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Treatment of Refractory Hypertension via Percutaneous Renal Denervation 

Curator: Aviva Lev-Ari, PhD, RN

UPDATED  8/5/2013

VIEW VIDEO – Editorial the Heart.org

Renal denervation: Clinical lessons from around the world

Renal Denervation treatment represents a medical subfield, it has its roots in surgical sympathectomy techniques dating back to the 1930s. This radical approach to blood pressure control, which did not specifically target renal nerves, was ultimately abandoned due to associated perioperative complications. However, experience in renal transplantation, a procedure in which the renal nerves are selectively severed, suggests that the denervated kidney can maintain volume and electrolyte homeostasis.

http://ajpregu.physiology.org/content/298/2/R245.full

http://www.ncbi.nlm.nih.gov/pubmed/3326559?dopt=Abstract

Potential effects of renal denervation are on improved glucose control, sleep apnea, and treatment of heart failure syndromes and renal dysfunction – all consequences of sustained hypersympathetic activity.

Based on these observations, the specific targeting of renal nerves as a major operative in the pathophysiology of hypertension and other conditions associated with increased sympathetic activity (renal dysfunction and heart failure) appears to be an attractive therapeutic approach.

http://bmctoday.net/evtoday/2012/02/article.asp?f=renal-artery-denervation-a-brave-new-frontier

A new therapeutic paradigm of percutaneous renal artery denervation using the application of radiofrequency (RF) energy (Symplicity renal denervation system [Ardian, acquired by Medtronic, Inc., Minneapolis, MN]) has recently been demonstrated to be safe, effective, and durable in significantly reducing systolic blood pressure in patients with resistant hypertension.

This new technology represents the first time that physicians have been able to target renal nerves specifically via a catheter-based intervention. This endovascular approach opens the door to better understanding the relationship between sympathetic hyperactivity and hypertension.

Current therapeutic strategies center on lifestyle changes and pharmacologic interventions; however, the rates of blood pressure control and therapeutic efforts to reduce the rate of progression of hypertensive end-organ damage (resulting in myocardial infarction, stroke, and renal dysfunction) remain a neglected priority.

http://rd.springer.com/article/10.1007/s11906-010-0119-1

Renal denervation is used to treat uncontrolled hypertension, or high blood pressure, by the ablation of the nerves that line the renal arteries using a catheter. The Cleveland Clinic called renal denervation the No. 1 healthcare innovation of 2012. More than 12 million patients worldwide whose blood pressure remains uncontrolled despite taking three or more anti-hypertensive medications representing a global market opportunity for renal denervation that could ultimately grow to $30 billion. The Millennium Research Group estimates that the hypertension-treating devices could generate $4.4 billion per year, Bloomberg reported. That number could swell if the FDA indicates the systems for simple hypertension and not just the drug-resistant sort. As Bloomberg notes, a boom in hypertension devices would be a welcome development for the device industry, which has struggled over the past four years with recalls, litigation and regulatory woes, leading to a 7% decline in Standard & Poor’s Healthcare Equipment Index.

“At least 23 companies, mainly smaller, private companies are developing products,” Wang said, based on information she gathered at the American College of Cardiology Conference in Chicago in March.

http://medcitynews.com/2012/04/medtronic-aside-a-whole-host-of-firms-chasing-hypertension-market/

http://www.fiercemedicaldevices.com/story/bloomberg-hypertension-devices-could-pay-big-us/2012-05-25?utm_medium=nl&utm_source=internal

According to the American Heart Association, a 5 mm Hg (millimeters of mercury) reduction in systolic blood pressure results in a 14 percent decrease in stroke, a 9 percent decrease in heart disease, and a 7 percent decrease in overall mortality. Renal denervation has shown in clinical studies to be safe, durable and effective in reducing systolic blood pressure by as much as 20 percent.

Numerous analysts suggest that there are more than 12 million patients worldwide whose blood pressure remains uncontrolled, despite taking three or more anti-hypertensive medications. This represents a global market opportunity for renal denervation approaching $30 billion.

Procedure Benefits

Hypertension, though often asymptomatic, is the number one risk factor for premature death worldwide.¹ Renal Denervation (RDN) treatment aims to address this condition at its source to provide a substantial and durable reduction in blood pressure. After the procedure, people can often return to their normal activities quickly. The benefit is often achieved after several weeks to months.

Benefits and New Indications for Usage of Intravascular Stimulation/Ablation of Autonomics

1. Reduction in Heart Rate and Heart Rate Variability

Dr. Scherlag experiments noted changes in heart rate which have also been reported in SYMPLICITY HTN-1 and SYMPLICITY HTN-2 (8-9).  The SYMPLICITY HTN-2 study demonstrated profound bradycardia in 13% of patients that was treated with atropine.

The intra-procedure effect on heart rate during renal artery denervation documented in the  SYMPLICITY trials is also manifest long term by measuring heart rate variability (10). Indeed, cardiac effects would be expected with autonomic modulation.  Besides the two example above showing that cardiac sympathetic denervation effects heart rate, there are many more that are just beginning to be reported in the literature.

