In a 2-part series, TCTMD looks at the concept behind renal denervation and the enthusiasm generated by early data showing a significant impact on resistant hypertension. It also explores the need for rigorous clinical testing and disciplined application of the new technology. Finally, it takes note of signals that denervation may play a role in treating a broad range of conditions related to sympathetic nerve overactivity.

Renal denervation is one of the fastest-moving new areas in interventional cardiology. The innovative catheter-based procedure for treating resistant hypertension has gone from proof-of-principle studies in 2009 to rapid approval and uptake in Europe and Australia, even being hailed as the top medical innovation of 2012 by the Cleveland Clinic. But as proponents begin to assess the procedure for a host of related conditions, many are urging caution as clinicians outside the United States forge ahead.

The main reason for such remarkable progress and optimism is that renal denervation has been shown to lower blood pressure dramatically in patients with drug-resistant hypertension—individuals who have few options and face increased long-term cardiovascular risks. Moreover, it does so safely, employing relatively straightforward interventional technique.

Sympathectomy Tamed

Proof of the concept behind renal denervation dates from the 1920s and 1930s, when various forms of radical surgical sympathectomy were shown to produce profound reductions in blood pressure. But the procedures were unpredictable and often caused severe hypotension, with side effects such as dizziness and bladder and erectile dysfunction. With the advent of more effective antihypertensive agents in later decades, surgery was largely abandoned.

Recently, however, the concept of sympathectomy was given new life as use of renal catheterization opened the possibility of selective denervation, thanks to the accessibility of the sympathetic nerves in the renal artery adventitia. 

Renal Denervation 101

The pioneering denervation device, the Symplicity system (originally Ardian, now Medtronic, St. Paul, MN), consists of a 6-Fr catheter attached to a radiofrequency (RF) generator. After gaining femoral access, the operator navigates the catheter to a renal artery and advances the electrode-equipped tip just beyond the first bifurcation. As the catheter is retracted and rotated, 4 to 6 applications of low RF energy, each lasting about 2 minutes, ablate the nerves in a helical pattern. The same procedure is then repeated in the contralateral renal artery. The entire procedure takes about 40 minutes.

One drawback of Symplicity is that, apart from an impedance signal showing contact with the vessel wall, operators receive no immediate feedback that the nerves have in fact been ablated. The patient’s reporting of back pain is a signal that the afferent sensory nerves to the brain have been damaged, Krishna Rocha-Singh, MD, of Prairie Vascular Institute (Springfield, IL), told TCTMD in a telephone interview, but that does not account for the other key component of sympathetic activity, the efferent nerves to the kidneys. “In the cath lab, we don’t have real-time indicators to be able to say, ‘Hey, we’ve killed enough nerves, let’s take off the gloves and go home,” he commented.

Interestingly, Dr. Rocha-Singh observed, while operators were initially concerned about delivering too much RF energy during a procedure, “we have now evolved in our experience to the more zaps, the better.”

Engineers are at work trying to develop a renal artery catheter that can measure sympathetic nerve activity in the vessel wall, providing operators reliable online information about the effect of RF applications, reported Murray D. Esler, MD, of the Baker IDI Heart and Diabetes Institute (Melbourne, Australia), in a telephone interview with TCTMD.

Trial Evidence Builds

Three years ago, data emerged from a small feasibility study (Krum H, et al. Lancet. 2009;373:1175-1181) showing that among 45 drug-resistant hypertensive patients who underwent denervation with an early Symplicity catheter, office-based blood pressure decreased by 27 mm Hg systolic/17 mm Hg diastolic at 12 months, although the systolic decline was less than half that in a subgroup whose blood pressure was assessed with more reliable ambulatory monitoring.

With a few exceptions, denervated patients remained on an average of 4.7 blood pressure medications. However, per protocol, physicians were instructed not to alter the regimen unless clinically necessary. “Also, bear in mind that these people likely had been hypertensive for many years,” noted Raymond R. Townsend, MD, of the University of Pennsylvania (Philadelphia, PA), in a telephone interview with TCTMD. Over time, their vessels adapted to the higher pressure, and it may take about 2 years for the vessel wall hypertrophy to regress enough to permit withdrawal of some medications, he explained.

Meanwhile, from a physiological standpoint, testing in a subgroup of patients showed a sharp reduction in noradrenaline spillover, indicating that efferent nerves had in fact been ablated.

Follow-up of these and similar hypertensive patients (n = 153), reported at the American College of Cardiology (ACC)/i2 Scientific Session in March 2012, showed that roughly the same blood pressure reductions were sustained out to 3 years. Importantly, by the end of the study period, all patients had at least a 10 mm Hg decline in systolic pressure from baseline.

The substantial reduction seen in most patients has a major clinical payoff. “If you can knock 25 or 30 mm Hg off the systolic pressure, you’ve reduced the likelihood of a future stroke or heart failure by 50%,” Dr. Townsend said.

