Renal Denervation: Where Are We?

Murray Epstein, MD


July 01, 2015

When Hypertension Drugs Fail

Helping patients reach their blood pressure goals can be difficult in some cases. Resistant hypertension is defined as a blood pressure that remains above goal despite the concomitant use of full doses of three or more antihypertensive drugs from different classes.[1] Depending on the populations studied and the methods applied, the prevalence of treatment-resistant hypertension has been reported to be from 10% to 15%.

As a result, there has been increasing interest in developing device-based therapeutic strategies that target the sympathetic nervous system, including surgically implanted barostimulator devices and catheter-based renal denervation (RDN) devices. In this commentary, I will focus on the potential attributes and shortfalls of RDN.

The rationale for RDN rests on a strong neuroscience foundation comprising excellent studies by Murray Esler, Gerald DiBona, and Vito Campese.[2,3,4] These investigators have clearly demonstrated that renal sympathetic nerves contribute to both the development and the maintenance of hypertension; their attention has focused on interventions to counter or quiet renal sympathetic tone. On this foundation, catheter-based RDN has emerged recently as a potential treatment modality for resistant hypertension. Smaller, nonrandomized studies have shown that RDN is capable of lowering blood pressure in patients with resistant hypertension.

The recent SYMPLICITY HTN-3 trial was initiated to fill this gap in supporting evidence. As many readers know, the launch of the study was met with great enthusiasm and optimism; in Rudyard Kipling's words, like "the dawn comes up like thunder outer China."

The hype accompanying the study was fast and furious. Dr Mehmet Oz, host of the nationally syndicated television talk show, reflected the premature excitement.[5] Dr Oz commented that "there is reason for a happier New Year" (if one has hypertension), adding that promising results were awaited in 2012 from the "large SYMPLICITY trial. However, he failed to caution his audience that if one has hypertension, the disorder must be resistant to antihypertensive treatment consisting of "full doses" of three medications (including a diuretic) in order to be considered for the procedure.

In the end, it was clearly inappropriate of Dr Oz to extrapolate the benefits of this one specialized procedure to an entire group of patients with hypertension. Most of these patients, in fact, would not even qualify for renal arterial ablation therapy. Rather, they should seek care from their physicians. If a patient's blood pressure is abnormally elevated, then that person should receive the appropriate class of antihypertensive medication as treatment.


Well what of SYMPLICITY HTN-3? Unfortunately, as reported by the trial sponsor in January 2014,[6] and subsequently in the New England Journal of Medicine,[7] this study failed to meet its primary efficacy endpoint.

There are several factors that may explain this; I believe that they are multifactorial and include inadequate screening at entry with resultant lack of certitude that the enrollees had "true" resistant hypertension. Additional problems included the glaring lack of experience of many operators with the SYMPLICITY device and excessive procedure variability. These shortcomings are readily attested to by the large number of patients in the clinical trial who had a reduced number of ablation "quadrants."

Does the failure of SYMPLICITY HTN-3 constitute the "end of the road" for renal denervation? I believe the answer is a resounding NO.

While adopting an optimistic tenor, I believe that if we learn from the mistakes of SYMPLICITY HTN-3, RDN may well be a viable intervention to manage select patients with resistant hypertension.

The Promise of New Devices

In considering the future of renal denervation, the most important question is whether we are to remain "shackled" to the use of the first-generation device, which has several drawbacks. Although the catheter is easy to maneuver, the exact positioning of burns is difficult with conventional fluoroscopic guidance. Furthermore, the earlier SYMPLICITY catheter does not allow a physician to perform four ablations simultaneously, so the procedure is long and tedious.

Fortunately, the recent resurgent interest in renal denervation, coupled with the earlier success of the SYMPLICITY HTN-1 and -2 trials, has helped spur multiple new start-up companies with newer technologies to successfully accomplish RDN. The next-generation RDN catheters have attributes that circumvent some of the drawbacks of the earlier SYMPLICITY device.

Additionally, investigations are currently underway on several alternative devices with catheters that allow multiple, simultaneous, spatially arranged focal burns with radiofrequency or ultrasound energy during a single treatment of each renal artery.

An additional innovation involves catheters that facilitate microneedle delivery of guanethidine or ethanol. These have also shown excellent promise. Collectively, these newer catheter-based technologies may offer the advantages of shorter procedure times and less patient discomfort.

The most futuristic of the RDN systems are noninvasive, delivering externally focused ultrasound energy to the renal nerves using Doppler-based ultrasound image guidance to track and correct for renal artery motion during treatment. This approach has shown promise in early trials and animal studies.

What does the future hold for RDN? My answer is that the imminent availability of technologically improved ablation catheters will render the procedure easier, faster, and more likely to be successful. We should anticipate the new RDN clinical trials with great interest and with an optimistic tenor.


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