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1 Could it be PARADISE Found or is SYMPLICITY the Answer to the Treatment of Hypertension: The Resurrection of Renal Denervation to Treat Hypertension New Studies and Newer Options Richard R Heuser, MD and Nachiket J. Patel, MD St. Luke s Medical Center, Phoenix, Arizona. Abstract: The American College of Cardiology and American Heart Association, along with other partner organizations, released new hypertension guidelines introducing a classification system that decreased the threshold, defining hypertension as a blood pressure 130 mm Hg systolic or 80 mm Hg diastolic. The goal blood pressure for all is now lowered from <140/90 mm Hg to <130/80 mm Hg. With nearly 50% of hypertensive patients either not on antihypertensive agents or if treated not at goal, the possibility of a single procedure to reduce blood pressure without medications is still a worthy endeavor. With two recently published studies suggesting this may be obtainable, we revisit this strategy and discuss a new approach. VASCULAR DISEASE MANAGEMENT 2018;15(10):E120-E125. Key words: blood pressure; hypertension; renal denervation The American College of Cardiology (ACC) and American Heart Association (AHA), along with other partner organizations, released new hypertension guidelines, introducing a classification system that decreased the threshold, defining hypertension as a blood pressure 130 mm Hg systolic or 80 mm Hg diastolic. The goal blood pressure for all is now lowered from <140/90 mm Hg to <130/80 mm Hg. 1 This new definition has increased the prevalence of hypertension among United States (US) adults to 45.6% (or 103 million people) compared to 31.9% according to the prior guideline from the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 2 Worldwide, 40% of people over 25 years old have hypertension, representing approximately 1.4 billion people. 3 Hypertension often has no presenting signs or symptoms. It is, however, a silent killer, and a strong risk factor for ischemic heart disease, stroke, and renal disease. In the US, adults with hypertension increase their annual health-care costs by $1920 compared to those without hypertension. Unfortunately, this increase in cost burden may prompt many to discontinue their anti-hypertensive medications. People with hypertension have 2.5 times the inpatient cost when hospitalized. Hypertensive patients have nearly double the outpatient costs and nearly triple the prescription medication costs of their peers without high blood pressure. Nationally, healthcare costs associated with hypertension is estimated at $131 billion per year. 4 In the 1930s and 1940s, surgical procedures to remove the sympathetic nerves were performed to treat hypertension. 5 While these procedures worked effectively to lower blood pressure, they were invasive and had many complications, and were discontinued with the introduction of pharmacologic agents for hypertension management. Despite advances in pharmacotherapy, achieving blood pressure control is not without problems. Often, the recognition of hypertension by defining the real blood pressure of patients, discarding the white-coat effect, and discovering masked hypertension can be difficult. Additionally, control of hypertension with lifestyle modifications, including exercise and reduction of salt intake, along with proper adherence to a medical regimen can pose a challenge to patients. Unfortunately, it is not surprising that only 34% of Americans with hypertension are being adequately treated. 6 Over the last 5 to 8 years, there have been a number of medical device companies that had encouraging results in managing hypertension by treating the periarterial nerves supplying the kidneys. 7 One of the pioneers of this treatment, Murray Esler, stated early on that periarterial treatment is effective in 50%-85% of patients with resistant or difficult-to-control hypertension, but may not have an effect up until 1 year after treatment. 8 Early enthusiasm resulted in the involvement of over 20 companies in this treatment with an eye toward a multibillion dollar health-care opportunity, and the goal of replacing a lifetime of pill-taking with a single, safe, minimally invasive, and permanently effective procedure for the management of hypertension. 7 In January 2014, this optimism was burst when a major renal denervation study known as SYMPLICITY HTN-3 9 concluded that the periarterial interventional procedure worked no better than placebo. However, a reassessment of the study design suggested that perhaps there was a problem with the design of the trial, the technique used, and the training of the operators With further pathologic studies on humans, it was thought that perhaps an optimal approach would be to treat some of the branches of the renal arteries with multiple ablations Vascular Disease Management Volume 15, No. 10, October 2018 E120

