Part 1 explained the concept behind renal denervation and detailed early evidence for the therapy’s effectiveness in treating drug-resistant hypertension. In Part 2, the story continues with a discussion oflonger-term safety and efficacy, the evolving technology, and the potential for extending the therapy to everyday hypertension and other sympathetic-mediated conditions such as heart failure—as well as the risk of overzealous dissemination.

The swift uptake of renal denervation has been facilitated by the relative straightforwardness of the procedure. “With the Symplicity system, there are certain algorithms to help get the catheter in the right place and get the right level of impedance so that the [radiofrequency] dosing is right,” Murray D. Esler, MD, of the Baker IDI Heart and Diabetes Institute (Melbourne, Australia), told TCTMD in a telephone interview, adding that the procedure is not technically complexand can be mastered in a short time by a well-trained peripheral interventionalist.

It is a natural fit for interventional cardiologists, who generally have good skills in instrumenting arteries, noted Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), in a telephone interview with TCTMD. And though they may not be “card-carrying” hypertension experts, they have considerable experience treating hypertension, he added. However, interventional radiologists are also likely to get in on the action, as well as some endovascular surgeons, he said.

Although European practitioners report that the learning curve is small, the US experience remains very limited, Dr. Bhatt cautioned, and it is important not to trivialize the potential for complications and variability in operator skill. “With enough volume, it’s only a matter of time before somebody [causes] a renal artery perforation,” he commented.

Treatment Response Unpredictable

One finding casting a shadow over the procedure’s overall success is that in the trials, about 10% of patients have not responded to denervation initially, meaning that systolic pressure does not decline by at least 10 mm Hg. However, Dr. Bhatt was quick to point out that “a 90% response rate is terrific—there are few interventions where we can say that.” In fact, current antihypertensive drugs are ineffective almost one-third of the time, observed Raymond R. Townsend, MD, of the University of Pennsylvania (Philadelphia, PA), in a telephone interview with TCTMD.

According to Dr. Esler, in principle, poor response could be due to a shortcoming of the technology, poor operator skill, or a patient’s individual pathophysiology, which simply may not be driven by overactivity of sympathetic nerves.

Interestingly, Krishna Rocha-Singh, MD, of Prairie Vascular Institute (Springfield, IL), told TCTMD in a telephone interview that in his early experience with denervation, up to a quarter of patients were nonresponders at 6 months. But when followed out to 1 year, almost all ended up meeting response criteria.

“So the question becomes: Is a 6-month [cutoff for judging] success appropriate?” he said. In fact, European investigators recently reported a similar pattern at the ACC/i2 Scientific Session in March 2012, suggesting that many early nonresponders may simply be slow responders.

“We’re trying to look deeper into the databanks to see what differentiates patients who don’t respond at 6 months but do later—whether it might be a difference in the severity or duration of their hypertension,” Dr. Rocha-Singh said. “Are there some markers that will tell us an individual is going to take a little bit longer and we need to be patient?”

Whether it is possible to improve response by tweaking the technique—for example, ratcheting up the RF dose or perhaps performing another round of ablation—remains to be seen, Dr. Bhatt said. But developing the ability to identify, and perhaps weed out, patients who are unlikely to respond to the procedure should be a goal of future research, he added.

All the experts interviewed stressed that renal denervation should be viewed as a tool to manage hypertension—not a cure. After all, growing older is a relentless driver of increasing systolic blood pressure, at least in the developed world, Dr. Townsend noted.

One issue that nags at the notion that denervation might be a permanent fix is whether ablated renal nerves regrow. Clearly, lack of attenuation of antihypertensive effect 3 years after the procedure is reassuring, as is the fact that no functional efferent re-innervation has been seen in transplanted kidneys. But whether afferent nerves, which transmit signals from the kidneys to the central nervous system, regenerate is unknown, said Dr. Townsend. Also unknown is whether retreatment of a patient whose hypertension has recurred would be as effective—and safe—as the first time around.

Safety: So Far, So Good

In the early days, denervation patients typically reported significant flank pain during the procedure, so now patients are routinely given sedatives or intravenous narcotics. And shortly after denervation, some patients have experienced precipitous drops in blood pressure, which is the main reason some centers require an overnight stay.

Aside from a few expected catheter-related complications, however, no adverse events have been seen. Still, Dr. Esler observed, it should be kept in mind that in the trials, denervation has been limited to patients with favorable anatomy—for example, no accessory arteries, adequate arterial length (at least 20 mm), and minimum diameter (4 mm) to tolerate elevated RF temperatures—and no more than mild renal insufficiency.

Initially, Dr. Esler noted, researchers worried that RF catheters might damage the renal arterial lining, resulting in stenosis, or weaken the arterial wall, leading to aneurysm. But those complications have not been seen, perhaps because the energy in the Symplicity system is distributed in a spiral fashion, he suggested. “But some of the newer catheters deliver energy in a single circumference, so it will be important to establish if that is as safe as spiral application,” he noted.

