Renal Denervation for the Treatment of Hypertension

Can Afferent Nerve Ablation Cure Essential Hypertension?

Jeffrey Westcott, Robert Bersin, James Zidar, William O’Neill

Background: Hypertension remains an enormous issue worldwide, and because of its impact on cardiovascular events and mortality, is a major public health issue.  Because of its impact on cardiovascular events and mortality, small sustained changes in blood pressure (10 mm systolic, 5 mm diastolic) can have an incredible impact, a 40% lower risk of stroke-related death, and a 30% lower risk of death from other vascular causes.  Unfortunately, 30% of patients go untreated, and 35% are treated and uncontrolled, and approximately 10% of patients are uncontrolled despite the administration of 3 or more anti-hypertensive drugs.  It is this subset of medically refractory hypertension that the clinical trials of renal artery denervation have focused.

Gaps in current knowledge: The clinical trials of renal denervation have demonstrated a significant reduction in systolic blood pressure in the medically refractory population.  The trials have not yet established the long-term durability of this benefit, nor have they established the long-term safety, not just in terms of the patency of the treated renal artery and the functionality of the treated kidney, but also in scenarios where a blood pressure response is desirable or needed, but potentially may no longer available, such as in sepsis, hemorrhage, trauma, shock, etc.  It is also not established whether the measured drop in systolic blood pressure with the denervation procedure results in the same clinical benefit to the patient as an equivalent drop achieved with anti-hypertensive medications, as many anti-hypertensive medications have benefits independent of their blood pressure lowering actions, such as the effects of beta blockers on cardiac arrhythmias or the effects of ACE inhibitors on endothelial function.

Summary and recommendations: A large scale randomized trial of best medical therapy versus renal denervation with long term follow-up of more than two years will be needed in the resistant hypertensive population to determine whether the blood pressure lowering effect of renal denervation is durable and affords the same or greater clinical benefit in terms of reduction of major cardiovascular and cerebrovascular events and mortality as best medical therapy.  Additional trials will be needed to see if this benefit can also be extended to less resistant hypertensive populations.

 

 

Panel Discussion

                  Speaker:                    Jeffrey Westcott

                  Moderator:                 Robert Bersin

                  Panelists:                    Jim Zidar and William O’Neill

 

Robert Bersin: The next new technology is in what I would call a breakthrough area, an area where no previous interventional treatments have been available, and I would like to welcome my partner Jeff Westcott back up to the podium to talk about afferent nerve ablation in the renal arteries.

Jeffrey Westcott: Thanks Bob, I am rookie so be kind to me. I really did take seriously the IAGS rule about limiting the number of our slides, but this is an impossible topic to talk about in three slides. I think I figured out how to do it. This is the first disruptive technology, maybe other than BVS, that we have talked about today. Hypertension is a public health issue. The sequelae of hypertension is a public health issue and I think this therapy has the potential of being a real homerun. If you take a look at the number of companies that are involved in this I think it makes sense.

Obviously, hypertension is a huge issue worldwide. Small reductions in blood pressure, 10 mm systolic, 5 mm diastolic maintained throughout middle age have an incredible impact, a 40% lower risk of stroke death, 30% lower risk of death from other vascular disease. If we take a look at the population of patients with hypertension, we’ll see that there are 30% untreated, 35% that are treated and controlled, and 35% that are treated but uncontrolled. Of the last group, some people are on 3 or more drugs about 10% of the time. That is the subset that the clinical trials around renal artery denervation have focused upon. It is a large population and what is happening is that the sympathetic nervous system gets overstimulated, and all kinds of other interesting physiological changes start to occur, one is that we get vasoconstriction. We know that long-term we wil see hypertrophy, leading to increased risk of cardiac arrhythmias, hypertrophic cardiomyopathy, the hypertensive cardiac hypertrophic and then on to heart failure — the kidneys retain increased sodium, there is a decrease in renal blood flow and renin secretion, all of these changes leading to an increasingly serious problem. You start seeing norepinephrine spillover with feedback into the central nervous system and accentuating this loop. It leads to chronic kidney disease, hypertension, and a new thing we realize now is that it also leads to increased insulin resistance. So this is an incredible physiology that is all mediated by this empathetic nervous system. If you go back to the surgical sympathectomy data in the 50s it certainly did control hypertension, but when these people stood up their blood pressure went to 60. It wasn’t a good idea. Guanethidine tried to do this long ago but it was not a well approved drug. The nice thing about the renal artery is that it is a very localized location of fibers. If you could figure out a way to fry those fibers, in fact you could have a localized sympathectomy and that is really what we are trying to get at with this technology. That is really one of the challenges and on the slide you will notice that both the afferent and efferent nerves are lying in the same space in the adventitia.