These articles shows the effects of renal denervation on heart rate.

http://www.ncbi.nlm.nih.gov/pubmed/1735574
http://www.ncbi.nlm.nih.gov/pubmed/8777835

A Cleveland Clinic review article states: “Additionally, the resting heart rate was lower and heart rate recovery after exercise improved after the procedure, particularly in patients without diabetes.”
http://www.ccjm.org/content/79/7/501.full

2. Renal Sympathetic Denervation lowers Atrial Fibrillation

This article discusses the effect of renal sympathetic denervation on atrial fibrillation.

http://www.ncbi.nlm.nih.gov/pubmed/22585944

3. Regression of Left Ventricular Hypertrophy, Increase in Ejection Fraction (EF) and improved Diastolic Dysfunction

“Brandt reported regression of left ventricular hypertrophy and significantly improved cardiac functional parameters, including increase in ejection fraction and improved diastolic dysfunction, in a study of 46 patients who underwent renal denervation. This findings suggests a potential beneficial effect on cardiac remodeling.” (Brandt MC, Mahfoud F, Reda S, et al. Renal sympathetic denervation reduces left ventricular hypertrophy and improves cardiac function in patients with resistant hypertension. J Am Coll Cardiol 2012; 59:901–909)

4. Reduction in Ventricular Tachyarrhythmias (VT)

“Ukena reported reduction in ventricular tachyarrhythmias in two patients with congestive heart failure who had therapy-resistant electrical storm.” (Ukena C, Bauer A, Mahfoud F, et al. Renal sympathetic denervation for treatment of electrical storm: first-inman experience. Clin Res Cardiol 2012; 101:63–67)

5. Intravascular Stimulation of Autonomics Effects on Heart Failure

The most recent data from Europe shows the following effects on heart failure:

http://www.eurekalert.org/pub_releases/2012-08/esoc-rdg082712.php
http://www.theheart.org/article/1364267.do

Dr. Scherlag, writes, [N]early ten examples of the effects of “CARDIAC SYMPATHETIC DENERVATION” and what are the effects on the kidney?

No change in GFR.  No change in creatinine.

http://pharmaceuticalintelligence.com/2012/09/02/imbalance-of-autonomic-tone-the-promise-of-intravascular-stimulation-of-autonomics/

Procedure Risks

Although major complications are uncommon, RDN treatment carries many of the same risks as an angioplasty procedure for the treatment of artery disease. The catheter insertion site could become infected, become bruised or bleed heavily. Other possible complications include heart attack, stroke, kidney damage or malfunction, heart rhythm disturbances, arterial damage, hypotension, sudden cardiac death, burns and pain. Imaging agents, pain medications and anti-spasm agents are commonly used during the procedure and carry known risks.

1. Mathers, C., et al. World Health Organization; 2009

http://www.ardian.com/ous/patients/benefits-risks.shtml

Medical Debate on the Procedure – The candidates are hypertensive patients receiving blood-pressure-lowering medication that are truly “resistant.”

The Symplicity system (Medtronic) is the far-and-away front runner, having demonstrated average office-based BP drops of 32/12 mm Hg at six months in the SYMPLICITY HTN 2 trial, as reported by heartwire, with 84% of patients having had a >10-mm-Hg drop in systolic blood pressure from baseline.

Upwards of 20 other companies, according to Dr Ron Waksman (Washington Hospital, DC), are busy developing competing systems, some of which were featured in a EuroPCR session devoted to emerging technologies in May 2012 in Paris.

Leading this pack is St Jude’s EnligHTN system, which received CE Mark on the opening day of the meeting. Dr Stephen Worthley (Royal Adelaide Hospital, Australia) presented 30-day results in 47 resistant-hypertension patients treated with the multielectrode, RF-ablation-based system. Mean office BP changes at one month in EnligHTN 1 were -28 systolic and -10 diastolic (p<0.0001 from baseline), with 78% of patients having systolic BP drops of >10 mm Hg.

https://www.massdevice.com/news/europcr-st-judes-enlightn-lowers-blood-pressure-faster-rival-systems

In terms of safety, no serious complications were seen in the renal artery or at the access site in the EnligHTN study; minor procedure-related events included four hematomas, three vasovagal responses to sheath removal, and two postprocedure transient bradycardias.

Other devices featured in the session included a second RF-energy system and two ultrasound systems, see below technology description by supplier.

The risk of cardiovascular death doubles with every 20 point increase in systolic blood pressure, so an average blood pressure reduction of 28 points is quite significant and demonstrates just how effective the technology is. Principal investigator Prof. Stephen Worthley said in prepared remarks. “From other clinical trials studying the impact of renal denervation we have learned that blood pressure continues to be reduced over time, so I would not be surprised to see this trend continue and see an even greater benefit for patients.” St. Jude’s study included 47 patients with high blood pressure that wasn’t managed with drug therapy. Participants had an average of 176/96 mmHg baseline blood pressure, despite taking multiple medications, before the denervation procedure and an average of 148/87 mmHg after. More than 40% had systolic rates below 140 mmHg.

http://investors.sjm.com/phoenix.zhtml?c=73836&p=irol-newsArticle&ID=1695802

Interventionalists who spoke with heartwire were unvaryingly excited about the potential of renal denervation, with some caveats.

“You need enthusiasm to develop new things, and in hypertension we haven’t seen an innovation in decades,” Dr Thomas Lüscher (University Hospital Zürich, Switzerland) told heartwire. “So just the possibility that you would be able to have a persistent treatment effect by a procedure that helps severe hypertension patients and maybe in the future even the option to cure hypertension is very exciting indeed. But I agree it’s a dream at this point. I think we need the SYMPLICITY HTN 3 trial, which hopefully will confirm what the other studies have shown.”

