study programs, whether you're looking at radiofrequency or ultrasound, renal denervation was associated with a reduction in blood pressure that was greater than sham in a statistically significant way, and all of the off-med studies have shown that.

With the on-med studies, either with radiofrequency or with ultrasound, have looked at, well, could we control the medical regimen to some extent, in other words, have a stabilization period of medicines and then treat patients with denervation vs sham? And if denervation like the off-med studies were to work, we would see a lower blood pressure in patients randomly assigned to denervation vs sham. And what we've seen actually is exactly that. We do see lower blood pressures with denervation vs sham. Now what's different though is what happens with medications in those on-med designs. And for the trials that have really been able to strictly control the medication burden, we clearly see reductions in blood pressure that are greater with denervation vs sham.

For the trials that either through design or actually through implementation perhaps being conducted within the pandemic, perhaps being conducted in a scenario where patients are taking medicines that are not even necessarily prescribed to them, what we see is that if there's a greater medication effect, we always see that in the sham arm compared to denervation, then the blood pressures tend to equalize. And so why would that be?

The reason is because denervation can work and medications can work, and the effect has to be looked at together in an additive way. And so, if you have denervation plus medications, that's going to lower your blood pressure to a greater extent than denervation plus less medications. And if you have denervation with less medications, that may be similar to sham, which has very little effect, plus more medications. So, it becomes a little bit complex when you actually look at how the data are analyzed, but actually if you think about it with 2 variables moving, it actually becomes a lot simpler.

Dr Mahfoud: David at last year's American Heart Association (AHA) [conference], you presented another trial, another important study, an extension to what we've just discussed, which is the on-med pilot trial, which was extended by another 200 patients, 250 patients almost summing up to 350 patients. So, when you look at the data, what does these data tell us and what can we learn from the outcomes of this study?

Dr Kandzari: Thank you, Felix. The SPIRAL on-meds extension study combined the 80 patients as you mentioned from the pilot, sham-controlled, randomized, on-med study with an additional cohort for a total population of 337 patients overall, randomized in a 2-to-1 fashion to renal denervation therapy to vs sham control and examining the 6-month endpoint in change in blood pressure. And in the study, we demonstrated a statistically significant reduction in office systolic blood pressure compared with sham, but not end of 24-hour ambulatory blood pressure. We also demonstrated the success of renal denervation therapy with regard to the win ratio of having the opportunity to reduce either blood pressure or medication burden, medication burden defined as either medication dose and or number.

The unexpected point of this was not meeting the primary endpoint of the study by what's termed a bayesian analysis, with regard to the change in 24-hour ambulatory blood pressure, and with some history or themes revisited from the simplicity HTN-3 study. We unexpectedly observed a larger drop in blood pressure in the sham control group. And upon further exploratory analysis, this was largely principally driven by changes in medications in the sham control group prior to ascertainment of the primary endpoint blood pressure at 6 months. Specifically, a large proportion of patients added on either an increasing dose and or number of medications in the sham control group disproportionate to the renal denervation group that largely accounted for a reduction of blood pressure or would favor blood pressure lowering with medications in the sham control group.

It highlights Ajay's earlier introduction that medications do work when patients take them. When you're in the clinical trial and everything is supposed to be held constant and it's not, then this is really when the confounding is introduced into the results of these clinical trials. I would say overall, however, that the absolute reductions in both 24-hour and office blood pressure achieved with renal denervation in this study are remarkably consistent with what we've observed in previous sham-controlled, randomized clinical trials that have met their endpoints. And moreover, the procedure as before proved to be a very safe one and met the primary safety endpoint as well.

Dr Mahfoud: And not to forget that most of the patients were enrolled during the COVID pandemic, which may have an unmeasurable effect on the primary outcome, right?

Dr Kandzari: That's right. There are some suggestions, too, that patterns of blood pressure may have been different in the patient's enrolled during the COVID pandemic period, perhaps as described elsewhere due to changes in lifestyle or adherence patterns that were clearly distinct from patients that were enrolled in a pre-COVID pandemic period.

Dr Mahfoud: So, what provides the proof of principle that renal denervation lowers blood pressure? Is it that it lowers indeed office systolic and diastolic and ambulatory systolic and diastolic blood pressure in the absence of antihypertensive drugs in the purest population you can think of? Is that a statement, or would you say it's the totality of evidence that we have seen from on-med trials, but also off-med studies, confirming that this approach truly affects sympathetic activity and thereby lowers blood pressure?