2 SPYRAL HTN-ON MED 16 was a patient- and assessor-blinded proof-of-concept trial designed to test the safety and treatment response after renal denervation using the Symplicity Spyral renal denervation system (Medtronic) vs a sham control. Eligible participants from 25 centers worldwide (n = 467) had office systolic blood pressure (SBP) between mm Hg and diastolic blood pressure (DBP) 90 mm Hg, and 24-hour ambulatory SBP between mm Hg despite being on 1-3 antihypertensives, with stable doses for at least 6 weeks. Surveillance was used to assess medication adherence. A 9 mm Hg drop in 24-hour ambulatory SBP and 6 mm Hg drop in DBP at 6 months was seen in the renal denervation arm compared to the 1.6 mm Hg SBP reduction in the sham control arm (P<.01). Office SBP was also reduced by 9.4 mm Hg and 2.6 mmhg, respectively (P=.02). Interestingly, in spite of patients being involved in a carefully monitored study, about 40% of the patients in both arms were non-adherent; in other words, they did not take their medications correctly. A second trial, RADIANCE-HTN, 17 evaluated endovascular renal denervation with the Paradise Renal Denervation Ultrasound System (ReCor Medical). This study evaluated the reduction of ambulatory blood pressure in hypertensive patients who were not currently on antihypertensive medications. There were two study cohorts: SOLO, which included patients who were removed from antihypertensive medications; and TRIO, which included patients who were put on standard antihypertensive medications. Both groups were randomized, blinded, sham controlled, and powered independently for efficacy. The international study in 44 centers included 146 patients with ambulatory blood pressure of 135/85 mm Hg and <170/105 mm Hg after a 4-week discontinuation of at least 2 antihypertensive medications. The patients were randomly assigned to renal denervation or a sham procedure of renal angiography only. In the study arm, the reduction in ambulatory systolic blood pressure was significantly greater from baseline at 2 months compared with controls (-8.5 mm Hg vs -2.2 mm Hg; P<.001). In the renal denervation group, 20% of patients achieved daytime ambulatory blood pressures of <135/85 mm Hg off medications compared with just 3% of patients in the sham group achieving control of blood pressure (P<.01). For the past 6 years, we have been working with a renal denervation device that works via a different mechanism. 7 From pathologic data, we know that the majority of afferent nerves hypothesized to control central sympathetic tone are in the renal collecting system or renal pelvis Working with a small budget and a small number of individuals, as well as the fact that we were behind the other renal denervation devices in terms of longevity of our research design and development, we felt a biologic proof of concept for our approach was necessary. This ended up being quite serendipitous. Since our procedure would be at least initially performed almost exclusively by urologists, we went to a very busy urologic center in India to perform our first studies. Patients already affected by renal disease and in whom there was a plan for nephrectomy were the first patients treated. Unlike the periarterial approach via the renal arteries, this approach was done with a cystoscope under general anesthesia in the operating room by a small number of urologists using the NephroBlate (Verve Figure 1. The NephroBlate renal denervation device. Figure 2. Ultrasound image of the NephroBlate renal denervation device. Medical) (Figures 1, 2). The patients underwent nephrectomy 1 month later and we performed histopathologic analysis. In a total of 9 patients treated in this way, we observed that the nerves were extremely superficial, not particularly variable, and easily fully ablated by histopathologic evaluation in control and treated areas (Figure 3). Unlike the arterial approach, there are no patients that cannot be treated with this approach even if they are affected by ureteral disease, since urologists and interventional radiologists are comfortable using the ultrasound-guided flank approach for access if necessary (Case #1). We subsequently treated patients with difficult-to-control resistant hypertension and found we effectively were able to drop their blood pressure by a SBP of 44 mm Hg and a DBP of 18 mm Hg (Figure 4). These procedures were done under general anesthesia and the blood pressure was not affected by the general anesthesia before the ablation, but post ablation we saw an immediate and long-lasting blood pressure response within about 20 seconds. PERIARTERIAL VERSUS RENAL COLLECTING SYSTEM DENERVATION Histopathologic studies suggest that the majority of afferent nerves controlling central sympathetic tone are in the collecting Vascular Disease Management Volume 15, No. 10, October 2018 E121