Now enrolling at as many as 90 US centers, SYMPLICITY HTN 3, Lüscher pointed out, has design characteristics addressing two concerns with the earlier trials, namely a sham procedure for the control group and ambulatory blood-pressure monitoring in all patients.

During the same emerging-technologies session, Lüscher explored the albeit-scant data supporting a role for renal denervation in other conditions: everything from metabolic syndrome and obstructive sleep apnea to heart failure, atrial fibrillation, and polycystic-ovary syndrome.

But his counterpoint, Dr Jean Renkin (UCL St Luc University Hospital, Brussels, Belgium), was skeptical, pointing to the myriad unanswered questions with the technology.

“Currently, reasonably solid data are available only for patients with hypertension resistant to pharmacotherapy, which cannot necessarily be extrapolated to other forms of hypertension or conditions referred to [by Dr Lüscher]. However, at this point in time, no clouds have appeared in the sky, so let us dream on.”

Dr Renkin had one staggering number for the audience to consider: of 5000 patients who have undergone renal denervation, only 250 were actually treated as part of clinical studies. While no device has US approval, five denervation systems already hold CE Mark in Europe and are being used with increasing frequency.

Treating the Truly Medication Treatment “Resistant”

For a comprehensive presentation of Triple Antihypertensive Combination Therapy Significantly Lowers Blood Pressure in Hard-to-Treat Patients with Hypertension and Diabetes, refer to

http://pharmaceuticalintelligence.com/2012/05/29/445/

Another talking point is the proportion of patients who are truly “resistant.” The number agreed on by Lüscher, Waksman, and session comoderator Dr Robert Whitbourn (St Vincent’s Hospital, Fitzroy, Australia) was that just 3% of all hypertensive patients receiving blood-pressure-lowering medication are truly “resistant.” Numbers as high as 30% have been suggested in other reports, he noted.

“Interestingly, when we’ve been involved in various trials, every cardiologist says they have hundreds of these patients, but when we actually go to get them, no one actually has any,” Whitbourn quipped. “I think it should be a sobering thought—the numbers are actually quite small.”

Dr William Wijns (Cardiovascular Center Aalst, Belgium), also speaking with heartwire, agreed that the subset was “small” but argued it was “still big numbers, millions of people,” and “a massive unmet need.”

Waksman, insisting he was “excited” by what he called “robust reductions in blood pressure,” nevertheless urged eager interventionalists to work with hypertension experts and resist the urge “to jump on patients before we truly verify that they are resistant to medical treatment.”

In the vast majority of people even for whom renal denervation is appropriate, it “won’t be a cure,” Waksman said. “Most of these patients will have to continue on medical treatment—this is not replacing medical treatment, it is just getting [patients] more in control.”

http://www.theheart.org/article/1402321/print.do

The Global Supplier Ecosystem for Renal Denervation Systems

US Campbell, CA Kona Medical is attempting to address these limitations. The system delivers energy from outside the patient to the renal nerves. Ultimately, the procedure will be a “no puncture,” noninvasive technique, compatible with technologies that will allow for temperature and lesion mapping. A noninvasive procedure will allow titration of the therapy— that is, the application of patient-specific dose fractions while monitoring therapeutic effect in between fractions. The basis of the technology is focused ultrasound, not high intensity (HIFU) as one might see and expect in the treatment of tumors, but low-intensity focused ultrasound (LIFU). The biologic underpinnings of this treatment are described in past literature for treating nerves using ultrasound. Kona noninvasive system. The system is depicted in a custom chair; another version of the system is compatible with a standard fluoroscopy or MRI table. Both ultrasound (through elastography and the evolution of temperature mapping and MRI) allow further imaging and analysis of the treatment area. The dose distribution surrounding the artery is that of an annular ring around the wall of the artery. Kona has shown in animal studies that a heat/vibratory cloud at one plane along the artery is highly effective at long-term inhibition of renal nerves with no visible effect on any portion of the artery at any time point.

US, Ronkonkoma, NY & Germany – Paradise  by ReCor Medical 6-F compatible catheter with a cylindrical transducer that emits ultrasound energy circumferentially, allowing for a more efficient renal denervation procedure First-in-human (15 patients at 3 months) BP drop, mm Hg -32/-16 at 3 mo. The ultrasound transducer lies within a low-pressure balloon that allows for self-centering of the transducer and gentle contact with the artery wall for uniform circumferential denervation. This means that nerves below the surface of the artery wall are damaged in 360° with a single emission. The balloon also enables cooled fluid to circulate during the energy delivery process, thereby cooling the endothelial wall and protecting it from any excessive heating that could be caused by other energy sources or designs. Preliminary F-I-M clinical data for PARADISE were reported previously at the “TRenD 2012” transcatheter renal denervation scientific meeting by cardiologist Thomas A. Mabin, M.D., Vergelegen Medi-Clinic, South Africa. The updated PARADISE data show that systolic blood pressure was reduced by a statistically significant average of 36 mm Hg in 8 patients at 90-days follow-up. The scientific literature demonstrates that only a 5 mm Hg reduction in BP results in a 14% decrease in stroke, a 9% decrease in heart disease, and a 7% decrease in mortality.