renal slide.jpg

 

 

 It is possible to do that. So the question then is what can you accomplish? You certainly can reduce blood pressure, you could decrease the whole systemic sympathetic activation, induce LVH regression, ventricular remodeling, kidney function, decreased arterial compliance and decreased arrhythmias and now we think also reduce insulin resistance if you treat this effectively.  Here is the story actually: you take arteries pretreatment, you fry them, whether you do it sequentially or whether you do it with a spiral pattern and then down the line they really do look normal. So the question in the human model is what is the best way to do this. What catheter shape should be used, how do you monitor it, can you measure temperature as you are doing it, can you really do this safely?

Those are the issues. I would raise the following two challenges for our discussion. The first challenge will be the approval process. One of the keys to the approval process it needs to be tagged with remuneration. The DRG for this needs to be set up at the beginning because there is some expense related to doing this procedure. Secondly, how can you do it effectively? There are a number of techniques where you do multiple burns. Alternatively, can you do it instead with a single application of heat?  How can you measure that? Then, how can we focus on the safety to really see if this an appropriate disruptive technology?

Bob Bersin: Thanks Jeff. So Bill, Jim, I think the proof of principle has been demonstrated. We have had prospective evaluation of ablation that has demonstrated benefit in the highly resistive patient, a 10% subpopulation that is on multiple drugs and still has refractory hypertension, but one of the clinical questions that will come up immediately is where is the cut point? Is this a cure for the not so resistant hypertensive? And, who should this be applied to, and who should it not be applied to, and how are we going to find out?

Bill O’Neill:  I would go back a little further than that and I would label myself as an optimistic agnostic. The reason is because I am just going through the list of the new technologies that this group has dealt with over the years…. Do you remember the heating balloon that Richard Spears had and how great that was going to be? And then our dear friend Richard Myler had a glazing procedure where he took a laser and glazed shut the sections and the coronaries? That was going to be great also…. A lot of us here did laser TMR where we were burning holes in the myocardium to improve anginal function… I could go on. I would have to say that I have learned that I am not very good at picking the winners from losers. In the same vein, but on the flip side, I thought biventricular pacing was not going to work. I just thought it was really stupid and there was no way you were going to make the ventricle better by doing that. So, I still have some degree of agnosticism at least in terms of the current clinical trial. I should disclose that I am the chairman of the steering committee for Simplicity Three, so I should be a very strong advocate, but I am just going to wait and see. We have one trial, I worry about the current technology because there really is no endpoint for knowing how many burns and where and how often. Then are you going to be able to say that the therapy didn’t work on an individual patient? If so, was the concept wrong? Or were you ineffective at causing the scar formation? So those are some of the concerns I have going forward. But I think the data are going to play out and they have a huge Simplicity Three trial that is actively enrolling and many of you are probably involve. I think it will just be a matter of a year or two before we know. So I am optimistic. The other thing we didn’t talk about is the application for this in congestive heart failure, which I think could be as big or bigger because of the renal denervation that can occur with that. Those are all things for us to think about but all of us have to really understand that we are faced with all of these promising things and a lot of them go crashing down and I hope that this one doesn’t.

