One of the exciting new frontiers for interventional cardiology is the use of renal denervation therapy to treat pharmacologically uncontrolled hypertension. The American Heart Association estimates more than 75 million people in the United States have high blood pressure, and the economic costs to treat these patients exceed $50 billion annually. Despite public awareness and the availability of numerous pharmaceutical therapies, only about half of all treated hypertension patients achieve adequate blood-pressure control. Compounding the problem is that between 10 and 20 percent of this population have drug-resistant or refractory hypertension. It is estimated there are more than 10 million drug-resistant hypertension patients in the United States, so renal denervation (RDN) may offer a massive new market for cath labs to tap into.
A normal blood pressure is typically at or below 120 systolic and 80 diastolic (120/80 mmHg). Hypertension is blood pressure greater than 140/90 mmHg. The risk of cardiovascular death is cut in half with every 20 mmHg decrease in systolic blood pressure. Clinical data from several RDN trials to date have shown an average reduction of about 25 mmHg.
A hyperactive sympathetic nervous system is believed to be a major contributor to hypertension. The concept of denervation is to use catheter ablation to kill the sympathetic nerves in the outer adventitial layer of the renal arteries. This overrides the body’s regulation of vasoconstriction in these arteries, keeping them open for improved blood flow into the kidneys. Technologies developed for renal artery ablation include catheters delivering radiofrequency (RF) energy, ultrasound energy or drugs.
The Symplicity Catheter Opens the Flood Gates
The concept of disrupting the sympathetic nervous system in the renal arteries to control hypertension had been discussed theoretically for several years. The concept, however, rapidly gained attention and validity after start-up company Ardian showed study data in 2010 that its Simplicity RDN catheter system could deliver rapid and sustainable drops in blood pressure.
Soon after the release of that data, Medtronic further focused attention on RDN by purchasing Ardian for $800 million — a company that had not commercialized any products. Medtronic had previously invested several million in the company in 2009. Since 2010, several other companies developed or purchased RDN systems, including Covidien, St. Jude Medical and Boston Scientific.
The FDA approved the Symplicity HTN-3 in August 2011, which was the first U.S. clinical trial l for a RDN system. Enrollment in this study was expected to be complete by the summer of 2013. The single-blind, randomized, controlled trial was designed to evaluate the safety and effectiveness of the Symplicity system in patients with drug-resistant hypertension. The study randomized 530 patients at 90 U.S. medical centers. Patients in the clinical trial will be randomized to receive either RDN and treatment with anti-hypertensive medications or treatment with anti-hypertensive medications alone. The primary endpoints of the study are the change in blood pressure from baseline to six months following randomization and incidence of major adverse events one month following randomization.
The U.S. Food and Drug Administration (FDA) and the Centers for Medicare and Medicaid Services (CMS) announced in March that they accepted the inclusion of the Symplicity system in their parallel review program. This will allow CMS to begin consideration for national coverage determination while the FDA completes its review of safety and efficacy. The Symplicity system is one of the first medical devices to participate in the pilot program for concurrent review, designed to facilitate the development of innovative new products and increase the efficiency of the review processes for both agencies. The two federal agencies accepted the Symplicity renal denervation system into the parallel review pilot program through a selection process that was limited to a few innovative devices per year. The parallel review will be based primarily on results from Symplicity HTN-3 trial.
Outside the United States, in 2012, Medtronic launched the Global Symplicity patient registry, which will evaluate the real-world, long-term impact of renal denervation in more than 5,000 patients, as well as the Symplicity-HF trial, the first trial to look at RDN in patients with chronic heart failure and renal impairment.
New Designs to Simplify the Procedure
One issue with the original Symplicity catheter is that it required multiple ablations, each time requiring the catheter to be rotated to create a continuous lesion. To simplify this procedure, St. Jude Medical, Covidien and Boston Scientific developed new catheter designs that simplify and shorten the procedure.