Although denervation does not seem to halt the gradual decline in renal function from chronic hypertension, as originally hoped, Dr. Esler said, by the same token the procedure itself does not have a negative impact on renal function in the short term.

That is reassuring, Dr. Townsend observed, because sometimes when blood pressure is reduced, renal blood flow declines, which in turn adversely affects renal function. That has not been seen in the predominantly white populations treated thus far, but it will be important to watch for any such reflexive decline in kidney function in African-American and Asian patients included in Symplicity HTN-3, he added.

Another, theoretical concern centers on whether destruction of the renal sympathetic nerves might compromise the ability to maintain electrolyte or volume homeostasis. For example, might denervated patients who experience trauma be at risk of hemorrhage? Dr. Esler asked. Or might patients with infective diarrhea lose so much fluid that they suffer circulatory collapse? Such dire outcomes have not been observed in transplant patients where renal nerves have been severed, he pointed out, but with denervation now being evaluated in India, where diarrhetic diseases are endemic, the potential risk will receive a more rigorous test.

An Evolving Technology

Renal denervation catheters have evolved substantially since the early days, and there are more improvements to come, said Dr. Rocha-Singh. “I called the first-generation catheter from Ardian ‘Sputnik’ because it was so primitive, but it got the job done,” he said. “The second-generation [device] was more elegant; it went down from 8 Fr to 6 Fr, and it was a lot easier to use.”

The promise of renal denervation has spurred development of multiple technologies to compete with the Symplicity system, most of them just emerging from preclinical testing.

St. Jude Medical (St. Paul, MN) presented first-in-human data for its EnligHTN system at the 2012 EuroPCR meeting in Paris, France, showing an average 28 mm Hg drop in systolic pressure and 10 mm Hg decline in diastolic pressure at 30 days in 47 drug-resistant hypertensive patients. The company simultaneously announced CE Mark approval in Europe for its multielectrode device, which it says has the potential to provide quicker, more consistent ablation.

Among the more innovative entries are:

• The TIVUS system (CardioSonic, Tel Aviv, Israel), which uses high-intensity nonfocused ultrasound to accomplish ablation in about 10 minutes per artery. Real-time ultrasound feedback allows for accurate positioning of the device to avoid contact with the arterial wall.
• A low-intensity focused ultrasound device (Kona Medical, Campbell, CA) that will ultimately deliver energy noninvasively from outside the body; the therapeutic effect of its dose-specific vibratory mechanical energy can be monitored between applications.
• The Bullfrog microinfusion catheter (Mercator MedSystems, San Leandro, CA), which relies on pharmacological rather than mechanical ablation; it injects the drug guanethidine through the vessel wall directly into adventitial tissues, where it destroys the renal nerves (both catheter and drug are FDA approved).
• The OneShot system (Maya Medical/Corvidien, Saratoga, CA), which features a balloon platform to deliver RF energy in a single, consistent movement.

Other large players are poised to enter the field,Dr. Rocha-Singh reported, setting up the likelihood of future rounds of lawsuits to settle issues of intellectual property rights.

While growing competition bodes well for progress in the field, Dr. Bhatt cautioned that, just as with the introduction of novel stents, each new iteration of denervation technology should be evaluated independently.

Beyond Resistant Hypertension: Natural Progression or Slippery Slope?

Though numbers are hard to pin down, drug-resistant hypertension is probably present in about 10% of Americans with high blood pressure, or about 7 million people, Dr. Townsend said. But many renal denervation advocates are also excited by the prospect of extending the procedure to a wider spectrum of hypertensive patients as well as by signals that it may play a role in treating an array of other sympathetic-mediated conditions.

While not opposing broader application in principle, Dr. Bhatt cautioned against overselling the procedure, especially while it is still in the early stages of evaluation. “We need to insist upon high-quality data before just going out there and doing it, as is already occurring in some parts of the world,” he said.

Ideally, a balance must be struck between giving a new procedure free rein and holding back innovation, he said. With the novel TAVR procedure, for example, a kind of dual track worked, he commented, whereby the early European experience accurately foreshadowed what was ultimately shown in the US randomized PARTNER trial. But the 2 experiences might very well have diverged, he noted.

Dr. Esler said that thus far in Australia, potential candidates for denervation typically have been filtered through hypertension specialists. But in Germany, he reported, some patients are “just being treated on the basis of direct referral to interventionalists—even sometimes through self-referral.

“Once things get into the hands of interventional cardiologists, who are a rather intrepid bunch, it’s clear the [patient eligibility] rules will be relaxed,” Dr. Esler suggested. Signs that this is already happening include denervation of multiple renal arteries on one side and treatment in the vicinity of renal stenosis, he noted.

More important, Dr. Esler said, some clinicians are starting to offer the procedure to patients with milder forms of hypertension. In fact, in Europe off-label use may be approaching 25% to 35%.