US, San Leandro, CA The Mercator Bullfrog by Mercator MedSystems, Inc. is a catheter-guided system designed to inject therapeutic agents directly, nonsystemically, and safely through blood vessel walls into adventitial tissues and has received US Food and Drug Administration 510(k) clearance. The Bullfrog catheter is tipped with a balloon-sheathed microneedle and is guided and inflated in a manner similar to an angioplasty catheter but with far lower expansion pressures (2 atm vs 6–20 atm) in vessels of 3 to 6 mm in diameter. It is compatible with 0.014-inch guidewires and 6-F introducer sheaths. When the desired injection site is reached, the balloon is inflated with saline and radiopaque contrast, securing the system for injection and sliding the microneedle through the vessel wall. Nonclinical studies have shown that the Bullfrog catheter is able to deliver up to 5 mL per injection into the renal artery adventitia with no apparent safety concerns. Guanethidine Ismelin) is delivered to the renal artery adventitia to accomplish sympathetic denervation. Given locally, guanethidine is known to induce an autonomic denervation directly and through an immune-mediated pathway. Mercator’s preclinical experiments have shown that guanethidine, injected at appropriate concentrations into the adventitial space around renal arteries, selectively ablates the nerves in the adventitia around the renal artery after a single, 20-minute procedure

J Neurosci. 1983;3:714-724

US – Laguna Hills, CA – V² Radiofrequency Baloon by Vessix Vascular, Inc. Bipolar RF balloon catheter REDUCE-HTN pilot (10 patients)

BP drop, mm Hg -30/-11 at 1 mo V ² catheter, a patented noncompliant balloon catheter with RF electrodes and thermistors mounted on the exterior of the balloon, and the proprietary V ² bipolar RF generator. Once inserted into the renal artery, a 30-second inflation/treatment per renal artery delivers simultaneous RF therapy with independent temperature control to all electrode pairs. V ² catheter is available in balloon diameters ranging from 4 to 7 mm, with a balloon length of 25 mm. Larger-diameter balloons have eight electrode pairs, and smaller-diameter balloons have four to six electrode pairs made of solid gold, which are biocompatible and facilitate good electrode contact with the renal arterial wall. In addition, the electrodes are radiopaque, allowing the V ² catheter to be easily visualized under fluoroscopy. Beginning in the first quarter of 2012, the V 2 renal denervation system will be utilized in the company’s first international, multicenter clinical study: REDUCEHTN.

Israel, Tel Aviv – Tivus by Cardiosonic  A6-F transducer-tipped catheter, ultrasound energy (Animal data only) The solution for renal denervation is a high-intensity, nonfocused ultrasonic (US) catheter system named TIVUS (Therapeutic IntraVascular UltraSound) (Figure 3). By applying ultrasonic energy, the TIVUS technology enables remote, localized, controlled, and repeatable thermal modulation of the renal vessel wall tissue, resulting in safe renal nerve ablation. The remote thermal effect is located in the adventitia and perivascular region, with no thermal damage to the endothelium and media, therefore, preventing the development of vessel injury processes. Swine kidney tissue NE concentrations at 30- and 90-day follow-up have demonstrated successful renal denervation as witnessed by a 50% or more decline in tissue NE. Localized tissue thermal modulation/ablation, without damage to the blood vessel wall.

US, MN – SYMPLICITY HTN 2 by Medtronic   average office-based BP drops of BP drop, mm Hg 32/12 mm Hg at six months in the SYMPLICITY HTN 2 trial, as reported by heartwire, with 84% of patients having had a >10-mm-Hg drop in systolic blood pressure from baseline. 14 points in 30 days and 27 points after 1 year. Available in Europe. Medtronic is the furthest ahead in its development process, predicting it will get Symplicity on the American market by 2015. catheter in the renal artery near each kidney to deliver radiofrequency energy to ablate the nerves. A single electrode in contrast to St. Jude’s mutli-electrode approach, is already on the road to FDA review with clinical trials approved last summer in the U.S. Symplicity system has been safely used in nearly 5,000 patients since commercialization

US, MN – EnligHTN 1 by  St Jude radiofrequency (RF) energy to create lesions (tiny scars) along the renal sympathetic nerves Mean office BP changes at one month in BP drop, mm Hg 28 systolic and -10 diastolic after 1 month (p<0.0001 from baseline), with 78% of patients having systolic BP drops of >10 mm Hg. St. Jude Medical’s (St. Paul, MN) announcement in late 2011 of the first patient to be enrolled in their first-in-man ARSENAL trial ¹⁵ at the University of Adelaide

Ireland, Dublin – OneShot™ by Covidien acquisition of Maya Medical, Saratoga, CA New Irrigated RF Balloon Catheter secure first human use for the device in the third quarter of this year, followed by a CE mark for the drug-resistant hypertension treatment in 2013. Presumably, a filing with the FDA would follow that. the OneShot renal denervation system, was born out of the company’s extensive expertise in radiofrequency (RF) ablation and percutaneous coronary interventions (PCI), drawing upon the benefits and best practice standards of each distinct yet complementary clinical discipline. The result is a unique product platform that could further accelerate the paradigm shift in the management of resistant hypertension. consistent with Maya’s balloon-based approach is the ability to deliver predictable apposition of the RF electrode to the vessel wall for more controlled targeted delivery of the RF energy. By offering a more reliable single-treatment approach coupled with enhanced ease of use and reduced procedure times, Maya Medical believes its OneShot renal denervation system has the potential to significantly expand clinical adoption

http://bmctoday.net/evtoday/2012/02/article.asp?f=renal-artery-denervation-a-brave-new-frontier

US, Natick, MA Boston Scientific lags behind in the race to cash in on hypertension-treating devices, incoming CEO Michael Mahoney said at a Monday conference that it has a plan for its RDN renal denervation system. As MassDevice reports, Mahoney said Boston Sci expects to secure first human use for the device in the third quarter of this year, followed by a CE mark for the drug-resistant hypertension treatment in 2013.