Covidien’s OneShot system uses a unique electrode design, which is wrapped in a spiral around a balloon to allow procedures to be completed in a single ablation of each renal artery. The over-the-wire, balloon-based system also has irrigation ports on either side of the electrode to cool the tissue as the lesion is formed. The balloon can be filled with contrast to show if it is fully opposed before beginning the ablation.
Covidien received the CE mark in February 2012 and began its European market launch of the OneShot system in January 2013.
St. Jude’s EnligHTN system uses a basket catheter containing four electrodes, one on each strut of the basket. The struts expand to contact the electrodes with the vessel wall. Each electrode is then activated separately for 90 seconds. The catheter is then pulled back and rotated 45 degrees and a second set of ablations are made.
The EnligHTN III trial, announced in May, is an international, nonrandomized study evaluating the safety and performance of the next-generation EnligHTN system. Advancements include the ability to deliver simultaneous ablations and an intuitive touch screen generator, potentially enabling faster procedure times. These features reduce the total ablation time from 24 minutes to just four minutes. The EnligHTN III study will enroll up to 50 patients with drug-resistant, uncontrolled hypertension at sites in Australia and New Zealand.
St. Jude received CE mark approval and began its European launch of the EnligHTN in May 2012. It is the second RDN system to enter U.S. trials in an attempt to gain FDA approval. In June, the FDA granted approval to begin the EnligHTN IV, a randomized, single-blind, controlled, multi-center trial to demonstrate the safety and effectiveness of the system in reducing systolic blood pressure when measured in an office setting. The study will enroll approximately 590 patients between the ages of 18 and 80 with an office systolic blood pressure of 160 mmHg or greater, who are taking three or more anti-hypertension medications including a diuretic. Study patients will be enrolled at up to 80 sites in the United States and Canada.
St. Jude Medical is conducting several other studies to add to the body of evidence supporting the potential of the new therapy. The EnligHTN I trial of 46 patients in Australia and Greece showed a rapid and sustained drop in blood pressure. After 30 days, systolic blood pressure was rapidly reduced by an average of 28 mmHg. At six months, it remained stable with an average reduction of 26 mmHg
The EnligHTN II trial is being conducted at 40 sites in Europe and Australia and will enroll about 500 patients with less severe forms of hypertension, specifically, blood pressure readings greater than 140 mmHg. The study began enrollment in January 2013 to evaluate the reduction in systolic blood pressure at six months across all enrolled patients after having renal denervation, and within subgroups with varying degrees of kidney functionality.
The EnligHTNment trial is the largest randomized, prospective clinical study ever conducted for renal denervation. It will enroll about 4,000 patients around the world at up to 150 sites to evaluate the long-term effects of renal denervation using the EnligHTN system in patients with uncontrolled hypertension to see if there is also a reduction in risk of major cardiovascular events such as heart attack, stroke, heart failure requiring hospitalization and cardiovascular death.
Boston Scientific acquired Vessix Vascular and its V2 RDN system for $425 million in late 2012. It had already received CE mark in Europe and TGA approval in Australia. The V2 system has multiple electrodes mounted on a balloon catheter, the use of which is already familiar to interventional cardiologists and vascular specialists. It has an easy-to-use push-button interface and a 30-second treatment time.
In June, Boston Scientific reported interim data from the REDUCE-HTN clinical program, which demonstrated a significant and sustained reduction in the blood pressure of patients treated with the system. Data on the first 41 subjects enrolled in the program were presented at EuroPCR. Highlights included that all patients underwent successful bilateral renal denervation treatment and, at the primary endpoint of six months, patients experienced a significant 27.6 mmHg reduction in systolic blood pressure. No device-related adverse events or procedural renal artery complications were reported. Long-term efficacy was demonstrated, with a sustained 28.4 mmHg reduction in systolic blood pressure in the subset of patients for whom 12-month data are available
“Medtronic has a several year lead on the other vendors,” said Krishna Rocha-Singh, M.D., Prairie Heart Institute, Springfield, Ill., and a leader in the renal denervation field. He said Medtronic just completed its Symplicity HTN-3 trial and will likely submit the data for FDA review in 2014.