Dr. Esler said his group in Melbourne is now setting up trials of patients with various categories of moderate hypertension. “If the safety data hold up, we may even be emboldened to test the procedure” in patients with mild hypertension who cannot tolerate medications, are not compliant, or simply strongly oppose taking drugs, he observed.

Dr. Esler acknowledged, however, that in these groups blood pressure reductions may not match those seen in drug-resistant patients. “The renal injury that is thought to activate the sensory afferent nerves [which carry nerve signals to the brain and are key contributors to severe hypertension] may be absent in milder grades,” he observed. “We’ll have to see.”

Moreover, Dr. Bhatt pointed out, the bar for avoiding procedural complication would be higher for such patients, since in many cases encouraging better compliance or prescribing a more tolerable antihypertensive agent might enable them to control their blood pressure.

“There are perhaps millions of patients like that in the United States,” Dr. Bhatt observed. “And while it would be great for cath labs if all of them needed renal denervation, the economic consequences would be profound. It would be important to rigorously study denervation in those patients before just doing it because a patient wants it.”

And yet, he conceded, if the procedure enabled patients to control hypertension early in its course, that would have a major impact on reducing future adverse consequences. So the issue is worth investigating, he concluded.

An Expanding Horizon of Potential Applications

Already, researchers are training their sights on several conditions beyond hypertension that share an underlying involvement of sympathetic nerve overactivity and affect a large and growing population, said Dr. Townsend. In fact, he added, denervation proponents are beginning to feel as if they “have a hammer in their hands and are looking at a series of nails.”

According to Dr. Esler, perhaps the next logical target is heart failure. In this condition, renal sympathetic nerve activity has been shown to be a strong predictor of mortality, he observed, “so there’s a strong theoretical basis to think that ablating these nerves might be helpful.”

REACH, a British pilot study of patients with chronic heart failure, has already provided early signals of benefit, Dr. Esler reported. And Medtronic has announced the phase 2 Symplicity HF trial in Europe and Australia to test the safety and efficacy of renal denervation in about 40 patients with systolic heart failure and renal impairment.

Already, in a recent study of patients with hypertensive heart disease (Brandt MC, et al. J Am Coll Cardiol. 2012;59:901-909), renal denervation significantly reduced left ventricular mass and improved diastolic function—a more robust effect than has been achieved with medication, the authors noted. And in a pair of patients with chronic heart failure suffering therapy-resistant “electrical storm,” denervation helped control ventricular tachycardia without reducing already low blood pressure (Ukena C, et al. Clin Res Cardiol. 2012;101:63-67).

In addition, common conditions like obesity, insulin resistance, and metabolic syndrome—often precursors of diabetes—are also drawing attention as potential targets for denervation because of their association with sympathetic overactivity, Dr. Esler said.

In fact, preclinical evidence suggests that renal denervation may improve glucose uptake in skeletal muscle. And in a recent pilot study (Mahfoud F, et al. Circulation. 2011;123:1940-1946), the procedure not only reduced patients’ resistant hypertension but also improved impaired glucose tolerance and insulin resistance.

And in a small study (Witkowsky A, et al. Hypertension. 2011;58:559-565), renal denervation improved obstructive sleep apnea, perhaps by reducing fluid retention. Sleep apnea, often present in obese hypertensive patients, is thought to both contribute to and be exacerbated by sympathetic nerve activity.

“In real life, many of these [conditions] cluster together, so if one procedure could tackle multiple cardiovascular risk factors simultaneously, that could in theory have a profound impact on hard outcomes,” Dr. Bhatt observed.

Great Promise Requires Great Care

Clearly, renal denervation has generated “a lot of excitement in the interventional community, and deservedly so,” said Dr. Bhatt. “But that’s exactly why we want to be cautious and make sure that it is evaluated rigorously and that there aren’t any untoward side effects.

“Otherwise,” he continued, “we could be in a situation where we have a technology that patients are demanding and that cath labs are happy to provide—but we don’t really know whether it’s the right thing to do, for the patient and the health-care system.”

 

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Disclosures:

• Dr. Esler reports serving as principal investigator for the Symplicity HTN-2 trial and receiving research grants and consulting fees from Ardian and Medtronic.
• Dr. Bhatt reports receiving research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi-Aventis, and The Medicines Company and serving as coprincipal investigator for the Symplicity HTN-3 trial.
• Dr. Townsend reports serving on the US advisory board for the Symplicity HTN-3 trial.
• Dr. Rocha-Singh reports serving as a consultant for CardioSonic, Medtronic, and Vessix Vascular.

Related Stories:

• Symplicity Itself: Endovascular RF Ablation Lowers Resistant Hypertension
• Novel Catheter-Based Treatment Reduces Resistant Hypertension
• Endovascular Renal Nerve Ablation Safely Reduces BP During Exercise

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