St Jude’s EnligHTN system

Said Frank Callaghan, president of the St. Jude Medical Cardiovascular Division “This launch is important because it represents a significant growth opportunity and exemplifies our commitment to advancing the practice of medicine. We’ve applied the decades of insight we’ve gained from developing successful ablation technologies that treat cardiac arrhythmias to establish an innovative solution for hypertension.” With the unique basket design, each placement of the ablation catheter allows a consistent and predictable pattern of four ablations in 90-second intervals. Compared to single electrode ablations, the multi-electrode EnligHTN system has the potential to improve consistency and procedural reliability, save time as well as result in workflow and cost efficiencies. Additionally, the minimal catheter repositioning may result in a reduction of contrast and fluoroscopic (x-ray) exposure. The technology includes a guiding catheter, ablation catheter and ablation generator. The generator uses a proprietary, temperature-controlled algorithm to deliver effective therapy.

http://investors.sjm.com/phoenix.zhtml?c=73836&p=irol-newsArticle&ID=1695802

http://medgadget.com/2012/05/st-jude-medical-launches-enlightn-renal-denervation-system.html

St Jude’s EnligHTN system – view video

http://www.sjmprofessional.com/Products/Intl/Renal-Ablation-Therapy/enlightn-renal-denervation-system.aspx

Covidien

Unveiled a Novel Renal Denervation System OneShot™ at EuroPCR congress in Paris on 5/16/2012. “Live” Cases with New Irrigated RF Balloon Catheter for Treatment of Medication-resistant Hypertension and poor outcomes of pharmacological agents. The OneShot system is an irrigated, radiofrequency (RF) based balloon catheter used to ablate the renal sympathetic nerves located in the outer wall of the renal arteries. The OneShot technology received CE mark clearance in February 2012.

The OneShot system was featured in “live” cases at the Covidien-sponsored “Tools & Techniques (TNT) Interventions” presentation and panel session for hypertension and renal denervation at the EuroPCR congress. Professor Dirk Scheinert performed two cases at Park Hospital in Leipzig, Germany, that were transmitted live at the Palais des Congrès de Paris. In addition, John Ormiston, MD, Medical Director for Mercy Angiography and President of the Asia-Pacific Society of Interventional Cardiology in New Zealand, presented first-in-human results of cases performed with the OneShot system in New Zealand. The OneShot system and Covidien’s other endovascular solutions was on display at the EuroPCR meeting.

Additional faculty in the TNT session is a distinguished group of speakers including:

Professor Karl-Heinz Kuck, MD, F.A.C.C. – Director, Cardiology Department
Allgemeines Krankenhaus St. Georg – Hamburg, Germany

Dr. Stephen R. Ramee, FACC, FSCAI
Ochsner Medical Center – New Orleans, Louisiana

Dr. John Ormiston, MBChB, FRACP – Medical Director
Mercy Hospital Angiography Unit – Auckland, New Zealand

Professor Marc Sapoval, MD, PhD – Department Head
Cardiovascular/Interventional Radiology – Hospital Pompidou University – Paris, France

Dr. Renu Virmani – Medical Director
CVPath Institute – Gaithersburg, Maryland

Covidien discloses that it purchased Maya Medical for $60 million in cash on April 20. If Maya Medical meets certain regulatory and sales milestones, it will receive up to an additional $170 million. Covidien notes that Maya Medical’s OneShot system received the CE Mark in February.

MedCity News was the first to report Covidien’s interest in Maya Medical on 5/8/2012.

In a note to investors Monday, analyst Bob Hopkins of Bank of America said that renal denervation “has the potential to be one of the largest new markets in medtech over the next 2-4 years and for [Covidien] this looks like another small deal with big potential.”

http://medcitynews.com/2012/05/covidien-discloses-60m-purchase-of-hypertension-treatment-firm/?edition=medical-devices

Clinical Trial for RAPID is ongoing

 Rapid Renal Sympathetic Denervation for Resistant Hypertension (RAPID)

This study is currently recruiting participants.

Verified June 2012 by Maya Medical

First Received on January 25, 2012.   Last Updated on June 4, 2012   History of Changes

Sponsor:	Covidien (Maya Medical)
Collaborator:	Meditrial Europe LTD
Information provided by (Responsible Party):	Maya Medical
ClinicalTrials.gov Identifier:	NCT01520506

  Purpose

Maya Medical OneShot™ Ablation System use is to deliver low-level radio frequency (RF) energy through the wall of the renal artery to denervate the human kidney.