“It would be ideal if denervation were durable 10 years or more,” commented Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), in a telephone interview with TCTMD. “But even if you can reduce somebody’s systolic blood pressure by 20 mm Hg for a few years, that’s better than we can achieve on [drug] monotherapy, especially if you factor in how few patients are no longer on their medications a year after starting.”

In the only completed randomized trial to date, the multicenter Symplicity HTN-2 trial, 52 patients who underwent denervation while maintaining their antihypertensive regimen were compared with 54 patients who simply continued on antihypertensive agents. At 6 months, office-based blood pressure in the denervated group had declined by 32 mm Hg systolic/12 mm Hg diastolic compared with virtually no change in controls. Overall, 84% of denervated patients achieved a systolic reduction of at least 10 mm Hg. No serious procedure- or device-related complications were seen, and adverse events did not differ between the groups.

In a 1-year update of the trial presented by Dr. Esler at the ACC-i2 Scientific Session in March 2012, 35 control patients who crossed over to denervation at 6 months reduced their blood pressure substantially (by 27.5  mm Hg systolic/8.4 mm Hg diastolic) but somewhat less than the original denervation group, suggesting that there may be a penalty for delaying intervention.

Reassuringly, recent data from an extension of Symplicity HTN-2 (Ukena C, et al. J Am Coll Cardiol. 2011;58:1176-1182) showed that denervation also reduces high blood pressure without impairing exercise capacity or recovery.

Symplicity HTN-3 Adds Rigor to Randomization

Over the past 2 years, renal denervation has been approved in Europe, Australia, and New Zealand despite a paucity of randomized data, and early adopters have sometimes stretched patient selection criteria set in trials and experimented with alternative technologies. Against this backdrop, in October 2011 Medtronic launched a US pivotal trial of renal denervation with the Symplicity system. Aiming to enroll more than 500 patients at 60 centers, Symplicity HTN-3 will be the largest—and most rigorous—test of the procedure thus far, noted Dr. Bhatt, who serves as co-principal investigator.

For example, candidates will be assessed by a multidisciplinary team including a hypertension expert and an interventional cardiologist to ensure that they meet strict eligibility criteria.

In addition, a major effort is being made to exclude confounding by ‘pseudoresistance,’ due to uneven medication adherence or so-called white coat hypertension. In the latter case, that means applying the ‘reality check’ of ambulatory blood pressure monitoring. Moreover, before patients can be enrolled, any secondary causes of hypertension must be identified and treated.

Most important, patients must have an office systolic pressure of at least 160 mm Hg while on at least 3 different antihypertensive medications, including a diuretic, at maximally tolerated doses. In fact, noted Dr. Townsend, investigators “will be bending over backward” to make sure potential participants’ hypertension has been well managed, which often includes prescription of an aldosterone receptor antagonist such as spironolactone, a drug that was underrepresented in the Symplicity HTN-2 population.

Countering a widely cited limitation of the earlier studies, control subjects will be given a sham procedure. This minimizes the possibility of a placebo effect, which can be substantial in hypertension therapy, Dr. Esler noted. In addition, both patients and assessing doctors will be blinded to the treatment given.

The main results are expected in early 2013, although patients will be followed for 3 years.

Dr. Bhatt cautioned that the blood pressure reductions emerging from Symplicity HTN-3 are likely to be less pronounced than those in earlier studies. “Anytime you do a larger trial with a more diverse patient population and diverse operators—especially if it is blinded and properly controlled—there is almost always a lower effect size than in preliminary studies,” he said. “But that’s OK, because any significant reduction that seems to be sustained for at least 2 years has a potential role in clinical medicine.”

With many questions about renal denervation unanswered, it is all the more important to evaluate the procedure in a rigorous manner, Dr. Bhatt observed. “If we have a bunch of cowboys out there just doing this on their own, there almost certainly will be bad side effects and complications. And that could harm not only patients but the entire field,” he added.

“My hope is that the FDA will base its approval decision on the primary endpoint of 6-month blood pressure data,” Dr. Bhatt said. “But ongoing follow-up will be important to enable the medical community to get a sense of how durable the effect is and whether there are any late complications.” 

Keeping Track of the Real World 

Noting that many European operators are already expanding their practice beyond the strict patient eligibility boundaries set by Symplicity HTN-2, Dr. Bhatt said “the situation feels a bit like TAVR, where the definitive PARTNER trials were led by the United States. Similarly, Symplicity HTN-3 will in a rigorous way really nail down what the effect of denervation is.” At the same time, “there will be much experience outside the United States before interventionalists here get their hands on the technology,” he added. 

At least with the recent launch by Medtronic of the Global Symplicity Patient Registry, comprehensive ‘real-world’ data on longer-term safety and efficacy as well as clinical outcomes will now be collected on some 5,000 patients at about 200 centers worldwide. Of course, data from procedures performed with other devices will not be included, Dr. Esler noted. 

The second half of this feature, which will appear June 11, will address questions of  longer-term safety and efficacy and the potential for extending the therapy  to everyday hypertension and a cluster of sympathetic-related conditions such as heart failure—as well as the risk of overzealous dissemination.

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

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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