Coverage Policy Manual
Policy #: 2012052
Category: Surgery
Initiated: August 2012
Last Review: September 2018
  Radiofrequency Ablation of the Renal Sympathetic Nerves as a Treatment for Resistant Hypertension

Description:
Radiofrequency ablation (RFA) of the renal sympathetic nerves is a non-pharmacologic treatment for hypertension. This treatment is intended to reduce sympathetic nerve activity in the renal system, thus leading to lower blood pressure. Patients with hypertension that is resistant to treatment with standard medications may derive benefit from this approach.
 
Background
Resistant hypertension. Hypertension is a widely prevalent condition, which is estimated to affect approximately 30% of the population in the United States (Acelajado, 2010). It accounts for a high burden of morbidity related to strokes, ischemic heart disease, kidney disease, and peripheral arterial disease. Resistant hypertension is defined as elevated blood pressure (BP) despite treatment with at least 3 antihypertensive agents at optimal doses. Resistant hypertension is also a relatively common condition, given the large number of individuals with hypertension. In large clinical trials of hypertension treatment, up to 20-30% of participants meet the definition for resistant hypertension, and in tertiary care hypertension clinics, the prevalence has been estimated to be 11-18% (Acelajado, 2010). Resistant hypertension is associated with a higher risk for adverse outcomes such as stroke, myocardial infarction (MI), heart failure, and kidney failure.
 
There are a number of factors that may contribute to uncontrolled hypertension, and these should be considered and addressed in all patients with hypertension prior to labeling a patient resistant. These include non-adherence to medications, excessive salt intake, inadequate doses of medications, excess alcohol intake, volume overload, drug-induced hypertension, and other forms of secondary hypertension (Doumas, 2011). Also, sometimes it is necessary to address comorbid conditions, i.e., obstructive sleep apnea, in order to adequately control BP.
 
Treatment for resistant hypertension is mainly intensified drug therapy, sometimes with the use of non-traditional antihypertensive medications such as spironolactone and/or minoxidil. However, control of resistant hypertension with additional medications is often challenging and can lead to high costs and frequent adverse effects of treatment. As a result, there is a large unmet need for additional treatments that can control resistant hypertension. Non-pharmacologic interventions for resistant hypertension include modulation of the baroreflex receptor, and/or radiofrequency (RF) denervation of the renal nerves.
 
Radiofrequency denervation of the renal sympathetic nerves. Increased sympathetic nervous system activity has been linked to essential hypertension. Surgical sympathectomy has been shown to be effective in reducing blood pressure but is limited by the side effects of surgery and was largely abandoned after effective medications for hypertension became available. The renal sympathetic nerves arise from the thoracic nerve roots and innervate the renal artery, the renal pelvis, and the renal parenchyma. Radiofrequency ablation (RFA) is thought to decrease both the afferent sympathetic signals from the kidney to the brain and the efferent signals from the brain to the kidney. This decreases sympathetic activation, decreases vasoconstriction, and decreases activation of the renin-angiotensin system (Zile, 2012).
 
The procedure is performed percutaneously with access at the femoral artery. A flexible catheter is threaded into the renal artery and controlled, low-power RF energy is delivered to the arterial walls where the renal sympathetic nerves are located. Once adequate RF energy has been delivered to ablate the sympathetic nerves, the catheter is removed.
 
Regulatory Status
No radiofrequency ablation (RFA) devices have been approved for ablation of the renal sympathetic nerves as a treatment for hypertension. There are several devices that have been developed for this purpose and are in various stages of application for U.S. Food and Drug Administration (FDA) approval.
  • The Symplicity™ renal denervation device (Medtronic Inc., Minneapolis, MN) consists of a flexible catheter that is specifically intended for use in the renal arteries, and an external power generator.
  • The EnligHTN™ multi-electrode renal denervation system (St. Jude Medical, Plymouth, MN) is an RFA catheter using a 4-point multiablation basket design. In January 2014, the EnligHTN™ Renal Guiding Catheter received clearance for marketing through the 510(k) process based on substantial equivalence to predicate devices (product code: DQY) for the following indication: percutaneous use through an introducer sheath to facilitate a pathway to introduce interventional and diagnostic devices into the renal arterial vasculature.
  • The One-Shot Renal Denervation System™ (Covidien, Dublin) is an irrigated RFA balloon catheter, consisting of a spiral shaped electrode surrounding a balloon that is intended to ablate using 1 application. On January 21, 2014, Covidien announced it will exit its OneShot Renal Denervation program.
  • The Renal Denervation System (Boston Scientific Marlborough, MA; formerly the V2 renal denervation system, Vessix Vascular) is a combination of a RF balloon catheter and bipolar RF generator technologies, intended to permit a lower voltage intervention.
  • The Thermocouple Catheter™ (Biosense Webster, Diamond Bar, CA) is an RFA catheter that is in clinical use for cardiac electrophysiology procedures, and also has been used for RFA of the renal arteries.
 
Coding
Effective January 1, 2014, there are CPT category III codes for this procedure:
 
0338T Transcatheter renal sympathetic denervation, percutaneous approach including arterial puncture, selective catheter placement(s) renal artery(ies), fluoroscopy, contrast injection(s), intraprocedural road mapping and radiological supervision and interpretation, including pressure gradient measurements, flush aortogram and diagnostic renal angiography when performed; unilateral
0339T bilateral
 
These CPT category III codes cannot be reported with codes 36251, 36252, 36253, and 36254.
 
Effective Prior to January 1, 2014
There are no specific CPT codes for this procedure.
 
It is possible that one of the renal artery catheter placement codes (36251-36254) might be reported for placement of the catheter. These codes include the fluoroscopic guidance for the catheter placement. The radiofrequency ablation might be reported using the unlisted nervous system procedure code 64999.
  

Policy/
Coverage:
Radiofrequency ablation of the renal sympathetic nerves for the treatment of resistant hypertension does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. This procedure is still be studied in clinical trials.
 