Condition	Intervention	Phase
Hypertension, Resistant to Conventional Therapy	Device: Maya Medical OneShot	Phase 2

Study Type:	Interventional
Study Design:	Endpoint Classification: Safety/Efficacy StudyIntervention Model: Single Group AssignmentMasking: Open LabelPrimary Purpose: Treatment
Official Title:	Rapid Renal Sympathetic Denervation for Resistant Hypertension Using the Maya Medical OneShot™ Ablation System

http://www.clinicaltrials.gov/ct2/results?term=Renal+Denervation&pg=2&show_flds=Y

Covidien into direct competition with Medtronic, whose Symplicity renal denervation system is approved in Europe. Currently, the system is being tested in the U.S. St. Jude Medical, Medtronic’s in-state rival, is also developing a therapy and that is expected to have a limited European market launch before the end of the year. But it is not only the larger players that Covidien will have to play against in Europe. A whole host of companies is developing products there, including ReCor Medical.

http://www.canada.com/entertainment/ReCor+Medical+discloses+data+from+clinical+study+PARADISE+ultrasound/6430884/story.html

Medtronic

Medical device giant Medtronic (NYSE: MDT), November 23, 2010 said it has agreed to pay $800 million upfront, plus commercial milestone payments through 2015, to acquire Mountain View, CA-based Ardian. Medtronic had previously built up an 11 percent ownership stake in Ardian, when it invested with its venture backers, which include Morgenthaler Ventures, Advanced Technology Ventures, Split Rock Partners, and Emergent Medical Partners. Ardian’s windfall comes about one week after it presented some eye-opening clinical trial results in The Lancet, and at the American Heart Association’s scientific meeting.

http://www.xconomy.com/san-francisco/2010/11/23/medtronic-buys-ardian-for-800m-upfront-grabs-novel-treatment-for-high-blood-pressure/

Clinical Trial for SYMPLICITY is ongoing.

Renal Denervation in Patients With Uncontrolled Hypertension (SYMPLICITY HTN-3)

This study is currently recruiting participants.

Verified June 2012 by Medtronic Vascular

First Received on August 15, 2011.   Last Updated on June 11, 2012   History of Changes

Sponsor:	Medtronic Vascular
Information provided by (Responsible Party):	Medtronic Vascular
ClinicalTrials.gov Identifier:	NCT01418261

  Purpose

The Symplicity HTN-3 study is a, multi-center, prospective, single-blind, randomized, controlled study of the safety and effectiveness of renal denervation in subjects with uncontrolled hypertension. Bilateral renal denervation will be performed using the Symplicity Catheter – a percutaneous system that delivers radiofrequency (RF)energy through the luminal surface of the renal artery.

Condition	Intervention	Phase
Uncontrolled Hypertension	Device: Renal denervation (Symplicity Catheter System)	Phase 3

Study Type:	Interventional
Study Design:	Allocation: RandomizedEndpoint Classification: Safety/Efficacy StudyIntervention Model: Parallel AssignmentMasking: Single Blind (Subject)Primary Purpose: Treatment

http://clinicaltrials.gov/ct2/show/NCT01418261

 The Symplicity™ Renal Denervation System has two main components:

The elements are designed to work together as an integrated system to ensure consistent performance:

Symplicity™ Catheter – Low profile, endovascular energy delivery catheter

Symplicity™ Generator – Automated, portable RF generator

The Symplicity Renal Denervation System uses controlled, low-power radiofrequency (RF) energy to deactivate the renal nerves, thereby selectively reducing both the pathologic central sympathetic drive to the kidney and the renal contribution to central sympathetic hyperactivity. The outcome, we hope, will be a significant and sustained reduction in both blood pressure and the level of systemically damaging neurohormones. Since the endovascular procedure does not involve an implant, patients recover quickly and can soon return to their daily living. The device may usher in a new era in the treatment of hypertension, hopefully allowing a one-time procedure to offer patients a long-lasting benefit.

Medtronic Procedure – view video

http://www.ardian.com/ous/medical-professionals/procedure.shtml

Conclusions

The entire industry subsegment is awaiting the results of SYMPLICITY HTN-3. Forecasts of market share by supplier will be predicated on this Clinical Trial completion.

Shutting down overactive nerves around the kidneys as a strategy for fighting resistant hypertension is “one of the most exciting growth markets in medical devices,” Sean Salmon, vice president and general manager of Medtronic’s coronary and peripheral business, said in a statement.

I had a piece in these pages last week about what kind of difference the Ardian treatment was making. The most recent Ardian study showed the new treatment, in combination with standard drugs, was able to bring average blood pressure scores down from 178 over 97 to 146 over 85 after six months of follow-up, while those who just got standard treatments were essentially unchanged. The results were “a big achievement,” according to Murray Esler, the study’s principal investigator.

http://www.xconomy.com/san-francisco/2010/11/23/medtronic-buys-ardian-for-800m-upfront-grabs-novel-treatment-for-high-blood-pressure/

Resources

REFERENCES for Dr. Scherlag’s 1999 Patent and pioneering work on Intravascular Stimulation/Ablation of Autonomics

1. Schauerte P, Scherlag BJ, Scherlag MA, Goli S, Jackman WM, Lazzara R. Transvenous parasympathetic cardiac nerve stimulation: an approach for stable sinus rate control. J Electrophysiol. 1999 Nov;10(11):1517-24.

