Henry R. Black, MD; Domenic A. Sica, MD

Disclosures

May 21, 2010

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Henry R. Black, MD: Hi, I'm Dr. Henry Black, immediate past president of the American Society of Hypertension, clinical professor of internal medicine at the New York University School of Medicine, and a member of the Center for the Prevention of Cardiovascular Disease at that institution. I am speaking to you today from the 25th annual meeting of the American Society of Hypertension in New York City. I'm here with my colleague and friend Dr. Domenic Sica, Professor of Medicine at Virginia Commonwealth University, and Head of Clinical Pharmacology in Hypertension.

Dom is one of the real experts in clinical pharmacology and especially how we interpret drug levels in people with renal disease in particular, but of late he's become very interested in devices to lower blood pressure. What kind of devices are out there?

Domenic A. Sica, MD: Well, we've got a long history. The devices are several, the most recent vintage, or the latest vintage if you will, there's a respiratory device which is a form of synchronized breathing to music, which [for] a substantial number of people can have a positive impact on blood pressure. A lot of times with that particular device -- at least in our hands -- where we're looking at that as a failsafe for those people who really can't tolerate medicine, so have some inherent bias to medication taking.

Dr. Black: How does that work?

Dr. Sica: The device itself, part of it's a training process, part of it is a change in chemoreceptor sensitivity that occurs. But in clinical hypertension it's not a small number of people in whom there's a need to stabilize the mood. The mood contribution to blood pressure by way of sympathetic activation can be quite substantial, and a lot of our resistant hypertension -- maybe a lot is not the right word -- but a not insignificant amount of our resistant hypertension has at its foundation poorly treated excess sympathetic activity, and we don't have good drugs. Clonidine, as you know, which we've grown up with, is a particularly pernicious compound with lots of side effects, and long-acting forms of clonidine are poorly used in clinical practice. We have the old drug Aldomet [methyldopa], which isn't that bad, but anything that can diminish sympathetic activity has a positive impact on blood pressure.

Dr. Black: Yes, there are people who talk to us all the time about how we don't need any more drugs. We need something that works in the brain and deals with those things. We have nothing that's really well tolerated and very effective, in my opinion.

Dr. Sica: Yes, no question [that] what works on the brain has an impact on blood pressure, and it's poorly understood because it takes -- you have to be really seasoned at blood pressure management, and there's an artfulness to blood pressure management, which derives from repetitive interactions with patients with specific phenotypes of hypertension. And after a while you just kind of learn what things will work, and, if you're a careful student observing what goes on with the patient, then the odds are that you could pick out these things --sympathetic activity -- as important determinants of the blood pressure. If you're young at the business you're just not ready yet. You haven't seen enough.

Dr. Black: So wouldn't beta-blockers and alpha-blockers be enough?

Dr. Sica: Well, beta-blockers and alpha-blockers have a role. The alpha-blockade -- some of the peripheral alpha-blockers -- most certainly are good adjunct therapies that could decrease the amount of clonidine you need, if that was the case. But they too carry with them a certain amount of risk with fatigue and somnolence and just generalized malaise with even modest doses at the peripheral alpha-blockers.

Dr. Black: And they don't work in the brain anyway.

Dr. Sica: They work at the location of action of the excess activity, but it's how we -- and I use the word "cobble" together -- a respiratory device, for example, does certain things, careful listening to the patient, treating mood disorders -- if they're anxious, trying to figure out a way to treat that, if depression is there, treating the depression, if they've got a sleep disturbance, treat that. All of these are sympathetic activity driven; anxiety/panic attacks, depression, and/or sleep apnea, or sleep disturbances creates residual sympathetic activity the next day. So, a lot of times trying to retrain the body? The device, in a way, retrains the body to be less receptive to the signals, so there's less overall sympathetic activity or the efferent limb of the sympathetic nervous system.

Dr. Black: Now I know you've worked with the so-called Rheos® device. What is that?

Dr. Sica: The Rheos® device is another, I think, fairly clever way to address hypertension, arbitrarily defined as resistant hypertension. There is a considerable debate about what constitutes resistant hypertension. There is a label -- there is a definition that says 3-drug therapy maxed out -- 1 of which is a diuretic -- and failure to achieve goal. To me I look at that, and it's a rather convoluted definition, because it's a big lumping definition. If I was to then find the right drug as the fourth drug and then dismiss 2 of the other drugs, and I've got the patient controlled on 2-drug therapy, well, I guess they're not resistant. Maybe the right drug was never selected. So I'd favor the term like difficult-to-treat hypertension, and, realizing there are certain pathways operationalized for blood pressure elevation, [if] you find the right pathway it's like almost hitting a home run, and then you surround that drug with other adjunct therapies to maximize the overall effect.