3 Figures 3A 3C. One month after renal denervation with the NephroBlate device, nephrectomy and histopathologic analysis were performed. In 9 patients treated this way, we observed that the nerves were extremely superficial, not particularly variable, and easily fully ablated by histopathologic evaluation in control and treated areas. A B C Figure 4. Baseline and 1-month blood pressure measurements in patients with difficult-to-control resistant hypertension treated with the NephroBlate device, systolic blood pressure dropped by 44 mm Hg and diastolic blood pressure dropped by 18 mm Hg. system Unlike the kidney pelvic approach, over 20,000 patients were treated with the periarterial approach before any careful analysis of the renal system in humans was evaluated, and only one human post-nephrectomy study was performed after a patient died post renal denervation in a case where a patient with longstanding hypertension clearly did not have any ablation of the nerves by using the periarterial approach. 22 No patients have ever had human studies on individuals prior to planned nephrectomy to delineate biologic proof of concept with the periarterial approach despite the fact that patients have a risk of arterial complications and renal artery stenosis. 23 When treating the collecting system, no manipulation of the ablation catheter is necessary because the renal pelvis is a potential space, and a single 2-minute ablation is performed on each kidney. When the periarterial approach was performed with the Symplicity Spyral device (Medtronic), 45.9 ± 13.7 ablations were performed with utilization of a mean ± ml of contrast. The denervation time itself took over 60 minutes (60.8 ± 25.3 minutes), with many ablations in the main and branch vessels; this is a long interventional procedure even in a skilled operator s hands. 16 With the NephroBlate device, the average procedure time was 15 minutes to treat both kidneys, and there was no training necessary for the urologists, since they have been doing procedures of this type for over 100 years and have over 20 years of experience using radiofrequency energy in the urologic system. No systemic contrast is utilized, since contrast in the collecting system does not result in any systemic exposure. Previous studies on the Symplicity Spyral device and Paradise device (ReCor Medical) suggest that only 50% of patients with hypertension can be treated with the periarterial approach and any patient with renal insufficiency was disqualified. 16,17 With the NephroBlate device, the collecting system is fairly homogenous in patients with hypertension, and if severe fibrosis or disease is present in the collecting system of a patient, this procedure can be done via the flank approach using ultrasound guidance. The periarterial procedure requires heparinization, antiplatelet agents, and careful angiographic follow-up. Although rare, Vascular Disease Management Volume 15, No. 10, October 2018 E122

4 Figure 5. Case #1: A 27-year-old male with a history of adiponectin chronic kidney disease and a large renal stone requiring nephrectomy underwent renal denervation with the NephroBlate catheter. renal artery stenosis can occur after the periarterial procedure. 23 The NephroBlate device does not involve access to the arterial system; thus, access site and angiographic restenosis, etc, do not play a role in this procedure, which is done via a natural orifice (the urethra). With publication of the two studies, an accompanying editorial by Peter J. Vankestijn and Michael Bots 24 stated that, it is now appropriate to start exploring the role in other patient groups as well as patients with hypertension only. They state that from a pathophysiologic point of view, patients with chronic kidney disease, heart failure, certain arrhythmias, and kidney-related pain syndromes should be considered irrespective of the level of blood pressure. A procedure that results in immediate blood pressure reduction, already tested in a biologic human nephrectomy model and shown to cause ablation of significant nerves in the Figure 6. Case #1: A helical probe allowed circumferential ablation with the NephroBlate catheter. collecting system, may be one answer. Since the NephroBlate approach does not result in systemic contrast administration, which is a major issue in patients with chronic kidney disease, this could be its specific sweet spot in renal denervation. Central sympathetic tone may be related to other disorders, such as sleep apnea; in fact, recent studies continue to suggest that patients with sleep apnea appear to have fewer apnea events after renal denervation. 25 The opioid crisis has had considerable impact on the US, and the US Food and Drug Administration recently began soliciting information for studies in chronic pain patients to perhaps reduce dependence on these dangerous drugs. Fifty percent of patients with chronic kidney disease have chronic pain, and groups have looked at surgical denervation to deal with this pain issue in lieu of narcotics. 26 This might be an ideal treatment group to consider for the renal pelvic approach with cystoscopy in a urologist s office. Figures 7A and 7B). Case #1: Successful nephrectomy 1 month post renal denervation with the NephroBlate device. Vascular Disease Management Volume 15, No. 10, October 2018 E123