2. Schauerte P, Scherlag BJ, Scherlag MA, Goli S, Jackman WM, Lazzara R. Ventricular rate control during atrial fibrillation by cardiac parasympathetic nerve stimulation: a transvenous approach. J Am Coll Cardiol. 1999 Dec;34(7):2043-50.

3. Schauerte P, Scherlag BJ, Pitha J, Scherlag MA, Reynolds D, Lazzara R, Jackman WM. Catheter ablation of cardiac autonomic nerves for prevention of vagal atrial fibrillation. Circulation. 2000 Nov 28;102(22):2774-80.

4. Scherlag MA, Scherlag BJ, Yamanashi W, Schauerte P, Goli S, Jackman WM, Reynolds D, Lazzara R. Endovascular neural stimulation via a novel basket electrode catheter: comparison of electrode configurations. J Interv Card Electrophysiol. 2000 Apr;4(1):219-24.

5. Scherlag BJ, Yamanashi WS, Schauerte P, Scherlag M, Sun YX, Hou Y, Jackman WM, Lazzara R. Endovascular stimulation within the left pulmonary artery to induce slowing of heart rate and paroxysmal atrial fibrillation. Cardiovasc Res. 2002 May; 54(2):470-5.

6. Hasdemir C, Scherlag BJ, Yamanashi WS, Lazzara R, Jackman WM. Endovascular stimulation of autonomic neural elements in the superior vena cava using a flexible loop catheter. Jpn Heart J. 2003 May;44(3):417-27.

7. Webster W Jr, Scherlag BJ, Scherlag MA, Schauerte P. Method and apparatus for   transvascular treatment of tachycardia and fibrillation. US Patent 6,292,695. Filed June 17, 1999.

8. Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, Kapelak B, Walton A, Sievert H, Thambar S, Abraham WT, Esler M. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373(9671):1275-1281.

9. Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. 2010;376:1903-1909.

10. Frank Himmel MD, Joachim Weil MD, Michael Reppel MD, Kai Mortensen MD, Klaas Franzen, Leidinger Ansgar MD, Heribert Schunkert MD, Frank Bode MD.  Improved Heart Rate Dynamics in Patients Undergoing Percutaneous Renal Denervation. Letter to the Editor. JCH. 31 MAY 2012.1751-7176.

Sympathetic Hyperactivity & Hypertension

For more information on hypertension, please visit the medical professional hypertension portal at TheHeart.org .

Siddiqi L, Joles JA, Grassi G, Blankestijn PJ. Is kidney ischemia the central mechanism in parallel activation of the renin and sympathetic system? J Hypertens. 2009 Jul;27(7):1341-9.

Augustyniak RA, Tuncel M, Zhang W, Toto RD, Victor RG. Sympathetic overactivity as a cause of hypertension in chronic renal failure. J Hypertens. 2002;20(1):3-9.

DiBona GF. Sympathetic nervous system and the kidney in hypertension. Curr Opin Nephrol Hypertens. 2002;11(2):197-200.

Mancia G, Grassi G, Giannattasio C, Seravalle G. Sympathetic activation in the pathogenesis of hypertension and progression of organ damage. Hypertension. 1999;34(4 Pt 2):724-728.

References in Scientific Journals about Renal Denervation Treatment

Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. 2010;376:1903-1909.

Symplicity HTN-1 Investigators. Catheter-Based Renal Sympathetic Denervation for Resistant Hypertension – Durability of Blood Pressure Reduction Out to 24 Months. Hypertension. Volume 57, Number 5, May 2011.

Rippy, M. et al. Catheter-Based Renal Sympathetic Denervation: Chronic Preclinical Evidence for Renal Artery Safety. Clin Res Cardiol. 2011 Dec; 100(12): Pages 1095-1101.

Mahfoud, F. et al. Effect of Renal Sympathetic Denervation on Glucose Metabolism in Patients With Resistant Hypertension. Circulation. Volume 123, No. 18, May 10, 2011. Pages 1940-1946.

Witkowski A., et al. Effects of Renal Sympathetic Denervation on Blood Pressure, Sleep Apnea Course, and Glycemic Control in Patients with Resistant Hypertension and Sleep Apnea. Hypertension. Volume 58, Number 4, October 2011. Pages 559-565.

Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, Kapelak B, Walton A, Sievert H, Thambar S, Abraham WT, Esler M. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373(9671):1275-1281.

Schlaich MP, Sobotka PA, Krum H, Lambert E, Esler MD. Renal Sympathetic-Nerve Ablation for Uncontrolled Hypertension. N Engl J Med. 2009;361(9):932-934.

Schlaich MP, Sobotka PA, Krum H, Whitbourn R, Walton A, Esler MD. Renal Denervation as a Therapeutic Approach for Hypertension. Novel Implications for an Old Concept. Hypertension. 2009;54(6):1195-1201.

Esler M. The 2009 Carl Ludwig Lecture: pathophysiology of the human sympathetic nervous system in cardiovascular diseases: the transition from mechanisms to medical management. J Appl Physiol. 2010;108(2):227-237.

Dibona GF, Esler MD. Translational Medicine: the antihypertensive effect of renal denervation. Am J Physiol Regul Integr Comp Physiol. 2010;298(2):R245-253.