He said St. Jude Medical and Boston Scientific also will likely be major contenders in this market. Rocha-Singh said both have the financial resources and will have U.S. pivotal trials in place by the end of this year.
“Ease of use for the interventionalists is important,” Rocha-Singh said of the technologies being developed. “Doctors are potentially going to like the Boston Scientific system because it is a balloon and over-the-wire system, which they are already familiar with.” But he does have concerns about the potential inability to direct the application of the energy source to avoid areas of renal artery plaque or calcification.
Spiral electrode systems show promise to speed procedure time, according to Rocha-Singh. He noted the third-generation Medtronic Simplicity catheter has a spiral electrode design and is now undergoing trials in Europe.
“The big elephant in the room is going to be when these other systems come into the U.S. market and we will likely see litigation over intellectual property rights,” he said.
Noninvasive External Denervation
Kona Medical’s Surround Sound RDN System may offer a new direction for denervation therapy, delivering ablation energy from the patient’s back, outside the body to eliminate the need to catheterize the patient. Kona’s system delivers targeted ultrasound energy to surround the artery and ablate the nerves located in the vicinity of the vessel.
Australian clinical sites using the technology in the WAVE I clinical trial of the device use an energy delivery time of about 12 minutes per artery. The planned WAVE II trial will reduce this to under three minutes.
In May, the company announced three and six month results from its WAVE I study, a first-in-man study evaluating the safety and efficacy of its Surround Sound system. WAVE I data showed no device-related serious adverse events. The 24 patients in the study experienced a 22 mmHg drop in systolic blood pressure and 9 mmHg drop in diastolic blood pressure at three months. In the 14 patients who had reached six month followups, there was a 29 mmHg drop in systolic blood pressure and 9 mmHg drop in diastolic blood pressure.
Other Systems in Development
The latest company to enter the RDN fray is Mercator MedSystems, which plans to use its Micro-Infusion drug delivery platform to deliver nerve modifying agents to the renal arteries. In late July the company announced it secured U.S. patents to expand the treatment portfolio of the system for this use. Mercator’s Micro-Infusion devices are currently used for treating peripheral artery disease (PAD), cardiovascular diseases and pulmonary disease, along with the delivery of stem cells.
ReCor Medical received the CE mark for its Generation-2 Paradise RDN system in January 2013. It offers a 6 French over-the-wire ultrasound device designed to optimize nerve damage through a 30-second energy delivery, while maximizing endothelial protection with a cooling mechanism. It is the only CE-marked system for RDN that is based on ultrasound, not radiofrequency (RF), energy. ReCor said the system offers the advantage of deeper tissue penetration to where the majority of the nerves are located. It also delivers heat circumferentially, to target all of the renal nerves in one location.
Cardiosonic Inc. completed its first phase of patient enrollment in its first-in-man TIVUS I clinical study in April. The study is designed to collect data on the safety and performance of the Tivus RDN system, which uses a high-intensity, non-focused therapeutic ultrasound catheter. The study enrolled the first five patients at Royal Perth Hospital (RPH), Australia and patient screening continues.
Sound Interventions Inc. completed its first-in-human study of its focused ultrasound RDN system in May 2012 in the Czech Republic.
Beyond the Renal Arteries
One issue Rocha-Singh foresees is once RDN systems gain FDA market approval, physicians will begin using them off-label for conditions other than hypertension. He said the success of RDN has spurred interest in other areas that may benefit from sympathetic denervation therapy, where there is little data so far to support its use.
The original developers of Ardian RDN therapy have created a new start-up company called Cibiem to expand the denervation concept to other disease states. Its Carotid Body Modulation (CBM) RF ablation catheter system is designed to treat sympathetic nervous system-mediated diseases such as hypertension, heart failure, diabetes and renal failure. The therapy focuses on the modulation of the carotid body, which is a key chemosensory located at the fork of the carotid artery that helps regulate respiratory activity.