Radiofrequency ablation of the renal sympathetic nerves is considered investigational for the treatment of resistant hypertension. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 

Rationale:
This technology requires high-quality randomized controlled trials (RCTs) to demonstrate efficacy. This is due to the natural variability in blood pressure (BP), the heterogeneity of the patient populations with increased BP, and the presence of many potential confounders of outcome. A sham-controlled RCT is ideal since it would also control for any placebo, or other non-specific, effects of BP treatment. Case series have limited utility for determining efficacy. They can be useful for demonstrating potential of the technique, for determining the rate of short- and long-term adverse effects of treatment, and to evaluate the durability of the treatment response.
 
Literature Review
The literature review identified one small, short-term RCT, a few non-randomized controlled trials, and several case series. These relevant studies are reviewed below.
 
Randomized, controlled trials
Simplicity HTN-2. The Simplicity HTN-2 trial was a multicenter, unblinded RCT evaluating renal sympathetic denervation versus standard pharmacologic treatment for patients with resistant hypertension (Esler, 2010). A total of 106 patients with a systolic blood pressure of at least 160 mm Hg despite 3 or more antihypertensive medications were enrolled. The trial was unblinded, and clinicians ascertaining outcomes were not blinded to treatment assignment. Patients were followed for 6 months with the primary endpoint being the between-group difference in the change in BP over the course of the trial. Secondary outcomes included a composite outcome of adverse cardiovascular events and adverse effects of treatment. Baseline BP was 178/98 in the RFA group and 178/97 in the control group.
 
At 6 months’ follow-up, the BP reductions in the RFA group were 32 mm Hg systolic (SD 23) and 12 mm Hg diastolic (SD 11). In the control group, there was a 1 mm Hg increase in systolic BP and no change for diastolic BP (p<0.0001 for both systolic blood pressure (SBP) and SBP differences). The percent of patients who achieved an SBP of 140 or less was 39% (19/49) in the radiofrequency ablation (RFA) group compared to 6% (3/51) in the control group (p<0.0001). There was no difference in renal function, as measured by serum creatinine, between groups at the 6-month time period. There were 3 patients in the RFA group who had adverse cardiovascular events compared to 2 in the control group (p=NS). Other serious adverse events requiring admission in the RFA group included one case each of nausea/vomiting, hypertensive crisis, transient ischemic attack (TIA), and hypotension.
 
The main limitations of this RCT are that it is small in size, unblinded, and has only a relatively short follow-up. A trial with a sham control would allow better determination of whether the treatment effect was due to a placebo effect, or other non-specific effects of being in a trial. The 6-month follow-up is too short to ascertain whether the reduction in BP is likely to reduce adverse cardiovascular outcomes such as myocardial infarction (MI) and stroke. It is unknown whether re-innervation of the renal sympathetic nerves occurs post-treatment. If re-innervation does occur, the efficacy of the procedure will diminish over time. Trials with longer term follow-up are needed to determine whether this is the case.
 
Non-randomized, comparative studies
Several nonrandomized studies with a control group have been published. The populations from some of these studies overlap to a large extent with the Simplicity HTN-2 trial. Additional cases may have been added to the study population using the same eligibility criteria, and only a small number of control patients were included in the analyses. Thus, these comparisons are not considered randomized. These studies examine different physiologic outcomes in addition to changes in blood pressure.
 
An echocardiographic sub-study was published in 2012 (Brandt, 2012). This trial compared 46 patients who underwent RFA to 18 control patients from the larger control group in the trial. The selection of patients for the control group was not specified. The main endpoints of this trial were echocardiographic measures of left ventricular hypertrophy (LVH) and diastolic dysfunction at 6 months post-treatment. There was a significant decrease in the LV mass index for the treatment group at 6 months, from a baseline of 112.4 + 33.9 g/m2 to 94.9 + 29.8 g/m2. In the control group, there was a slight increase in LV mass index from 114.8 + 41.6 g/m2 to 118.7 + 30.1 g/m2 (p=0.009 for comparison with RFA group). There was also a significant improvement in measures of diastolic dysfunction for the RFA group compared to controls at 6 months.
 
Another sub-study published in 2011 evaluated the response to exercise in 46 patients treated with RFA compared to 9 patients in the control group at 3 months post-treatment (Ukena, 2011). There were significant improvements in the achieved workload, and recovery from exercise in heart rate and blood pressure compared to controls. There were no differences in maximum oxygen uptake or maximum heart rate during exercise.
 
A third study that enrolled 50 patients measured parameters of glucose metabolism in treated and control patients. This population included a subset of patients from the Simplicity trial (n=17 treated and n=9 control patients) and also included another 20 treated patients and 4 control patients who met the same eligibility criteria used in the Simplicity HTN-2 trial. Outcomes at 3 months showed that there was an improvement in fasting glucose for the treated patients from a baseline of 118 + 3.4 mg/dL to 108 + 3.8 mg/dL (p=0.039). There was no change in the control group. Insulin levels and C-peptide levels were also reduced in the treatment group, as were peak glucose levels at 2 hours on a glucose tolerance test.
 
Mahfoud et al. (Mahfoud, 2012) enrolled 100 patients in a study that evaluated the impact of RFA on renal function and renal hemodynamics, 87 treated with RFA and 13 control patients. This population also overlapped with the Simplicity HTN-2 trial and all patients met the eligibility criteria used in Simplicity HTN-2. There was no discernable impact of RFA on the glomerular filtration rate or mean urinary albumin excretion at 6 months’ follow-up. There were significant improvements for the treated patients on the incidence of microalbumineria and the renal resistive index. There were no instances of renal artery stenosis, dissections, or aneurysms at the 6-month time point.
 
Case series
The largest case series was the Simplicity HTN-1 study, which was a multicenter, single-arm trial sponsored by the manufacturer (Symplicity, 2011; Krum, 2009). A total of 153 patients with resistant hypertension were treated at 19 clinical centers in the US, Europe and Australia. The mean baseline BP was 176/98, and participants were taking a mean of 5 antihypertensive drugs. Patients were followed for up to 24 months with the main endpoint being reduction in BP. Procedural complications occurred in 4 patients (3%), including 3 cases of groin pseudoaneurysms and one renal artery dissection. The mean BP reductions at 6 months, 12 months, and 24 months were 25/11, 23/11, and 32/14 respectively. There was no evidence for a diminution of the treatment effect over time.
 