Katholi RE, Rocha-Singh KJ. The role of renal sympathetic nerves in hypertension: has percutaneous renal denervation refocused attention on their clinical significance? Prog Cardiovasc Dis. 2009;52(3):243-248.

Doumas M, Faselis C, Papademetriou V. Renal Sympathetic Denervation and Systemic Hypertension. Am J Cardiol. 2010;105(4):570-576.

Schlaich MP, Krum H, Sobotka PA. Renal sympathetic nerve ablation: the new frontier in the treatment of hypertension. Curr Hypertens Rep. 2010;12(1):39-46.

Katholi RE, Rocha-Singh KJ, Goswami NJ, Sobotka PA. Renal nerves in the maintenance of hypertension: A potential therapeutic target. Curr Hypertens Rep. 2010;12:196-204.

Esler MD, Lambert EA, Schlaich M, Navar LG. The Dominant Contributor to Systemic Hypertension: Chronic Activation of the Sympathetic Nervous System vs Activation of the Intrarenal Renin-Angiotensin System. J Appl Physiol. 2010.

Fisher JP, Fadel PJ. Therapeutic strategies for targeting excessive central sympathetic activation in human hypertension. Exp Physiol. 2010;95(5):572-580.

Malpas SC. Sympathetic nervous system overactivity and its role in the development of cardiovascular disease. Physiol Rev. 2010;90:513-557.

Lambert GW, Straznicky NE, Lambert EA, Dixon JB, Schlaich MP. Sympathetic nervous activation in obesity and the metabolic syndrome–causes, consequences and therapeutic implications. Pharmacol Ther. 2010;126:159-172.

Masuo K, Lambert GW, Esler MD, Rakugi H, Ogihara T, Schlaich MP. The role of sympathetic nervous activity in renal injury and end-stage renal disease. Hypertens Res. 2010;33:521-528.

Schlaich MP, Socratous F, Hennebry S, Eikelis N, Lambert EA, Straznicky N, Esler MD, Lambert GW. Sympathetic activation in chronic renal failure. J Am Soc Nephrol. 2009;20(5):933-939.

Bock JS, Gottlieb SS. Cardiorenal syndrome: New perspectives. Circulation. 2010;121:2592-2600.

Goldsmith SR, Sobotka PA, Bart BA. The sympathorenal axis in hypertension and heart failure. Journal of Cardiac Failure. 2010;16(5):369-373.

Grassi G. Assessment of sympathetic cardiovascular drive in human hypertension: achievements and perspectives. Hypertension. 2009;54(4):690-697.

Ritz E. New approaches to pathogenesis and management of hypertension. Clin J Am Soc Nephrol. 2009;4(12):1886-1891.

Ritz E, Rump LC. Control of sympathetic activity–new insights; new therapeutic targets? Nephrol Dial Transplant. 2010;25(4):1048-1050.

Joyner MJ, Charkoudian N, Wallin BG. Sympathetic nervous system and blood pressure in humans: Individualized patterns of regulation and their implications. Hypertension. 2010;56:10-16.

Mann JF. Whats new in hypertension 2009? Nephrol Dial Transplant. 2010;25(1):37-41.

Bravo EL, Rafey MA, Nally JV, Jr. Renal denervation for resistant hypertension. Am J Kidney Dis. 2009;54(5):795-797.

King A. Hypertension: RF ablation of renal nerves. Nature Reviews Nephrology. 2009;5:364.

Doumas M, Douma S. Interventional management of resistant hypertension. Lancet. 2009;373(9671):1228-1230.

Paulis L. Novel therapeutic targets for hypertension. Nat Rev Cardiol. 2010.

OBrien E. Renal sympathetic denervation for resistant hypertension. Lancet. 2009;373(9681):2109; author reply 2109-2110.

Titze S, Uder M, Schmieder R. Renal nerve ablation: innovative therapy for treatment of resistant hypertension. MMW Fortschr Med. 2009;151(42):52-53.

Katona PG. Biomedical engineering in heart-brain medicine: A review. Cleve Clin J Med. 2010;77 Suppl 3:S46-50.

Abstracts about Renal Denervation Treatment

Schlaich M, Krum H, Walton T, Whitbourn R, Sobotka P, Esler M. Two-year durability of blood pressure reduction with catheter-based renal sympathetic denervation. Journal of Hypertension. 2010;28:e446.

Esler M, Schlaich M, Sobotka P, Whitbourn R, Sadowski J, Bartus K, et al. Catheter-Based Renal Denervation Reduces Total Body and Renal Noradrenaline Spillover and Blood Pressure in Resistant Hypertension. Journal of Hypertension. 2009;27(suppl 4):s167.

Schlaich MP, Krum H, Whitbourn R, Walton T, Lambert GW, Sobotka PA, et al. Effects of Renal Sympathetic Denervation on Noradrenaline Spillover and Systemic Blood Pressure in Patients with Resistant Hypertension. Journal of Hypertension. 2009;27(suppl 4):s154.

Schlaich M, Krum H, Walton T, Lambert E, Lambert G, Sobotka P, et al. A Novel Catheter Based Approach to Denervate the Human Kidney Reduces Blood Pressure and Muscle Sympathetic Nerve Activity in a Patient with End Stage Renal Disease and Hypertension. Journal of Hypertension. 2009;27(suppl 4):s437.

 

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