Dr Kirtane: For me, I would say a 100% [that] the off-med trials are the proof of concept, proof of principle. And by the way, I would add that it's not just daytime, it's also nighttime. And I know David's going to talk about this fact that it's always on. To me, though, the supplementary data from the on-med trials also is further buttressing to make for me to understand that denervation does work. I'm curious here. David's thoughts, though?

Dr Kandzari: Just to echo those comments and say, too, that it's not simply off-med trials, but just as a background, of course, we have a great wealth of preclinical data as well as even human clinical data demonstrating that renal denervation therapy is associated with a decreased sympathetic state, specifically decreased renal norepinephrine spillover or, alternatively, decreased muscle sympathetic nerve activity. So, at a very scientific basis, renal denervation therapy does affect the sympathetic signature of the body itself. But absolutely, as Ajay mentions, the off-med trials were really intended as demonstrating biologic proof of principle, that is, in the absence of any confounding from antihypertensive medications that unequivocally with both of these modalities to date, that is, radiofrequency energy and intravascular ultrasound, we see, and interestingly with 2 different modalities, quite similar and meaningful reductions in blood pressure over this 24-hour period. And so, it highlights as Ajay introduced, this always-on effect of blood pressure lowering that is independent of the limitations of pharmacokinetic profiles and dosing regiments and certainly may have a special meaning to individuals whose blood pressure phenotype conveys a very high cardiovascular risk, such as those with early morning or nocturnal hypertension, as well.

And what's also remarkable is that despite the limitations of even the HTN-3 study, and I think more relevant through the SPYRAL HTN on-meds pilot study, as you've demonstrated, Felix, now through 3 years of follow-up, we see a sustained reduction in the blood pressure over time that is not explained by an escalation and drug number or dose, as well. So, it seems to be a very durable, long-term, and safe procedure long term, as well.

Dr Mahfoud: And even outside randomized, sham-controlled studies, we see in the Global SYMPLICITY Registry with more than 3000 patients included. Now, these blood pressure reductions truly sustain over 4 years of follow-up now that is available. And obviously, the blood pressure lowering that we see with renal denervation associates with improvements in cardiovascular events. It reduces cardiovascular events such as stroke, myocardial infarction, and cardiovascular death, which we have shown through a measurement that we call time-in-therapeutic range.

And I'd like to ask David to explain us a little bit more about TTR, what that means and what we have learned from TTR as a measure to evaluate blood pressure control quality.

Dr Kandzari: I think that's a great introduction to thinking about what are the next steps for the field of hypertension and how we think about blood pressure control, because my analogy for this concept of time in therapeutic range or time in target range is that of glycemic control in diabetes. So, we started out with a point-of-care blood test for checking one's blood glucose to then transitioning to the hemoglobin A1c, which was some estimate at least of the preceding 6 weeks or so of the level of blood glucose control, to now having these very sophisticated monitors and wearable devices in which individuals can literally in real time track and adjust their therapies for blood sugar control. As we think about over longer periods of time, the sustainability of having targeted blood glucose levels.

And now, we extend that in some ways now to hypertension, specifically thinking not just about the routine visit to one's doctor and the blood pressure measurement in the doctor's office and looking every 6 to 12 months at those visits of what the blood pressure was doing, to home blood pressure monitoring, wearable technologies as well, but put simply, extending the data that we have in the number of assessments of blood pressure over a longer time to look at truly the burden of hypertension and how often an individual spends as defined as time in targeted range.

So, the target ranges may be arbitrary, a systolic blood pressure of less than 130, as Ajay introduced earlier, less than 140 by other prior guidelines, but the point is that how long is an individual spending in that time of an adequate blood pressure rather than a single measurement in which the blood pressure may be favorable and yet all other times it may be uncontrolled. And put simply, the longer time spent in time and target range, whether we've learned this through the SPRINT trial or as you've demonstrated through the Global SYMPLICITY Registry, Felix, that the longer time spent in a targeted range, intuitively it's associated with a remarkable decrease in major adverse events that include death, myocardial infarction, and stroke.

Dr Mahfoud: Great. Ajay, we're obviously introducing catheters into the body and we're ablating and we are remitting ultrasound or radiofrequency, a question that very frequently comes up when discussing renal denervation with patients, but also physicians, referring physicians, is the safety of the procedure. So, in general, how safe is the procedure? And what are common complications that you have to encounter?

Dr Kirtane: I think because we are intervening on a disease state before, in some cases, it's manifested any end-organ damage and we're looking for outcomes that are later, I think, one of the things that, Felix, I've heard you say many times on the podium is that this procedure has to be extraordinarily safe. Pretty much any adverse safety signal if we were to see it with statistically significant differences would almost be a nonstarter for something where you have medications, you have lifestyle, you have alternatives to treat it. And fortunately, for renal denervation, that's exactly what's been demonstrated through the randomized trials.