A few other very small case series have been published, reporting BP outcomes and adverse events from the procedure (Tsioufis, 2012; Mabin, 2012; Simonetti, 2012; Prochnau, 2012). The numbers of patients in these case series ranged from 2-12, which is generally too small to provide meaningful group outcome data.
 
Ongoing trials
A search of ClinicalTrials.Gov with the terms “renal artery denervation” yielded 24 relevant trials. Most of these were single-arm series of different types of renal artery denervation in various patient populations. There were 5 RCTs listed of renal denervation as a treatment for resistant hypertension, these are described briefly below.
 
Simplicity HTN-3 trial (NCT01418261). The Simplicity HTN-3 trial is a larger randomized, controlled trial of renal denervation with similar methodology as the Simplicity HTN-2 trial (Kandzari, 2012). Enrollment is planned for approximately 500 patients, who will be randomized to renal denervation or standard care. The primary efficacy endpoint is reduction in BP from baseline to 6 months. Other efficacy endpoints include the percent of patients achieving target BP and medication use. Safety endpoints include overall mortality, change in renal function, renal perforation, renal artery dissection, vascular complications, and hospitalizations for hypertension. The trial is expected to be completed in 2013-2014.
 
ReSET trial (NCT01459900). The Renal Sympathectomy in Treatment of Resistant Essential Hypertension (ReSET) trial is a sham-controlled, double-blind RCT of patients with elevated BP despite treatment with at least 3 medications. The primary endpoint is change in daytime systolic BP at 6 months of follow-up. Enrollment is planned for 70 patients, with an estimated study completion date of May 2013.
 
DEPART trial (NCT01522430). The Study of Catheter-based Renal Denervation Therapy in Hypertension (DEPART) trial is a sham-controlled, double-blind RCT of patients with elevated BP despite treatment with at least 3medications. The primary endpoints are changes in systolic/diastolic BP and glomerular filtration rate at 6 months of follow-up. Enrollment is planned for 120 patients, with an estimated study completion date of December 2016.
 
DENER-HTN trial (NCT01570777). The Renal Denervation in Hypertension (DENER-HTN) trial is a multicenter, unblinded RCT of patients with elevated BP despite treatment with at least 3 medications. The primary endpoint is change in daytime systolic BP at 6 months of follow-up. Enrollment is planned for 120 patients, with an estimated study completion date of July 2014.
 
RELIEF trial (NCT01628172). The Renal Sympathetic Denervation for the Management of Chronic Hypertension (RELIEF) trial is a single-blind RCT of patients with elevated BP despite treatment with at least 3 medications. The primary endpoint is change in 24-hour ambulatory BP at 6 months of follow-up. Enrollment is planned for 100 patients, with an estimated study completion date of January 2014.
 
Summary
RFA of the renal sympathetic nerves is a non-pharmacologic treatment for hypertension and has been proposed as a treatment option for patients with resistant hypertension. There are currently no devices that have FDA-approval for this indication. This is an active area of research, with numerous ongoing RCTs, including at least 2 double-blind, sham-controlled RCTs.
 
The published evidence consists of one small, short-term RCT that reports efficacy in reducing blood pressure over a 6-month time period. Other small studies with overlapping populations also report improvements in related physiologic parameters, such as echocardiographic measures of LVH. One case series suggests that improvements may be durable up to 24-months’ follow-up. There is no evidence that reports improvements in health outcomes as a result of treatment with RFA of the renal sympathetic nerves. Potential complications of this procedure include vascular access problems, perforation of the renal artery, and renal artery stenosis, but rates of complications have not been well-established. This evidence is insufficient to determine whether health outcomes are improved.
 
2014 Update
A literature search conducted through August 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
The published evidence consists of 4 RCTs, along with multiple nonrandomized comparative studies and case series. The largest and most recent trial, the Symplicity HTN-3 trial, which used a sham-controlled design to reduce the likelihood of placebo effect, demonstrated no significant differences between renal denervation and sham-control patients in office-based or ambulatory blood pressure (BP) at 6-month follow-up. The Symplicity HTN-3 results were in contrast to earlier studies, the largest of which, Symplicity HTN-2, reported efficacy in reducing blood pressure (BP) over a 6-month time period compared with a control group, and an extension study reported 12-month BP follow-up for treated patients in an uncontrolled fashion. Symplicity HTN-2 trial reported a decrease in systolic BP of approximately 30 mm Hg and a decrease in diastolic BP of approximately 10 mm Hg at 6 months and that this reduction was largely maintained at 12 months.
 
Single-arm studies with overlapping populations also report improvements in BP and related physiologic parameters, such as echocardiographic measures of left-ventricular hypertrophy, that appear to be durable up to 24-months of follow-up. There is no evidence that reports improvements in clinical outcomes as a result of treatment with RFA of the renal sympathetic nerves. Potential complications of this procedure include vascular access problems, perforation of the renal artery, and renal artery stenosis, but rates of complications have not been well-established. Given the findings from the Symplicity HTN-3 trial and evidence from earlier studies, it is uncertain whether RFA improves health outcomes compared with continued medical therapy, and therefore RFA of the renal sympathetic nerves is considered investigational.
 
SYMPLICITY HTN-3 Results of the Symplicity HTN-3 trial, a multicenter, single-blinded, randomized, sham-controlled trial of renal denervation were published in 2014 (Bhatt, 2014). Included patients had severe, resistant hypertension, with a systolic BP of 160 mm Hg or higher, on maximally tolerated doses of at least 3 antihypertensive medications of complementary classes, 1 of which had to be a diuretic at an appropriate dose. Five-hundred thirty-five patients were randomized to renal denervation with the Medtronic Symplicity renal denervation catheter or to renal angiography only (sham control).  Changes in antihypertensive medication were not allowed during the 6-month follow-up period unless they were considered to be clinically necessary. The primary efficacy end point was the mean change in office systolic BP from baseline to 6 months in the denervation group, compared with the mean change in the sham control group. The secondary efficacy end point was the change in mean 24-hour ambulatory systolic blood pressure at 6 months. The primary safety end point was a composite of major adverse events, defined as death from any cause, end stage renal disease, an embolic event resulting in end-organ damage, renal-artery or other vascular complications, or hypertensive crisis within 30 days or new renal-artery stenosis of more than 70% within 6 months.
 