Bob Bersin: Okay, so perhaps we should poll the audience. Do you think there is evidence for proof of principle on this, that afferent nerve ablation does result in improvement in hypertension in the refractory patient? (Large show of hands is evident). The response from this group is clearly “yes.” The question then becomes what about long-term safety? Do we have a consensus that there is sufficient evidence? The answer here is clearly “no.” So this is where the questions come up. Jim, comments?

Jim Zidar: Another aspect to address is the finances aspect. It gets back a little bit to the biodegradable stent technology, you can get a diuretic at WalMart for $10 for 90 days, you can get a beta blocker, you can get an ACE inhibitor and an ARB, you can get a calcium blocker, you get 4 or 5 different antihypertensive drugs at less than $200 a year, so what would be the control in a trial that would show you a cost effective benefit from this technology even out 10 years, you would have to say the device has to be $2000, it will be difficult unless it is for the resistant hypertensives only to make an economic argument for this technology. Now there may be people willing to pay because they don’t want to take all these medications but I think the price of medications with generics has come down so much in the US that we have to think through what are the financial implications so you don’t get into this carotid thing where you get FDA approval but then CMS doesn’t pay and then the insurers don’t pay so we get into this separation between approval and actual reimbursement. I think that is a huge issue.

Gary Roubin: I would like to address the points made by Bill and Jim. Bill, the difference between all of that stuff that we have dealt with over the last few decades, and one thing that we have done very effectively in this society and at this meeting over the years has been to declare technology worthless probably before it is ever done at a TCT, or an ACE course, or at the ACC or anywhere else. I think that fundamentally is important to say. The difference between this technology and the others you mentioned is this fundamental basic work has already been done on this approach and it has been done very rigorously, very carefully and by very good groups of individuals with no agenda except to try to understand the fundamental avenue to deal with hypertension using this type of approach. The difference between crackers and scrapers and holes in the heart is that there was never any really good fundamental work in those areas. Number two, I’d like to address Jim’s point about the cost effectiveness of this approach and say here is potentially a technology which is going to be very, very cheap. Whatever the device that we come up with that can get rid of these afferent nerve endings…this is potentially not an expensive technology, not an expensive technique, an outpatient technique for sure, very safe probably. The expense issue will be related to doing the trials to demonstrate the efficacy and safety. I have no doubt, no doubt at all that if we can show long-term safety and efficacy that the issue of cost effectiveness compared to multiple antihypertensive drugs won’t be an issue.

Bob Bersin: The scientific basis for the therapy has been laid, the groundwork has been well laid out.

Bill O’Neill:  I lived through enough of this and probably have to confess to missing the mark on more of the new technologies than anybody possibly in this room and having been presented with a lot of opportunities to look at them, but this one is really interesting, intriguing and I feel more positive about it partly because, and I have to take issues with those who may diminish the potential epidemiologic effect here, hypertension seems to have been destined to under- and non-treatment and non-efficacious treatment for the decades we have known about it. I don’t think you can overestimate the benefit of treating not just a 10% but I think if that works we will be treating the other 35% and then maybe the other 35%. It is important to note that the cost of hypertension treatment is far more than the cost of the drugs, it includes the cost of doctors’ visits and the cost of side effects. I recently had to hospitalize a patient with severe dehydration due to just simple chlorthalidone. That cost $35,000. This, to me, is huge! The other issues are not so clear yet, such as the proof of principle and the safety. I just think that we are still not there, but if this works this is bigger than a lot of things we have done.

Bob Bersin: I think a lot of people have been taken back also by the magnitude of benefit, in this refractory group the average of 30+ mm drop so it is catching a lot of attention because of the magnitude.

Jim Adams: I am constantly telling patients that the most expensive drug you will ever take is the one that doesn’t work. Some want it because it is cheap, but it doesn’t work. Beta blockers long-term haven’t been proven to be very effective. The angiotensin renal axis is much better at changing wall lumen thickness. So as they go forward with these things to prove efficacy, we are going to have to look at outcomes, we are going to have to look at the microvascular system, what is it doing and I think not saying it doesn’t have the potential, but I think one of the things we have seen is that if you are going to jump on a bandwagon you have to make sure it has an endpoint that we can follow. We need to look also to make sure that it is really truly not just lowering blood pressure but actually treating the microvascular effects of hypertension.

