Update on the renal denervation market

By Larry Haimovitch

Medical Device Daily Contributing Writer

November 4, 2013

SAN FRANCISCO —  Less than three years ago, Medtronic (Minneapolis) jolted the med-tech world with the $800 million cash (plus potential earnouts of another $500 million) acquisition of privately-owned, venture capital-funded Ardian (Mountain View, California). Generally unheralded, Ardian had pioneered a catheter-based procedure called renal artery denervation (RDN) for the treatment of resistant hypertension (RH).

Over the past couple of years, a body of clinical evidence has developed showing that RDN can indeed significantly reduce blood pressure in patients with RH. The most important study with data has been Medtronic’s SYMPLICITY HTN-2 trial, which is a randomized, controlled clinical trial of 106 patients at 24 centers in Europe, Australia and New Zealand.

The three-year results for SYMPLICITY HTN-2 trial, which were released here, continue to demonstrate results consistent with data reported previously at six, 12 and 24-months of follow-up. The data showed an average systolic blood pressure reduction of  33 mm Hg from baseline and an overall response rate (systolic blood pressure drop of greater than or equal to 10 mm Hg) for 85% of the patients. Despite a mean systolic blood pressure of 184 mm Hg pre-denervation, 50 percent of these patients achieved the goal of systolic blood pressure of less than 140 mm Hg.

The safety profile of renal denervation with the Symplicity system was also maintained at three years, with no newly reported device or procedure related serious adverse events.

In his TCT presentation, Robert Whitbourn, MD, associate professor and director of the Cardiovascular Research Centre at St. Vincent’s Hospital (Melbourne, Australia) stated that  “these data are an important contribution to the growing body of evidence supporting renal denervation with the Symplicity system as a therapy option for this underserved population.”

Medtronic completed enrollment for its pivotal SYMPLICITY HTN-3 trial in May 2013. The trial enrolled 535 patients at 90 U.S. sites and the results, which are keenly anticipated, are expected to be available during the first half of 2014. Medtronic is the clear RDN market leader at this juncture, its renal denervation system is backed by over five years of clinical experience in more than 5,000 patients and is available in more than 80 countries throughout the world.

Further confirming the momentum of RDN was the positive results of the St. Jude Medical (STJ; St. Paul, Minnesota) small (46 patients) EnligHTN-1 study. This prospective, multi-center trial, like SYMPLICITY HTN-2, showed excellent safety and efficacy with the average patient achieving a 22 mm Hg drop in blood pressure at 18 months. Like the Medtronic device, St. Jude’s is based on RF energy. However, STJ believes that its unique basket design has the potential to improve procedural accuracy and reduce the procedure time.

St. Jude attained CE Mark approval in June 2012 and in June 2013 launched the pivotal EnligHTN-IV trial in the U.S., with the plan to enroll 590 patients at 80 sites in North America.

Another major med-tech player, Boston Scientific (Natick, Massachusetts) joined the RDN sweepstakes in November 2012, acquiring privately-held Vessix Vascular (Laguna Hills, California) for $125 million in cash plus additional potential milestone payments.

Solid results of the non-randomized, prospective single cohort REDUCE-HTN trial, which enrolled 146 patients at 23 centers in Europe, Australia and New Zealand were provided here. Specifically, 85 percent of patients treated with the Vessix RF-based system experienced a clinically meaningful decrease in blood pressure. There was an approximate significant 25 mm Hg reduction in systolic blood pressure at six months and a sustained 30 mm Hg reduction in systolic blood pressure in the subset of patients for whom 12-month data are available.

Horst Sievert, MD, director of the Cardiovascular Center, Sankt Katharinen Hospital (Frankfurt, Germany) and the principal investigator in the REDUCE-HTN clinical program noted that this is the only renal denervation system to utilize bipolar energy, which he said will “provide a more localized, precise and most importantly more rapid ablation of the renal nerves.”

The Vessix System has both CE Mark and is currently available for sale in Europe, the Middle East, Australia, New Zealand and select markets in Asia.  The Vessix System has not been approved as yet for any clinical studies in the United States.

Yet another RF system in clinical development is the Covidien (Dublin, Ireland) OneShot irrigated balloon. Covidien joined the RDN race in May 2012, purchasing Maya Medical (Campbell, California) for $60 million cash upfront. It will pay up to an additional $170 million if Maya meets certain regulatory and sales milestones. The OneShot RF system received the CE Mark in February 2012.

Stephan Verheye, MD,  from the Antwerp Cardiovascular Institute  (Antwerp, Belgium) presented data here that was almost a mirror image of the other RF approaches, i.e., solid safety along with a significant reduction in systolic blood pressure in about two-thirds of the patients.

Whereas all four med-tech giants are pursuing the RDN market via catheter delivered RF energy, a privately-funded company, Kona Medical (Bellevue, Washington) has developed a non-invasive ultrasound system called Surround. A key advantage of this approach is that the energy to ablate the renal nerves is given from an external source, eliminating the need for a cath lab procedure.

At an RDN session here, Petr Neuzil, MD, head of cardiology at Homolka Hospital (Prague) noted that two early international feasibility trials, aptly dubbed WAVE-1 and WAVE-II, have demonstrated the system is both safe and effective. A total of 42 patients have been treated in these two trials and a third larger offshore trial, called WAVE-III, will begin after the optimal dosage level is determined.

Neuzil pointed to several potential advantages of this approach, including lower cost, a better safety profile and the possibility of expanding RDN to the moderately hypertensive population. He admitted that the biggest issue at this juncture is peri-procedural pain, which may require the need for conscious sedation for most patients.

Thus, it seems abundantly clear that RDN is both a safe and effective procedure. But, how big will the RDN market ultimately be? No doubt the RH population is huge, conservatively estimated by several industry analysts at 40 to 60 million persons. However, what is the true opportunity?

A study of nearly 1800 outpatients that appeared at the Emory Healthcare (Atlanta) clinic over a six-month period was presented at this year’s annual scientific sessions of the American College of Cardiology (Bethesda, Maryland). The goal was to determine which patients would be eligible for RDN based on the strict SYMPLICITY HTN-3 trial inclusion and exclusion criteria.

The conclusion of the study was that “patients meeting criteria for RDN based on published studies represent an exceedingly small proportion of the total hypertensive population.” Specifically, the authors indicated that less than 1% of the hypertensive patients in their clinic, if being screened today, would qualify for RDN.

Another RDN study was reported in the December 11, 2012 issue of the Journal of the American College of Cardiology. A retrospective analysis of over 3000 consecutive patients hospitalized for at least one day during 2011 at the Vascular Medicine and Hypertension Unit of the Hôpital Européen Georges Pompidou (Paris) found that only 15 patients or less than 1% of total hypertensive patients (17.2% of those with resistant hypertension) seemed to be fully eligible for renal denervation. The authors concluded that RDN is limited to "a highly selected fraction of patients with resistant hypertension, even in a specialist hypertension unit.”

In a subsequent interview with one of the physicians, it was noted that “about one half of our patients refused to participate in our trial.” Various reasons may account for this but foremost, many patients were reluctant to go ahead with a procedure after the doctor suddenly says, "We are going to put a catheter into your renal artery, it will be painful, you may need general anesthesia, and we are going to deliver low-level radiofrequency energy to destroy nerves in the renal artery."

TCT 2013

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