COMMENTARY

Renal Denervation: Where to After SYMPLICITY HTN-3?

Henry R. Black, MD; Raymond R. Townsend, MD; Michael A. Weber, MD

Disclosures

March 12, 2014

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SYMPLICTY HTN-3

Henry R. Black, MD: Hi, I'm Dr. Henry Black. I'm an adjunct professor of medicine at the Langone New York University School of Medicine, and a former president of the American Society of Hypertension. I'm here with my colleagues, Dr. Michael Weber and Dr. Ray Townsend. Michael?

Michael A. Weber, MD: Hi, Henry. I'm Michael Weber. I'm Professor of Medicine at the State University of New York Downstate College of Medicine. I'm Editor of the Journal of Clinical Hypertension -- and I should disclose, since we're going to be talking about the SYMPLICITY trial and renal denervation, that I'm one of the principal investigators of SYMPLICITY HTN-4, which is another trial. I have also given advice to Medtronic, Inc., the sponsor of SYMPLICITY HTN-3.

Dr. Black: Ray?

Ray R. Townsend, MD: Thanks, Henry. I'm Ray Townsend from the University of Pennsylvania Perelman School of Medicine in Philadelphia, where I am a professor of medicine -- and by way of disclosure, I was 1 of 10 people on the US advisory board to Medtronic for the SYMPLICITY HTN-3 trial. Also, our particular institution in Philadelphia enrolled patients in SYMPLICITY HTN-3, although I was not involved personally with that because I was serving on the advisory board for the trial.

Dr. Black: Thank you. One of the surprising items in cardiology research over the past few weeks or months was the fact that SYMPLICITY HTN-3 did not meet its primary goal . Ray, since you were part of the advisory board, what was that goal and what happened? Do you know?

Dr. Townsend: The goal was to enroll patients who had severe drug-resistant hypertension -- office values of 160 mm Hg or higher on at least 2 occasions while on at least 3 drugs at maximum tolerated doses, including a diuretic. Home blood pressure monitoring was done, and home adherence was measured as well. In addition, most of the centers involved in the SYMPLICITY HTN-3 trial had hypertension specialists evaluating these patients.

If you look at the enrollment data, you'll see that about 2 out of 3 patients initially involved in the SYMPLICITY HTN-3 trial never made it to randomization because their blood pressure regimen wasn't optimum. Optimization of that regimen knocked out a number of people from the actual trial itself.

Dr. Black: Didn't they also have to have ambulatory blood pressure monitoring (ABPM) done?

Dr. Townsend: Correct; they had to have a 24-hour systolic blood pressure of 135 mm Hg or higher, and the efficacy portion of the trial was built around an estimated 15 mm Hg reduction of systolic blood pressure in the office at 6 months postintervention.

Dr. Black: This study, which followed from SYMPLICITY HTN-1 and HTN-2, had a control group: a placebo group that got a placebo procedure. What was the procedure? What happened?

Dr. Townsend: Every randomization was proctored by a monitor, so that when you're on the cath lab table, every person in SYMPLICITY HTN-3 -- whether they were assigned to the sham procedure or the actual denervation procedure -- had to have anatomy that was conducive. They had to have at least a 4-mm lumen on the renal artery on both sides and the kidneys fed by basically one artery on each side, and they had to have 2 cm of workable segment of the kidney artery so that the spiral catheter could do its thing in terms of the radiofrequency ablation.

We did what were called "postintervention interviews" to see how well the procedure was masked, and one of the things that was consistent across all the sites is that the patient could not tell whether they actually got the denervation. Most thought they did, even if they were in the sham group.

Too Boring, or Too Challenging?

Dr. Black: Michael, is that what you were doing, or are you going to do SYMPLICITY HTN-4?

Dr. Weber: SYMPLICITY HTN-4 right now is in a holding pattern. I hope it will go ahead, and I think it will be a better study once we learn what happened in SYMPLICTY HTN-3 that could be changed in terms of our protocol.

I think there were 2 problems -- and I'm speculating, because I'm not on any of the committees that ran SYMPLICITY HTN-3. I am not privy to any data as yet, and like everyone else, I'll be waiting for the report at the American College of Cardiology meetings in March.

Ray, I don't know what your thoughts are, but in my opinion an ambulatory blood pressure goal of 135 mm Hg as an entry criterion when the office reading is 160 mm Hg is not stringent enough. I suspect we probably let some people into SYMPLICTY HTN-3 who are not quite as hypertensive as advertised, despite all the precautions that were taken.

The second thing that I worry about is that this was done at 89 different sites across the country (if I recall correctly), which meant that 89 people who had never done renal denervation in their lives were now running a major clinical trial. I've studied this pretty closely. I'm not an interventional cardiologist, but I've listened to a lot of interventionalists. I've been to a lot of meetings about this, and the catheter that was used -- the so-called SYMPLICITY catheter -- is difficult to use. It has to be pulled back 4 times during a procedure, and it has to be rotated meticulously in order to make sure that you destroy or ablate all of the fibers of the renal nerves. It's difficult, even for the people who have done it several times; they get better at it as time goes by.

I'm not sure how effective the procedure was. I've now had the opportunity of looking at a lot of reports on renal denervation particularly from Germany, where it's much more available than anywhere else. And when you look at the results of the trials, patients fall into a bimodal pattern. The ones who actually get the denervation -- about one half of them -- have really nice changes in blood pressure, and then nothing happens at all in the other half; if anything, their blood pressure goes up. Does that mean that we're dealing with 2 intrinsically different sets of people who are labeled as having treatment-resistant hypertension, or does it mean that about one half of the time, the guy doing the procedure gets it right and about one half the time he doesn't get an adequate ablation? I really don't know the answer to that.