At the 6-month follow-up point, there was no significant between-group difference in the change in office BP. There was a change in systolic BP (SBP) of −14.13±23.93 mm Hg in the denervation group versus −11.74±25.94 mm Hg in the sham control group, for a difference of −2.39 mm Hg (95% CI, −6.89 to 2.12; p=0.26 with a superiority margin of 5 mm Hg). At 6-month follow-up, the change in ambulatory BP was −6.75±15.11 mm Hg in the denervation group versus −4.79±17.25 mm Hg in the sham control group, for a difference of −1.96 mm Hg (95% CI, −4.97 to 1.06; p=0.98 with a superiority margin of 2 mm Hg). Major adverse event rates were similar between the denervation and control groups 1.4% and 0.6%, respectively).
 
Strengths of this study include its large size and blinded, sham-controlled design, which reduce the likelihood of a placebo effect. A limitation of the present publication is that the follow-up period reported is relatively short, leading to an underdetection of a treatment benefit differences between the groups manifest over time. The study subjects, including those who do not cross over to renal denervation, will be followed for 5 years to assess longer term outcomes.
 
Bakris et al reported more detailed ambulatory BP results from the Symplicity HTN-3 trial (Bakris. 2014). The change in average 24-hour ambulatory systolic and diastolic BP were as reported by Bhat et al. There were no significant differences in change in ambulatory BP between the renal denervation and control groups for any of the prespecified subgroup analyses, including the presence of coexisting diabetes mellitus; sex; race; body mass index of 30 kg/m2 or more; eGFR of 60 mL/min/1.73 m2 or more; age of 60 years or older; or any medication change during the study.
 
Three-year follow-up data from the Symplicity HTN-2 trial were reported in 2014 (Esler, 2014).  Follow-up was available for 40 of 52 subjects in the initial RFA group and for 30 of 37 subjects who were initially in the control group but who crossed over and received renal denervation 6 months after enrollment. After 30 months, the mean change in SBP was -34 mm Hg (95% CI, -40 to -27, p<0.01) and the mean change in DBP was -13 mm Hg (95% CI, -16 to -10, p<0.01). The degree of BP change was similar between the randomized and crossover subjects. Subjects in the initial RFA group had follow-up available at 36 months; at that point, the mean change in SBP was -33 mm Hg (95% CI, -40 to -25, p<0.01) and the mean change in DBP was -14 mm Hg (95% CI, -17 to -10, p<0.01). Beyond 12 months of follow-up, safety events included 5 hypertensive events requiring hospitalization; 1 case of mild transient acute renal failure due to dehydration; 2 episodes of atrial fibrillation requiring hospitalization; 1 case of acute renal failure due to acute interstitial nephritis that was deemed unrelated to renal denervation treatment; and 3 deaths that were deemed unrelated to the device or therapy.
 
The main limitations of this RCT are that it is small in size, unblinded, and has only a relatively short follow-up for the controlled portion of the trial. A trial with a sham control would allow better determination of whether the treatment effect was due to a placebo effect, or other nonspecific effects of being in a trial. The 6-month follow-up reported for the controlled portion of the trial is too short to ascertain whether the reduction in BP is likely to reduce adverse cardiovascular outcomes such as myocardial infarction (MI) and stroke. The 12- and 36-month follow-up reports provide some insight into longer-term outcomes following the procedure, although comparison with a control group is no longer possible due to the crossover design.
 
It is unknown whether re-innervation of the renal sympathetic nerves occurs post-treatment. If reinnervation does occur, the efficacy of the procedure will diminish over time. The BP change appears to be stable over the longer-term follow-up studies, suggesting that re-innervation did not occur in the 36-month follow-up.
 
Other RCTs
Fadl Elmula et al reported results from a smaller RCT that compared renal denervation with clinically-adjusted drug treatment in treatment-resistant hypertension after patients with poor drug adherence were excluded (Fadl, 2014). The study enrolled patients with office SBP greater than 140 mm Hg, in spite of maximally tolerated doses of at least 3 antihypertensive drugs, including a diuretic, and required that patients had an ambulatory daytime SBP greater than 135 mm Hg after witnessed intake of antihypertensive drugs. Twenty patients were randomized, 10 to adjusted drug treatment and 10 to renal denervation with the Symplicity renal denervation catheter (1 of whom was subsequently excluded due to a diagnosis of secondary hypertension). In the drug-adjusted group, the office SBP changed from 160±14 mm Hg at baseline to 132±10 mm Hg at 6-month follow-up (p<0.000); in the renal denervation group, the office SBP changed from 156±13 mm Hg at baseline to 148±7 mm Hg at 6-month follow-up (p=0.42). SBP and DBP were significantly lower in the drug-adjusted group at 6-month follow-up.
 
Section Summary
Several RCTs have compared renal denervation with drug therapy for the treatment of resistant hypertension, with conflicting results. The most rigorous evidence about the efficacy of renal denervationcomes from the largest of these trials, the Symplicity HTN-3 trial, which used a single-blinded, sham-controlled design to reduce the risk of placebo effect and showed no significant improvements in BP control with renal denervation at 6 months. The difference in findings between the Symplicity HTN-3 trial and earlier trials (ie, Symplicity HTN-2) suggests that the treatment effect seen in nonblinded trials may have been due to a placebo effect, or other nonspecific effects of being in a trial. Alternatively, BP control in the control arm may have been better in Simplicity HTN-3 trial compared with earlier studies.
 