Now, of course, there are some trials that show limited efficacy, and so, if you show very good safety but limited efficacy in the earlier trials, that's not really fair. But the trials that have shown benefit, and I think one of the ones that you've led, the Global SYMPLICITY Registry, is perhaps the best source to look for safety data. And within trials and registries like that, even the randomized data that we have to date, we really see an extraordinarily low rate of adverse clinical events. A lot of it has to do with the arterial access where you enter, just like any other catheter-based procedure. Let's admit as proceduralist, this is a procedure, it's not like taking medications, but they're also potentially long-term benefits.

A lot of people have been concerned about renal side effects, things like increase in the glomerular filtration rate (GFR), and it actually turns out that if you look at patients who are treated with denervation over the long term, the projected deterioration that they might have had in their GFR simply from untreated hypertension, all of that is mitigated because their blood pressure is perhaps better controlled. And that really gets back to what David was talking about with time in the therapeutic range over the longitudinal period.

So bottom line is that this procedure does appear to be safe. It is an endovascular-based procedure. You have to have good technique. You have to have good operators, people who are adequately trained. But if it's supplied that way with the data we have to date with ongoing follow-up from the randomized clinical trials, the safety signals don't appear to be significant.

Dr Mahfoud: Excellent. I'd like to conclude our session now by asking you both when you review the totality of evidence and to ask yourself, who's the ideal patient to receive renal denervation? Who's the most promising patient to respond to this therapy with a blood pressure fall? What would you reply? Who's the ideal patient in your mind?

Dr Kandzari: Sure. So, I would echo Ajay's comments. There's a remarkable consistency across the trials, though, whether it's in the on- or off-med settings for renal denervation with both of these modalities with regard to efficacy and safety. And this is an exciting time for both programs, as both are in the United States, at least approaching their plans for regulatory approval and review coming up and possibly introducing this therapy to a broader population in clinical practice. And so, it raises the next steps in renal denervation therapy of surveying renal denervation therapy like you have, Felix, in a broader, less-selected, patient population with hypertension, patients with other coexisting illnesses or conditions that were excluding them from these more rigorous sham-controlled, randomized clinical trials thinking about hypertension in a long-term context of time and target range, and also exploring patient preferences for therapies like this in combination with medications.

My answer to the question is that really, I consider this as a therapy for patients who are commonly encountered in clinical practice who persist with uncontrolled hypertension, which may be up to 60% of the US population with hypertension, who despite medications of 1, 2, 3, or more medications being prescribed to them have persistent, uncontrolled hypertension and are motivated and have a preference for reducing their blood pressure, but a preference for an alternative therapy rather than escalation of their drug dose and/or number alone.

Certainly, it needs to be a shared-decision-making process. Patients need to be informed of the purpose of this procedure and what we know to date with regard to its safety and its long-term durability. And also, I think, it's certainly a welcomed addition that all of these programs have been part of not only interventional cardiologists led, but hypertensionists, internal medicine, nephrologists, and other specialties to have multiple perspectives in encouraging a patient or recommending this therapy to an individual, as well. And then, the final part of it I would say is to have a very experienced center and experienced operator performing the procedure, as well.

Dr Mahfoud: All great points. So renal denervation as an alternative and not competitive treatment strategy in addition to lifestyle modifications, antihypertensive drugs. Ajay, what are your thoughts here?

Dr Kirtane: I can't agree more. And I just think that so many people have this construct that renal denervation has to unequivocally defeat medications and be the panacea for the treatment of hypertension. And that's just not how we practice clinical medicine. We have tools to treat various disease states, and if we have tools that are effective, especially, if we have multiple tools, why not use them in concert? Why not use them together and to figure out what the best way is to take care of our patients?

For me, the ideal patient would be somebody who either can't take, doesn't want to take, or has had side effects from conventional therapies, they've actually tried to do it; they've been screened for secondary causes of hypertension, so we know that there's nothing reversible that's going on that could be treated without a procedure; and who feel that a procedural sort of focus or a procedural way of dealing with this is a reasonable way to address it. So, for me, it's an education issue. It's trying to really talk to our patients, understand the way you started off, Felix, by just speaking about hypertension and the unmet need, why wouldn't we want a tool if shown effective to work in concert with everything else that we do?

Dr Mahfoud: Ajay and David, thank you very much for this great discussion. I very much enjoyed being together with you, and I'd like to thank also the audience for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

This transcript has not been copyedited.

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