Robert Bersin: Don’t throw away the ACE inhibitor even if it works, right?

Amir Lerman: I think this is a very exciting technology. I have several concerns, several issues that I would like to share. One of them is that I think ablation of the renal adventitia may result in long-term renal artery stenosis and I think this still needs to be resolved. If you take a vessel and you ablate that adventitia and the afferent nerves, you actually create a lesion… maybe not instantly, maybe not months but within a year you are going to see the development of the lesion. Second, we are still with the technology we don’t know, I think the challenge is going to be on who will perform this procedure, who are the right patients. It will be challenging to determine also who are the responders and nonresponders. Currently when you use a technology, you finish the procedure and you actually don’t know if you achieved your goal. I think whoever is doing the study needs to define a clear procedure following it to see if they actually achieved what they tried to do, whether it is going to be a volume challenge or stress challenge or something like that. The third one is that some of these patients may need this response when they are getting into a situation like sepsis and things like that. What is going to happen when you do an irreversible procedure and they cannot increase their systemic vascular resistance? It will work for hypertension maybe, but if you are in a situation where you shock or you are anemic then you could have a problem.

Barry Katzen: Having just sat through a Medicare MEDCAC meeting on carotid disease and listened to sort of the war between the proceduralist and the medical folks I can tell you that while it is exciting technology, and I happen to be very enthusiastic about it, I think the ability of getting this widely accepted across the hypertensive population, even the severely hypertensive population is going to be more difficult than people think. People are going to want to know not just what the blood pressure is doing but is there an actual reduction in stroke rate? Is there a reduction in the complications of hypertension? We are now dealing with more cost effective and value-based therapies rather than simply the reduction in blood pressure. So I would expect that as this technology becomes used more widely, as the general medical community, and the medical cardiology community, and the nephrology community becomes more aware of this technology, I think it is going to meet higher and higher bars for a really wide dissemination. I think rather than waiting till after the fact, as we have been burned in some other areas, I think we have to really design trials and outcomes that will answer the skeptics and the people who are really treating these patients rather than just sort of drinking their own Kool-Aid as we tend to do.

Bill O’Neill Yes Barry, I think those are really superb comments on where we are going. PFO closure is probably the epitome of where there is disagreement on benefit, because you have one society that is not in favor of it. Carotid stenting is another. We do not want renal denervation to fall into the same trap. I do think that Medtronic has actually done a very good job of incorporating hypertensive specialists into the protocol and there is a whole society of hypertension and they are incredibly forceful. So the trial that was designed is for resistant hypertension on patients that have to fail three drugs and one of them has to be a diuretic because the society insisted that one be a diuretic. Then there is a wash-in phase and then you go on protocol, so the trial was really designed to carefully find a group of patients that are specifically resistant hypertensive that have failed a three drug regimen. Now those are hard to find, I have to tell you. We are really having difficulty with recruiting but I think we have to stick with it because that is the group for which you are going to demonstrate proof of concept and it will be kind of a crisp, well-defined group. That will be the first phase. If it works there then they will go down to sort of less resistant levels, but I think your point is incredibly well taken. Nephrologists, cardiologists, hypertensive specialists all have to kind of come together to work on this and I am hopeful that this will work much better than the other areas where there was less cooperation.

Bob Bersin: We have time for just one more comment.

Jeff Marshall: I think the thing we have to do as proceduralists is to make sure that the endpoints are not always morbidity and mortality. We have to start thinking more about the quality of life of our patients. I think of the quality of life of somebody taking three anti-hypertensives. The side effects of those medications so adversely affect our patients’ quality of life that if you could do something to markedly reduce systolic and diastolic blood pressure the long-term effects of that would be really important. It is important to factor in the quality of life as part of the hard endpoint (and I realize that is kind of a soft way for a hard endpoint). But, the bottom line is if we don’t start doing that as proceduralists we are going to end up in the same predicament as with carotid stenting.