Systematic Reviews
Several systematic reviews that have included RCTs and nonrandomized studies have been published, although none include the Symplicity HTN-3 trial. In 2013, Davis et al11 published a systematic review and meta-analysis of renal denervation that included 2 RCTs (the Symplicity HTN-2 trial  and Pokushalov et al, described in the “Randomized Controlled Trials” section), 1 observational study with a control group, and 9 observational studies without a control group. In the 3 controlled studies, compared with medical treatment at 6 month follow-up, renal denervation was associated with a reduction in mean SBP of -28.9 mm Hg (95% CI, -37.2 to -20.6; p<0.000) and in mean DBP of -11 mm Hg (95% CI, -16.4 to -5.7; p<0.000). In uncontrolled studies, compared with prerenal denervation values, at 6 months of follow-up, SBP and DBP changed by -25.0 mm Hg (95% CI, -29.9 to -20.1) and -10.0 mm Hg (95% CI, -12.5 to -7.5) respectively.
 
Shantha et al conducted a systematic review and meta-analysis to evaluate the effects of renal denervation on obstructive sleep apnea (Shantha, 2014). In a pooled analysis of 5 noncontrolled studies that included 49 patients, renal denervation was associated with a reduction in mean apnea-hypopnea index at 6 months post-procedure (weighted mean difference, -9.61, 95% CI, -15.43 to -3.79, p=0.001
 
Nonrandomized Comparative Studies
Ewen et al evaluated the impact of renal denervation on BP, heart rate, and chronotropic index at rest, during exercise, and at recovery in 60 patients with resistant hypertension (50 who underwent renal denervation and 10 control patients) (Ewen. 2014). At 6-month follow-up, office BP was reduced by 26/7 mm Hg to 138±3/84±2 mm Hg in the renal denervation group (p<0.001 for both), whereas there was no significant change in BP in the control group (BP reduced by 2/0 mm Hg to 153±5/87±1 mm Hg; p=0.750/p=0.611). At 6- month follow-up, the intervention group demonstrated a significant reduction in percent of maximum systolic BP from baseline during exercise and recover.
 
 
Case Series
Krum et al reported 3-year follow-up for patients in the Symplicity HTN-1 study in 2014 (Krum. 2014). Among 88 patients who had complete follow-up data at 36 months, the mean change in SBP was -32 mm Hg (95% CI, -35.7 to -28.2) and DBP was -14.4 mm Hg (95% CI, -16.9 to -11.9). The proportion of patients with a SBP decrease of 10 mm Hg or more was stable over time: 69% at 1 month; 81% at 6 months; 85% at 12 months; 83% at 24 months; and 93% at 36 months. Adverse events included 4 cases of possible or suspected renal artery stenosis, 1 of which required stenting; 3 deaths that were deemed unrelated to the device or procedure; 2 hospitalizations for acute renal failure in the setting of other illnesses; and 13 hospitalizations for hypertensive episodes.
 
Numerous other small nonrandomized studies and case series have been published, reporting BP outcomes and adverse events from the procedure. These case series generally report similar BP reductions, as do the controlled studies with few complications. Some studies have reported on different populations such as the elderly population (Ziegler, 2013), those with moderately resistant HTN, and in patients with chronic kidney disease, or with an accessory renal artery.38 Other studies report additional outcomes, including improvements in quality of life,  favorable changes in renal hemodynamics,  changes in neurohormonal measurements (Ezzahti, 2014), improvements in LV mass and function (Mahfoud, 2014; Schirmer, 2014), changes in PR interval and heart rate (Ukena, 2013), reduction in microalbuminuria (Ott, 2014) and improvements in measures of vascular function.
 