Now the Rheos® system was trying to study in its pivotal trial patients with resistant hypertension, and, in so doing... The device is actually an implantable device. It's got a pulse generator which is localized subcutaneously with wires attached to the pulse generator, threaded up, and localized in a wrap around the carotid sinus, such that you can program the device, and the device then sends out -- or issues -- signals. The signals increase nerve traffic through the central nervous system, tricking the brain into believing the pressure is actually higher than it is. Then the outflow drops. And there's a range of adaptive changes of the neurohormones that occur, such that, at the end of the day, a not insignificant number of people get a significant reduction in blood pressure. But these are people otherwise dubbed resistant hypertensive. And many of the people enrolled in the studies being done with it are patients who had actually been reasonably well worked up for traditional secondary causes of hypertension, and, in so doing, you've got just the tough to manage hypertension. Now that is a trial with that device -- it's completed enrollment, and they're moving forward towards gathering the end of study information to really start to look at the absolute impact -- the net blood pressure reduction that occurs with the device.

Dr. Black: It sounds like a dangerous operation. Is it?

Dr. Sica: Well, no. I mean we've got several patients who have had enrichment, and, nationally, we're well over several hundred who have been in the trials.

Dr. Black: So patients are willing to do this?

Dr. Sica: Patients are quite willing to do it. A lot of patients do this out of desperation. Some do it because they believe they'll be on less medicine at the end of the day. Some just want better blood pressure control. Some are altruistic and really want to be involved. I think it's all sorts of different motivations.

Dr. Black: Does it have to be both carotids?

Dr. Sica: Right now it's both carotids. Down the road I think [that] if I was developing the device I would evolve technology to make the leads more sensitive, because the lead has to be -- the leads have to be on a sweet spot, which is mapped in the OR [operating room] as to optimizing the stimulation effect. And, ultimately, I would like to see it being unilateral, one side vs the other, which would cut down the surgery time substantially. Now, that would be my thinking about directions that should be going with that, and I think those are logical issues, but I think the technology is rapidly evolving, and as we learn what happens with 2-lead implantation -- now we've got a better appreciation of how it works.

Dr. Black: How big is this box?

Dr. Sica: The box is about the size of a cigarette pack.

Dr. Black: And it's getting smaller, I understand.

Dr. Sica: It's getting smaller, and then it's actually programmable externally so, and we're talking about small voltage -- 6 or 7 tops --as to what's needed, and you've got a better life. And you're hoping the battery just lasts long enough based on the amount of voltage needed on a minute-by-minute basis. Then your battery life is variable in nature. And there's a lot we're learning about this device. The programming is intriguing. What voltage, what amplitude, what width of the waveform -- a lot of different things have to be considered so it's almost like customizing for a patient. It's what your prescription is, not just the device. You're being prescribed a certain form of electrical stimulation that's unique to you. And as this becomes more adaptable to clinical practice, there will be an on/off time. It may be, for example, that some people are very well controlled overnight in their pressure, and the device could be all but shut off, therefore saving battery life. So, I think we're going to find a customized 24-hour pattern as it hits primetime -- because it will hit primetime, and I believe most likely will be approved by the Agency down the road. But it still has to pass muster. It still has certain hoops it has to jump through and these are good hoops, because it is a contribution to us in the hypertension community to have this.

Dr. Black: So these are put on the baroreceptors. What do the baroreceptors have to do with blood pressure?

Dr. Sica: The baroreceptors have a long and storied history. We like to see good baroreceptor function. If the pressure goes up, ultimately the brain does its best to shut pressure down and bring it back to its baseline. Baroreceptor dysfunction is common in clinical practice. Signals come in, but the right output doesn't drop. So, that's the simplest way to frame our thoughts about that. So baroreceptors -- we've had 40 years of interesting work with [them], and we're just finding that baroreceptor stimulation -- actually by this device -- has an important role in everything that goes down. Now, remembering [that] I said there's a history to the device, you could go back to the surgery literature in the late 50s and see that people already were thinking about this. So it was being thought about for bad hypertension. It was actually being thought about for refractory angina. So, right now at least, we have technology much superior to that of 45-50 years ago, but there's a lot of diseases to be considered here even beyond hypertension.

Dr. Black: So this is a way to help the brain do what it's supposed to do as opposed to alpha- and beta-blockade, which is at the periphery.

Dr. Sica: Yes.

Dr. Black: What other uses might this have? You're talking about --

Dr. Sica: Right now, I believe, there is a large trial being not just contemplated but started, which is looking at diastolic heart failure, or what we would now term "heart failure with preserved systolic function," trying to see if there could be some positive benefit afforded the system, which is a thick left ventricle with hypertension, in outcomes or blood pressure. Blood pressure and outcomes being...

Dr. Black: So that's under way?

