COMMENTARY

Renal Denervation Before the Fall. Guest: Deepak Bhatt

Samuel Z. Goldhaber, MD; Deepak L. Bhatt, MD, MPH

Disclosures

January 29, 2014

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Editor's Note
This discussion on hypertension and renal denervation was recorded at the American Heart Association (AHA) meeting in November 2013, before it was reported that the SYMPLICITY HTN 3 trial failed to meet its primary efficacy endpoint.

Samuel Z. Goldhaber, MD: Hello. This is Dr. Sam Goldhaber, for the Clot Blog on the heart.org on Medscape, talking to you from the American Heart Association meeting in Dallas. I'm here with my good friend and colleague, Dr. Deepak Bhatt. Deepak, welcome to the Clot Blog.

Deepak L. Bhatt, MD, MPH: Thank you.

Dr. Goldhaber: What we want to talk about today is resistant hypertension, and the exciting new treatment modality of renal artery denervation. But let's first step back, and you can educate us on hypertension in general for a minute or two. How important is it as a cardiovascular disease? And how important is it to reduce blood pressure by a couple of millimeters of mercury, either systolic or diastolic?

Dr. Bhatt: Those are great questions. Of course, we sometimes forget either from a patient perspective, or even a clinician's, just how important hypertension is and that even a few millimeters of mercury can matter.

With every 20 mm Hg or so increase in blood pressure, there's about a doubling in the rate of cardiovascular mortality.[1] It's actually a really big deal when people aren't at target with their blood pressure; in general, the target would be less than 140 mm Hg systolic.

Hypertension is a significant risk factor for cardiovascular mortality, but also for developing heart failure, stroke, and kidney failure. So it's really important to get blood pressure under control. And within that universe of patients with hypertension blood pressure, there is a proportion with so-called resistant hypertension.

Dr. Goldhaber: And is controlling systolic pressure any more important than diastolic pressure, or vice versa? Or doesn't it really matter?

Dr. Bhatt: Getting the blood pressure under control is important. In general, the data show that systolic blood pressure in particular is important to control. But the two oftentimes move together either up or down.

In fact, it's the opposite issue that had been a concern for many years. As you recall, there was a focus just on diastolic blood pressure and sometimes ignoring systolic blood pressure, in particular in older patients -- until such studies as the SHEP study showed that treatment of systolic hypertension, even isolated systolic hypertension, was important.[2]

Dr. Goldhaber: Before we launch into all the modern technology, I want to ask your advice. A very common problem I face in my own practice is when patients will come in and see me, and their blood pressure will be sky high. I have them purchase a blood pressure cuff and take their own blood pressure and come back to me with a diary. And oftentimes, it's under perfect control. So do they have hypertension?

Dr. Bhatt: That's a great question. What they likely have is so-called white coat hypertension when they're in the doctor's office. It could even be the nurse's white coat -- just being in that environment in some patients causes hypertension. But at other times, such as at home, they don't have that. So that condition is not as bad as full-blown hypertension, where the blood pressure is high all the time.

However, it's not as good as someone who is normotensive all the time either. It's hard to say just when you've got the office and home blood pressure, but potentially, that patient whose blood pressure is spiking in your office -- the same may be happening in traffic or when their boss is yelling at them.

So it's not necessarily as benign as some might think, but it's not as bad as having hypertension all the time. That's why some authorities recommend using ambulatory blood pressure monitoring. In the United Kingdom, recommendations from the National Institute for Health and Care Excellence (NICE) -- a rather conservative body that gives medical advice and sets guidelines -- actually says that patients who are being diagnosed with high blood pressure should have an ambulatory blood pressure measurement.[3]

Dr. Goldhaber: And if you don't have full-blown hypertension? We see this time and time again with particular patients. Let's say they're home, and they're in the upper range. Let's say their blood pressure is 135/86 mm Hg on average at home; should we give them a little antihypertensive therapy and bring them lower in the normal range at home, and try to abolish some of this white coat response?

Dr. Bhatt: It's not clear that treating prehypertension with medications is really indicated. No one has shown that that reduces cardiovascular outcomes. There may be side effects and some degree of cost, even with a generic antihypertensive.

In general, I wouldn't treat someone who's in the high-normal range just to treat them. I would treat them with lifestyle recommendations. Tell them to cut back on the salt and lose weight. Sometimes 5 or 10 lb of weight loss will do the trick. That's the advice I'd give that patient.

But if there's really diagnostic uncertainty -- for example, the blood pressure reading in the office is 180/100 mm Hg, and they come back and the home readings are all in the normal range -- first of all, I'd check to make sure their blood pressure cuff is calibrated, and that they know what they're doing and it's accurate. But then, I think I would do what the UK guidelines recommend: Bite the bullet and use the ambulatory blood pressure monitoring, because otherwise, we do run into situations where patients are potentially overtreated. And that's no good, but there are also patients being undertreated.

Dr. Goldhaber: Okay. So now let's go to the other extreme. You have a patient on 3 or 4 antihypertensive medications -- 1 from each of the classes, at maximally tolerated doses.

Dr. Bhatt: Right.

Dr. Goldhaber: We've all heard about renal artery denervation. Can you bring us up to speed on what to do next?