Ongoing and Unpublished Clinical Trials
A search of online database ClinicalTrials.gov with the terms “renal denervation” AND “hypertension” yielded 58 interventional studies actively recruiting patients. There were a number of ongoing RCTs listed of renal denervation as a treatment for resistant hypertension, which are described briefly next. There were also several RCTs of renal denervation plus cardiac ablation for atrial fibrillation versus cardiac ablation alone; these studies are not included on this list.
  • A Study of Renal Denervation in Patients With Treatment Resistant Hypertension (PaCE) (NCT01895140) – This is an open-label, randomized controlled trial to compare early renal denervation to delayed renal denervation, both with the Medtronic Symplicity catheter device, for patients with treatment-resistant hypertension. The primary outcome measure is average systolic 24-hour ambulatory BP. Enrollment is planned for 104 subjects; the estimated study completion date is November 2016.
  • Renal Denervation in Patients With Resistant Hypertension and Obstructive Sleep Apnea (NCT01366625) – This is an open-label RCT to compare renal denervation with the Medtronic Symplicity catheter device, along with continued antihypertensive medications and continuous positive airway pressure, to routine care, for patients with treatment-resistant hypertension and obstructive sleep apnea. Enrollment is planned for 60 patients; the estimated study completion date is December 2014.  
  •  Rapid Renal Sympathetic Denervation for Resistant Hypertension II (RAPID II) (NCT01939392) – This is an open label, Phase II/III RCT to compare bilateral renal ablation with the Covidien OneShot system with optimal medical therapy for patients with uncontrolled hypertension. Primary outcome measures are major adverse events for 30 days after randomization and change in office SBP from baseline to 6 months postrandomization. Enrollment is planned for 253 subjects; the estimated study completion date is September 2018.  
  • Renal Sympathetic Denervation for Treatment of Metabolic Syndrome Associated Hypertension (Metabolic Syndrome Study) (NCT01911078) – This is an open-label RCT to compare renal denervation with the St. Jude EnligHTN™ Renal Denervation System with control in patients with hypertension (excluding resistant or secondary hypertension) in the setting of the metabolic syndrome. The primary outcome measure is the change in insulin resistance from baseline to 3 months after renal denervation. Enrollment is planned for 60 subjects; the estimated study completion date is January 2015.  
  • Renal Denervation for Management of Drug-Resistant Hypertension (INSPiRED) (NCT01505010) – INSPiRED is a single-blinded, RCT to compare renal denervation with standard treatment for patients with treatment-resistant hypertension. The primary outcome measures are decrease in SBP on ambulatory measurement and change in glomerular filtration rate. Enrollment is planned for 240 subjects; the estimated study completion date is April 2016. The study’s protocol has been published.
  • Renal Denervation for Uncontrolled Hypertension (RDNP-2012-02) (NCT02016573) – This is an open-label RCT to compare renal denervation with the Medtronic Symplicity Renal Denervation Catheter to routine care for patients with uncontrolled hypertension. The primary outcome measure is the percentage of patients who achieve a BP target at 6 months postintervention. Enrollment is planned for 100 subjects; the estimated study completion date is December 2015.  
  • Renal Denervation for Resistant Hypertension (RDNP-2012-01) (NCT01865240) – This is an open label, RCT to compare renal denervation with the Symplicity Renal Denervation Catheter with routine care for patients with refractory hypertension. The primary end point is percentage of patients to achieve BP target (BP <140/90 mm Hg, or <130/80 mm Hg in diabetic patients) at 6 months postprocedure. Enrollment is planned for 100 subjects; the estimated study completion date is February 2016.  
  • Sham Controlled Study of Renal Denervation for Subjects With Uncontrolled Hypertension (WAVE_IV) (NCT02029885) – This is a randomized, double-blinded, sham-controlled trial to compare an ultrasound-based renal denervation system (the Surround Sound system) with sham control for patients with refractory hypertension. The primary outcome measures are safety at 6 weeks postprocedure and change in office SBP from screening to 6 months postprocedure. Enrollment is planned for 126 subjects; the estimated study completion date is September 2016.  
  • Sympathetic Renal Denervation Versus Increment of Pharmacological Treatment in Resistant Arterial Hypertension (NCT02039492) – This is an open label, randomized trial to compare renal denervation with aldactone for the management of treatment-resistant hypertension. The primary outcome measure is the change in ambulatory 24h-SBP from baseline to 6 months of follow-up. Enrollment is planned for 50 subjects; the estimated study completion date is December 2015.  
  • Denervation of the renAl sympathetic nerveS in hearT Failure With nOrmal Lv Ejection Fraction (DIASTOLE) (NCT01583881) – DIASTOLE is an open-label randomized trial to compare renal denervation with standard of care for patients with heart failure with preserved ejection fraction and hypertension. Enrollment is planned for 60 subjects; the estimated study completion date is December 2014.  
  • Renal Denervation to Improve Outcomes in Patients With End-stage Renal Disease (NCT02021019) – This is an open-label, RCT to compare renal denervation with standard of care for patients with end-stage renal disease and hypertension. The primary outcome measure is BP change (office-based) from enrollment to 6 months of follow-up. Enrollment is planned for 100 subjects; the estimated study completion date is December 2016.  
  • Renal Denervation in Patients With Heart Failure With Normal LV Ejection Fraction (NCT02115230) – This is an open-label RCT to compare renal denervation with irrigated RF catheter with Celsius Thermocool (Biosense Webster, California, US) with standard medical therapy for patients with hypertension and heart failure with normal ejection fraction and LV hypertrophy. Enrollment is planned for 40 subjects; the estimated study completion date is July 2016.  
  • Renal Sympathetic Denervation and Insulin Sensitivity (RENSYMPIS Study) (NCT01785732) – RENSYMPIS is an open-label, RCT to compare renal denervation with optimized medical therapy for the treatment of resistant hypertension. The primary outcome measure is office BP at 2 years post-intervention. Enrollment is planned for 60 subjects; the estimated study completion date is January 2016.  
  • Renal Denervation in Patients With Uncontrolled Blood Pressure (NCT01968785) – This is a double-blind, RCT to compare 2 radiation doses for the sympathetic renal denervation for patients with refractory hypertension. Enrollment is planned for 20 subjects; the estimated study completion date is December 2014.  
  • Renal Sympathetic Denervation as a New Treatment for Therapy Resistant Hypertension (SYMPATHY) (NCT01850901) – SYMPATHY is an open-label RCT to compare renal denervation with standard care for patients with medication-resistant hypertension. The primary outcome measure is change in average day-time SBPat 6 months post-procedure. Enrollment is planned for 300 subjects; the planned study completion date is June 2016.  
  • Renal Denervation in Patients After Acute Coronary Syndrome (ACSRD) (NCT01901549) – This is a double-blind, RCT to compare renal denervation (with percutaneous coronary intervention [PCI] and medical therapy) with PCI and medical therapy in patients with acute coronary syndrome and hypertension. The primary outcome measures are the rates of cardiovascular death, MI, stroke, and repeat revascularization in the year following the procedure. Enrollment is planned for 80 subjects; the planned study completion date is June 2016.
  • Radiofrequency Ablation for ADPKD Blood Pressure and Disease Progression Control (RAFALE) (NCT01932450) – RAFALE is an open-label RCT to compare renal denervation (with antihypertensive medications) with antihypertensive medications alone in the treatment of hypertension in patients with autosomal dominant polycystic kidney disease. The primary outcome measure is office-based blood pressure measurements. Enrollment is planned for 100 subjects; the planned study completion date is July 2015.  
  • Renal Denervation in Heart Failure Patients With Preserved Ejection Fraction (RESPECT-HF) (NCT02041130) – RESPECT-HF is an open-label RCT to compare renal denervation with the Symplicity Renal Denervation Catheter to routine care for patients with heart failure with preserved ejection fraction, with or without hypertension. Enrollment is planned for 144 subjects; the planned study completion date is December 2016.  
  •  Full Length Versus Proximal Renal Arteries Ablation (NCT01848275) – This is an open-label RCT to compare renal sympathetic denervation with the Thermocool catheter system for the whole length of the renal arteries with ablation through the proximal renal arteries for patients with drug-resistant hypertension. Enrollment is planned for 40 subjects; the planned study completion date is listed as December 2013, but no results have been posted.  
  • Renal Denervation in Treatment Resistant Hypertension (ReSET-2) (NCT01762488) – This is a randomized, double-blind trial to compare renal denervation to a sham comparator of renal angiography in patients with resistant hypertension. The primary end point is change in 24-hour ambulatory BP. Planned enrollment is for 70 patients; the estimated primary completion date is December 2014.  
  •  Renal Denervation by Allegro System in Patients with Resistant Hypertension (NCT01874470). This is a randomized, open-label study of renal denervation compared with standard medication in patients with resistant hypertension. The primary end point is change in SBP measured by 24-hour ambulatory monitor. Planned enrollment is for 160 patients; the estimated study completion date of was April 2014. No results have been posted.  
  • Renal Denervation by MDT-2211 System in Patients with Uncontrolled Hypertension (NCT01644604). This is a randomized, open-label study of renal denervation versus standard care in patients with uncontrolled hypertension. The primary end point is change in office BP. Planned enrollment is for 100 patients, with an estimated study completion date of March 2018.  
  • Renal Sympathectomy in Treatment Resistant Essential Hypertension, a Sham Controlled Randomized Trial (ReSET) trial (NCT01459900). (ReSET) is a sham-controlled, double-blind RCT of patients with elevated BP despite treatment with at least 3 medications. The primary end point is change in daytime SBP at 6-month follow-up. Enrollment is planned for 70 patients, with an estimated study completion date of April 2015.  
  • Effect of Renal Denervation on NO-mediated Sodium Excretion and Plasma Levels of Vasoactive Hormones (RENO) (NCT01617551) – RENO is a substudy of the ReSET trial (NCT01459900) to evaluate the effects of renal denervation on the effects of nitric oxide-mediated inhibition of renal, hemodynamic, and hormonal variables. This substudy’s primary outcome measure is the fractional excretion of sodium after acute L-NMMA treatment. Enrollment for this substudy is planned for 30 patients; the estimated study completion date is listed as June 2014, although no results have been posted.  
  • Study of Catheter Based Renal Denervation Therapy in Hypertension (DEPART) (NCT01522430). The (DEPART) trial is a sham-controlled, double-blind RCT of patients with elevated BP, despite treatment with at least 3 medications. The primary end points are changes in SBP/DBP and glomerular filtration rate at 6 months of follow-up. Enrollment is planned for 120 patients, with an estimated study completion date of December 2016.  
  • Renal Denervation in Hypertension (DENER-HTN) trial (NCT01570777). (DENER-HTN) trial is a multicenter, unblinded RCT of patients with elevated BP, despite treatment with at least 3 medications. The primary end point is change in daytime systolic BP at 6-month follow-up. Enrollment is planned for 121 patients, with an estimated study completion date of April 2018.  
  • Renal Sympathetic Denervation for the Management of Chronic Hypertension (RELIEF) trial (NCT01628172). (RELIEF) is a single-blind RCT of patients with elevated BP, despite treatment with at least 3 medications. The primary end point is change in 24-hour ambulatory BP at 6-month follow-up. Enrollment is planned for 100 patients, with an estimated study completion date of January 2015.  
 