Dr. Sica: And right now, as I think you know, we have no drugs indicated for preserved systolic function forms of heart failure, and most of the trials conducted have not been successful. Most of the trials, in point in fact, have been with the angiotensin-receptor blockers, two of which -- each has a little bit of flaw on the design. Candesartan work has been done and irbesartan work has been done. So, I think trying to find a device that can: A, affect change in blood pressure and, secondarily, influence myocardial structure and function, because blood pressure reduction would then have an additional effect for LV [left ventricular] mass regression. Now whether you can get a special effect in LV mass regression, which goes beyond the numbers as to blood pressure reduction -- that's where the rubber hits the road. Trying to do this study, you want to see how that changes, and then you want to see how events, for example hospitalization events, would be thought about. Can you change rates of hospitalization with this? Because there's a lot of soft and hard outcome data that you would seek out in a trial looking at preserved systolic function forms of heart failure.

Dr. Black: I want to talk about one other device and just a little historical issue as well. Back in the 30s and 40s Smithwick and his colleagues did sympathectomies, and back in the 60s and 70s we had operations for high cholesterol. Now we have operations for obesity. Diuretics came along, and we didn't need, didn't need the Smithwick procedure. Statins came along, and we didn't need the bypass -- the bypass we were doing. We still could use something for obesity, but the bariatric surgeons have pretty much shown some good things. And what was the Smithwick procedure?

Dr. Sica: Well, I mean the sympathectomy route -- there are a lot of cute terms applied to it. One term that has entered the literature was "barbaric." And I think sympathectomies would tend to help blood pressure, but led to significant salt and water retention, and a fair amount of orthostatic hypotension. So, you have almost a dysregulated system.

Dr. Black: We're not going to go back to doing that, are we?

Dr. Sica: No, but I think where we're going to go is another device/procedure, which is renal nerve ablation, and it's getting a fair amount of press. I mean the data is accumulating, and the procedure is really a percutaneous stick in the femoral artery. There is radioablation catheter which can be threaded up, and you can do both sides ultimately, and it's an endovascular procedure. So you basically nuke the renal nerves, which are found exterior, if you're looking more primarily in the adventitia of the vessel. And changing the nerves really then changes much of the sympathetic activity systemically. So renal nerve traffic -- we always think about the brain as being the source of nerve traffic -- renal nerve traffic can have a very important role as to there being more of a -- it's almost like autocrine/paracrine, local vs systemic. Local ablation has a systemic effect on sympathetic activity and probably will affect a number of different disease states there. Now the procedure is still in its early stages. They're going to have to think about persistence of positive effect for blood pressure. So far the data looks promising, probably out to about a year, and then you have to worry about whether or not there's any long-term change in vessel morphology as you do this, and that data looks promising so far.

Dr. Black: How long does that operation take?

Dr. Sica: From what I'm told (we're not doing it actively in Richmond), it's less an operation than maybe a procedure, a percutaneous procedure, so probably in skilled hands you get the whole thing done in under an hour.

Dr. Black: Are you going to damage the vessel, do you think?

Dr. Sica: Well, so far so good, from what I hear. No damage to the vessel. I think we've got to think about it 2 ways. Any time you ablate something, there is an inherent possibility [of] damaging the endothelium and, with that, having endothelial dysfunction and reactive change. On the flipside, if you change sympathetic activity, then maybe some of the natural deterioration in vessels, which occurs founded on excess sympathetic activity, may be diminished. So it washes out; you eliminate the factors that would be leading to vessel stenosis or an adverse response. That I think we need to figure out, but I can see it going either way with that.

Dr. Black: Right.

Dr. Sica: Now what we do with this procedure in renal artery stenosis remains a wonderfully interesting issue as to whether or not -- in renal artery stenosis, for which in some cases we have very poor treatments -- whether or not changing renal nerve traffic changes the natural history of the blood pressure that's a concomitant to renal artery stenosis. That to me would be really exciting data as we go after it.

A final point on this topic: Chronic kidney disease these days, for those of us who live and breathe that as I often do, more times than not has 2 role players. It's not a renin-driven disease for the blood pressure; it's an aldosterone-driven disease for the blood pressure -- not the least of which is because the rises in potassium act as an independent secretagogue for aldo. So, most CKD [chronic kidney disease] patients have for their volume state, which is generally a high-volume state, a higher aldo level than they should have. And then second, it's sympathetic activity in CKD, which is present in abundance, whether you're looking at renal nerve traffic, which is up, or whether you do microneurography on sympathetic nerves, where it's exceedingly high. So, I think when you look at this, there is an access for CKD-related hypertension, which is almost triangulated. You've got volume excess, you've got aldosterone that's disproportionately up, and then you've got sympathetic activity. And if you attack those in a systematic way, your odds of controlling pressure in CKD go up. It's not rocket science. Sometimes, paying attention to the basics of what drives the disease are going to get you there.

Dr. Black: Sometimes when we don't have a drug that works, we do have to resort to these or actually resort to old ideas that have a physiologic basis but not a therapeutic one so far.

Dr. Sica: Yes, that, and just saying that we use a lot of drugs and a lot of us use them skillfully, but any time you can get something that delimits the amount of drugs you need, then you're in the ballgame.

Dr. Black: Right. Thank you very much, Dom.

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