5 Figures 8A and 8B. Case #1: Histopathological analysis of the patient's kidney at the site of radiofrequency ablation showed no remaining nerves present. While hypertension is a major problem, chronic kidney disease is a problem with no true therapy. Forty million Americans are living with kidney disease and 700,000 have kidney failure. The patients with end-stage renal disease depend on Medicare benefits for life-preserving care. It is frustrating that end-stage renal patients have only two treatment options to sustain life: kidney transplantation or dialysis therapies. The US Congress has addressed this issue with initiatives to invest in kidney research in order to get new products in the hands of patients and physicians. With its 2018 launch, Kidney X will offer prizes for the commercialization of next-generation dialysis products. 27 Recently, tolvaptan was approved to treat autosomal dominant polycystic disease, as it has been shown to slow kidney function decline. 28 Perhaps renal denervation, whether via the periarterial approach or the pelvic approach, may be one option to offer these very difficult-to-treat patients to perhaps improve the quality of life. In our experience, it is not infrequent that patients with end-stage renal disease are A B frequently hospitalized because of either severe hypertension or even hypotension during dialysis. This population may, in fact, be ideal for renal denervation (Case #2). Perhaps it is quixotic to hope that we could perhaps stabilize the blood pressure in these patients and possibly even make an end-stage renal disease patient a more stable candidate for renal transplant after renal denervation. With 1.4 billion patients with hypertension worldwide, and over half of the patients unaware of their malady, 3 if a treatment performed in a doctor s office can result in even a small blood pressure drop as demonstrated in the SPYRAL HTN-ON MED trial and RADIANCE solo trial, it can make a huge impact. A study from the United Kingdom showed that a 2 mm drop in SBP can result in a 7% reduction in cardiovascular death and a 10% reduction in stroke mortality. 29 Perhaps we can find a Simple Paradise if renal denervation can begin to show its promise that many of us were so excited about just a short time ago. New studies and new information will answer that question in the future. Case #1 A 27-year-old male with a history of adiponectin chronic kidney disease and a large renal stone requiring nephrectomy underwent renal denervation with the NephroBlate catheter (Figure 5). He had hypertension and was on 3 medications. We used a new helical probe (Figure 6) that we designed in order to allow circumferential ablation, as it was felt that too much focal heat would cause damage, increasing the risk of calyceal stenosis. His systolic blood pressure dropped 24 mm Hg within 20 seconds, and his blood pressure maintained at this level until his nephrectomy. He underwent successful nephrectomy 1 month later (Figure 7). Histopathological analysis of his kidney at the site of radiofrequency ablation showed no remaining nerves present (Figure 8). Case #2 A 51-year-old male patient with a history of end-stage renal disease on hemodialysis, and resistant hypertension requiring the use of 5 antihypertensives (carvedilol, losartan, enalapril, doxazosin, and bisoprolol; 2 beta-blockers and 3 angiotensin inhibitors). He also underwent successful renal denervation with the NephroBlate catheter (Figure 9A). After ablation of both kidneys, his systolic blood pressure dropped 16 mm Hg (Figure 9B). Additionally, his antihypertensive medication requirements decreased to where he required only 2 medications (losartan and enalapril). Prior to the procedure, he was completely anuric; remarkably, post procedure, his kidneys made urine at approximately 8 ml/hour. n Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Heuser reports equity in Verve Medical. Dr. Patel has no conflicts of interest regarding the content herein. Manuscript submitted August 7, 2018 and accepted September 10, Address for correspondence: Richard R. Heuser, MD, FACC, FACP, FESC, MSCAI, 555 N. 18th Street, Suite 100, Phoenix, AZ richard.heuser@steward.org Vascular Disease Management Volume 15, No. 10, October 2018 E124

6 A B Figure 9. Case #2: A 51-year-old male with a history of endstage renal disease underwent successful renal denervation with the Phoenix catheter. (A) Renal pelvis pyelogram. (B) After ablation of both kidneys, systolic blood pressure dropped 16 mm Hg. REFERENCES 1. Whelton PK, Carey RM, Aronow WS, et al ACC/AHA/ AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018;71(19): Muntner P, Carey RM, Gidding S, et al. Potential US population impact of the 2017 ACC/AHA high blood pressure guideline. J Am Coll Cardiol. 2018;71(2): Mills KT, Bundy JD, Kelly TN, et al. Global disparities of hypertension prevalence and control: a systematic analysis of population-based studies from 90 countries. 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