Summary of Evidence
Radiofrequency ablation (RFA) of the renal sympathetic nerves is a nonpharmacologic treatment for hypertension and has been proposed as a treatment option for patients with resistant hypertension. There are currently no devices that have FDA-approval for this indication. This is an active area of research, with numerous ongoing randomized controlled trials (RCTs).
 
The published evidence consists of 4 RCTs, along with multiple nonrandomized comparative studies and case series. The largest and most recent trial, the Symplicity HTN-3 trial, which used a sham-controlled design to reduce the likelihood of placebo effect, demonstrated no significant differences between renal denervation and sham-control patients in office-based or ambulatory blood pressure (BP) at 6-month follow-up. The Symplicity HTN-3 results were in contrast to earlier studies, the largest of which, Symplicity HTN-2, reported efficacy in reducing BP over a 6-month time period compared with a control group, and an extension study reported 12-month BP follow-up for treated patients in an uncontrolled fashion. This Symplicity HTN-2 trial reported a decrease in SBP of approximately 30 mm Hg and a decrease in DBP of approximately 10 mm Hg at 6 months and that this reduction was largely maintained at 12 months.
 
Single-arm studies with overlapping populations also report improvements in BP and related physiologic parameters, such as echocardiographic measures of LV hypertrophy, that appear to be durable up to 24-months of follow-up. There is no evidence that reports improvements in clinical outcomes as a result of treatment with RFA of the renal sympathetic nerves. Potential complications of this procedure include vascular access problems, perforation of the renal artery, and renal artery stenosis, but rates of complications have not been well-established. Given the findings from the Symplicity HTN-3 trial and evidence from earlier studies, it is uncertain whether RFA improves health outcomes compared with continued medical therapy, and therefore RFA of the renal sympathetic nerves is considered investigational.
 
Practice Guidelines and Position Statements
In 2013, the European Society of Cardiology issued an expert consensus statement46 on catheter-based renal denervation that makes the following conclusions:
“Current evidence from the available clinical trials strongly support the notion that catheter-based radiofrequency ablation of renal nerves reduces blood pressure and improves blood pressure control in patients with drug-treated resistant hypertension, with data now extending out to 36 months. Accordingly, renal denervation can be considered as a therapeutic option in patients with resistant hypertension, whose blood pressure cannot be controlled by a combination of lifestyle modification and pharmacological therapy according to current guidelines.”
 
The statement outlined the following criteria patients should meet before renal denervation is considered:
  • Office-based systolic blood pressure (BP) ≥160 mm Hg (≥150 mm Hg in type 2 diabetes.)
  •  ≥3 antihypertensive drugs in adequate dosage and combination (including a diuretic).
  • Lifestyle modification.
  • Exclusion of secondary hypertension.
  • Exclusion of pseudoresistance using ambulatory blood pressure monitoring (average BP >130 mm Hg or mean daytime BP >135 mm Hg)
  • Preserved renal function (GFR ≥45 mL/min/1.73 m2)
  • Eligible renal arteries: no polar or accessory arteries; no renal artery stenosis; no prior revascularization.
 