Dr. Black: How are we going to certify that people know what they're doing, since you bring that up?

Dr. Townsend: I'd like to interject on a couple of things. First of all, the ambulatory blood pressure requirement was 135 mm Hg systolic over 24 hours. That includes the nighttime as well. Now as you know, blood pressure usually comes down at night, so a 24-hour measure of 135 mm Hg means a daytime of about 145 mm Hg on the ABPM. I wouldn't call that "not very stringent," at least in my mind.

The second thing, about the procedure itself (and I've talked to cardiologists who actually do it), is that it's boring. I hate to say it that way, but it's not scientifically challenging or technically challenging to actually run this. There is a gauge that tells you that the catheter is up against the wall. There's a certain radiofrequency energy bubble that's exuded by the catheters being turned on, and you do it for 2 minutes and you turn it 90 degrees, and you pull it back a little.

One of the problems though -- and you've hit the nail on the head -- is that you just don't know how effective the denervation is. There's no clinical marker for that. There's no drop in heart rate or sudden burst of norepinephrine or dead nerve endings or something that tells you that's it's been effective.

Placebo Effect?

Dr. Black: There's one thing I should have asked earlier. What was the primary endpoint that wasn't met?

Dr. Townsend: This is where a confidential disclosure agreement (CDA) comes in. I know the data, but I cannot tell you. However, I can tell you that when I heard the press release, I thought one of two things: Either there was no blood pressure response in the intervention group, or there was a huge placebo response in the group that got the sham procedure. And there's been a worry about renal denervation all along -- is it really a treatment for office (white coat) hypertension, because of the spotty use of ABPM?

You can argue what you will about the criteria for the threshold used for ABPM, but at least we incorporated it into the trial, which I think was an important aspect of the trial design. Other trials of renal denervation have not always done that, and when it's been done, there are often huge discrepancies between the ambulatory blood pressure data and the office blood pressure data.

Dr. Black: I think you should be congratulated on what was a brilliant protocol. It dealt with ABPM. Clearly, the people who passed through that filter (as you said, only 1 out of 3 originally screened) were the people we ought to be looking at.

I'm also very interested in what happened. It's hard to imagine there was a great placebo response, but this is reminiscent of the Vineberg procedure for myocardial perfusion done back in the 1950s -- where people got great responses, it seemed, from cardiac operations, but when it was compared with simply opening the chest and closing it up again, you got almost the same results.

Maybe there's something magical about having your chest cut open or having a catheter (or seemingly having one) stuck into your femoral artery, but I think there's a lot to learn. We didn't talk about the physiologic basis or the pathophysiologic basis for even doing renal denervation. Which of you would like to just take a crack at that? Why do we do this at all?

Don't Throw the Baby Out With the Bathwater

Dr. Weber: It goes back a long time to Dr. Smithwick and others like him, in the 1940s and 1950s, when they started doing that -- when they showed that surgical denervation of the sympathetic nervous system was wonderful for reducing your blood pressure.[1] That was the good news. You even lived longer.

Dr. Black: But you couldn't stand up, of course. One of the things that's always troubled me about this approach is if we could get the same results with an adequate pharmacologic approach, would we need renal denervation?

Dr. Weber: That's true, Henry. In fact, the first drugs beyond diuretics that seemed to be effective for treating hypertension were also sympathetic nervous system blockers -- going back to reserpine and quifenadine, then of course Aldomet (methyldopa), and clonidine. But none of them are well tolerated, so they've all fallen out of use -- which is a shame, because I'm sure the sympathetic nervous system in some people is an issue, and it ought to be interrupted.

Dr. Black: It may be the primary issue in some people, because we block most other systems that raise or lower blood pressure, but we don't seem to have anything successful for the sympathetic nervous system.

Dr. Townsend: At least nothing focused. I mean, we have a few drugs, such as clonidine, but the problem is that it's like shooting a butterfly with a 12-gauge shotgun. It just nails your sympathetic system, so you create a zombie for 6-8 hours at a crack with each dose when you use the multiple daily dosing of that drug.

Dr. Black: I think this renal denervation procedure or what happens after this procedure is still a very critical thing that we need to work on. I will also wait until March to see what we hear with the official report as to what happened, but right now, I think the investigators and the people who planned the study should be congratulated on a very good protocol, and we'll have to see what they missed and why they missed, to understand the future of this approach.

Dr. Weber: Let me add my congratulations, Ray, because I agree it was a diligently done study, difficult to enroll for and difficult to recruit for, and the fact that you got it done in a reasonably timely fashion and meticulously followed the rules is a great credit to everyone involved.

Dr. Townsend: By the way, 2 last things before we hang up here. First is that it did meet the safety criteria. It did not appear to do harm. They had a very strict definition of what harm would be, and they were well below that.

The other thing is that when you read the press release that Medtronic sent out, they really didn't halt the trials, they suspended them. I know that's semantically interesting. One of the things Medtronic will be doing before they potentially throw out the baby with the bathwater, or even withdraw this catheter in other parts of the world where it's currently approved, is to sift through these data a little more with an independent group of people who aren't part of the trial design or aren't part of the trial execution and see what can we do next to understand better where this thing presently fits in the care.

Dr. Black: We can't throw out the approach or an approach to that problem, because it's critical and we do so much with other things, but there's still a big unmet need that we have to face.

I want to thank my colleagues very much for an interesting discussion, and we'll all wait to see what happens in Washington in a few weeks. Thank you very much.

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