Dr. Bhatt: Sure. For the type of patient you just described, who would meet the definition of resistant hypertension -- they're on at least 3 medications, complementary classes, and at least 1 is an appropriately dosed diuretic -- if they meet that definition, about 10%-12% or so of patients seem to have resistant hypertension among the universe of adults with hypertension.

That's based on data from the REACH registry[4] and data from National Health and Nutrition Examination Survey.[5] Those folks potentially would then be candidates for renal artery denervation, an investigational procedure in the United States that is not approved by the US Food and Drug Administration. It is approved in several European countries. And several devices were approved in Europe.

Renal denervation involves introducing a catheter into the renal artery; from the patient's perspective, it would look and feel like renal artery angiography or like a cardiac catheterization with typically a femoral artery puncture, although in the future it could be done with a radial approach. A catheter is introduced. Angiography is performed to make sure there are no renal artery abnormalities, and no significant renal artery stenosis. Then a radiofrequency catheter is introduced, and energy is applied.

It's a similar procedure to radiofrequency ablation for atrial fibrillation, although it uses different energies and frequencies and it's done in the renal artery to denervate the kidney. That denervation, reducing the sympathetic inflow and outflow, the cross-talk between the kidney and the brain, appears to lower blood pressure.

Dr. Goldhaber: And how long does this ablation take?

Dr. Bhatt: Well, that's a changing number. Right now it takes about 20-30 minutes. But the technology is rapidly improving, going from single electrodes to multiple electrodes. The procedure -- even though again, it's investigational and not approved in the United States -- is already going through second and third iterations.

Dr. Goldhaber: A silly question, but does the patient feel anything while getting buzzed?

Dr. Bhatt: That's not silly at all. It's impossible to predict who will feel some discomfort and who won't. To be honest, it really depends largely on the amount of sedation that the interventionalist gives. I tend to believe in generous sedation to try to make any procedure comfortable. So if the patient is asleep, they're not going to feel anything. But that part of the body when you're applying energy -- doing a balloon or a stent in the renal artery, for example -- they can't feel it.

Dr. Goldhaber: And what are the parameters to say that the procedure was a success? What type of systolic and diastolic lowering of blood pressure -- you're looking for how many millimeters of mercury?

Dr. Bhatt: That's really a sophisticated question. Right now, there's no immediate feedback to the proceduralist to say, hey, this is a success. But the only way to tell is, did the blood pressure after the procedure go down or not? A significant response has been defined as a decrease in systolic blood pressure of 10 mm Hg or more.

That's an arbitrary definition. But by that definition, to date it appears that about 80%-90% of patients are responders. I should say that the data to date are very exciting. There have been some large reductions in blood pressure; by large, I mean 20-30 mm Hg systolic reported.

I would be cautious. I'm skeptical about that magnitude effect. I think there's probably something here, and the procedure works in the right patients. But I don't think it's going to be that magnitude effect, because that effect is reported from trials that have been nonrandomized and in some cases randomized, but not blinded and lacking control arms.

The problem with not doing trials in a really rigorous, blinded, randomized fashion is it can introduce various forms of measurement bias -- unintentional, innocent bias. But the fact is that when someone is taking a patient's blood pressure and they see a number that they don't believe, the blood pressure measurement is often repeated, and in an unblinded study that can unintentionally introduce bias.

There is an ongoing pivotal trial designed hopefully for FDA approval: SIMPLICITY HTN-3. George Bakris and I are the co-principal investigators of that study. Hopefully, that randomized, blinded trial of over 500 patients will give us a very accurate estimate of what blood pressure reduction we might expect, and also what side effects we might see. [Editor's Note: Since this discussion was recorded, SYMPLICITY HTN 3 failed to meet its primary efficacy endpoint.]

Dr. Goldhaber: One final question: Can you put all the SYMPLICITY trials in perspective -- briefly review with us SYMPLICITY trials 1, 2, and 3, and I guess the upcoming 4?

Dr. Bhatt: SYMPLICITY HTN-1 was a so-called first-in-man study, a nonrandomized study comparing patients' achieved blood pressure with baseline values.[6] And those early data are looking great. The procedure seems durable out to at least 3 years -- no reinnervation and reelevation of blood pressure -- but again, the study was nonrandomized. So you have to interpret it with some degree of caution.

SYMPLICITY HTN-2 was randomized but not blinded. It was a larger, more systematic evaluation and found similar reductions in blood pressure.[7] Again, the lack of blinding is a limitation, for the reasons I mentioned before.

SYMPLICITY HTN-3 is ongoing; it is randomized and blinded. The results hopefully will be available sometime by mid-2014 or so. We'll have an idea of what the effect is on 6-month office blood pressure and ambulatory blood pressure, as well as clear characterization of side effects.

And finally, SYMPLICITY HTN-4 has just launched. That's very similar to SYMPLICITY HTN-3 in all design elements, except the entry criteria are ratcheted down to allow patients in the range between 140 and 160 mm Hg who are on multiple medications to get in. [Editor's Note: SYMPLICITY HTN-4 suspended enrollment in light of the early termination of SYMPLICITY HTN-3.]

Dr. Goldhaber: Well, it's very exciting to think this is an approach that can really help millions of people with resistant hypertension above and beyond medication. Deepak, thank you very much for joining us on the Clot Blog. And this is Dr. Sam Goldhaber, signing off for the Clot Blog.

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