2015 Update
A literature search conducted through August 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Randomized Controlled Trials
DENERHTN
In 2015, Azizi and colleagues published results of the Renal Denervation for Hypertension (DENERHTN) trial, a prospective; open-label randomized controlled trial with blinded endpoint evaluation (Azizi, 2015). The study randomized 106 adults with confirmed resistant hypertension who had undergone 4 weeks of standardized triple antihypertensive therapy with sustained-release indapamide, ramipril (or irbesartan in cases of cough), and amlodipine to either renal denervation or control. Both groups received standardized stepped-care antihypertensive treatment (SSAHT), which involved the sequential addition of spironolactone, bisoprolol, sustained-release prazosin for systolic and diastolic pressures of 135 mm Hg or higher or 85 mm Hg or higher, respectively. Spironolactone could be started for home systolic and diastolic pressures of 170 mm Hg or higher or 105 mmHg or higher, respectively. Analysis was conducted using a modified intent-to-treat design, after excluding 5 patients in the intervention group who were missing primary endpoint measurements. For the study’s primary efficacy endpoint, the mean decrease in daytime ambulatory systolic blood pressure (SBP) was greater in the renal denervation group than in the control group (mean baseline-adjusted difference between groups: -5.9 mmHg; 95% confidence interval [CI] -11.3 to -0.5 mm Hg; P=0.0329). There were similarly greater decreases in nighttime and 24-hour SBP in the renal denervation group than in the control group. Nighttime blood pressure control was achieved at 6 months in 31.3% of renal denervation patients (vs 11.3% of controls; P=0.0137) and 24- hour ambulatory blood pressure control was achieved in 39.6% of renal denervation patients (vs 18.9% of controls; P=0.0126). Rates of daytime blood pressure control did not differ significantly between groups. The number of antihypertensive treatments at 6 months did not differ significantly between groups (mean 5.25 for renal denervation patients vs 5.36 for control patients; P=0.7005). Three renal denervation related adverse events were reported (lumbar pain in 2 patients and mild groin hematoma in 1 patient).
 
Prague-15 Study
Rosa and colleagues reported results of the Prague-15 study, an open-label RCT comparing renal sympathetic denervation with intensified pharmacologic treatment in patients with resistant hypertension (Rosa, 2015).  Although study enrollment was planned for 120 subjects to have a 90% power in detecting a difference in treatment response between the 2 groups with an alpha of 0.05, the study was prematurely halted after the results of the Symplicity HTN-3 trial were published after enrollment of 112 subjects (56 in each group.) Patients in the renal denervation group were maintained on baseline medical therapy; those in the control group received baseline medical therapy plus spironolactone. After 6 months, both groups demonstrated significant reductions in 24 hour average SBP (-8.6 mm Hg, P<0.001 [vs baseline] for renal denervation patients; -8.1 mm Hg, P=0.001 [vs baseline] for control patients. After 6 months, there were no significant differences in the absolute value of or the change in any of the blood pressure parameters reported between the renal denervation and control group.
 
Symplicity HTN-3
Bakris and colleagues reported 12-month follow-up from the Symplicity HTN-3 trial, including the original denervation group, the sham subjects who crossed over to renal denervation, and the sham subjects who did not cross over (Bakris, 2015). The 12-month follow-up was available for 319 of 361 denervation subjects and 48 of 101 non-crossover subjects and 6 month denervation follow-up was available for 93 of 101 crossover subjects. At 12 months of follow up, the changes in office SBP compared with baseline were significantly greater than at 6 months of follow up in the renal denervation group (-18.9 vs -15.5 mm Hg, P=0.025). However, there were no significant differences in ambulatory blood pressure monitoring between the 12 and 6 months results in the renal denervation group. In the crossover group, the 6 month drop in office SBP and 24-hour ambulatory SBP were -17.7 mm Hg (P<0.001 for comparison with baseline) and -9.2 mm Hg (P<0.001 for comparison with baseline), respectively. In the non-crossover group, 48 subjects had 12 month data available. Among those, the change in office SBP from baseline to 6 months was -32.9 mm Hg; the change in office SBP from 6 to 12 months was an increase of 11.5 mm Hg, for an overall SBP drop from baseline to 12 months of -21.4 mm Hg.
 
Other RCTs
Desch and colleagues reported results from a smaller RCT comparing renal sympathetic denervation with sham control among patients with treatment-resistant hypertension but only mildly elevated blood pressures (day-time SBP 135-149 mm Hg and DBP 90-94 mm Hg on 24 ambulatory monitoring) (Desch, 2015). Seventy-one patients were randomized to denervation (n=35) or sham control (n=35). Subjects and all investigators except for the physicians performing the active and sham procedures were blinded to treatment group. For the study’s primary endpoint, in intention-to-treat analysis, the mean change in 24-hour SBP at 6 months was -7.0 mm Hg for patients in the renal denervation group, compared with -3.5 mm Hg in the sham control group (P=0.15). In a per-protocol analysis, which excluded 2 patients in the renal denervation group who had incomplete procedures due to difficult anatomy or technical problems, and 1 patient for preexisting severe renal artery stenosis detected at 6 months, and 1 patient in the sham control group who did not receive the sham procedure, the change in 24-hour SBP at 6 months was -8 mm Hg in the renal denervation group, compared with -3.5 mmHg in the sham control group (P=0.042). The authors note that the trial may have been underpowered to detect a significant SBP effect.
 
Kario and colleagues reported results of the SYMPLICITY HTN-Japan study, which was an RCT comparing renal sympathetic denervation with standard pharmacotherapy in subjects with treatment-resistant hypertension (Kario, 2015). Enrollment was initially planned for 100 subjects, but the trial was halted early after results of the SYMPLICITY HTN-3 trial were published, after the randomization of 41 subjects (n=22 to renal denervation and n=19 to control). At 6 months, the change in SBP in renal denervation subjects was not significantly different than the change in SBP in control subjects (between-group difference -8.6; 95% CI -21.1 to 3.8; P=0.169). No major adverse events occurred. The authors note that the study was underpowered due to the early termination.
 
Another smaller trial which used sham control reported discrepant results between intention-to-treat and per-protocol analysis, but showed no significant improvements in SBP for patients treated with renal denervation compared with controls. Other trials which did not use a sham-control design, including the DENERHTN and Symplicity HTN-2 trials, did find a significant benefit in patients treated with renal denervation.
 
Systematic Reviews
In 2015, Fadl and colleagues published a systematic review of RCTs evaluating renal denervation for hypertension, which included 7 trials, including the Symplicity HTN-3 trial, along with the RCTs reported by Desch et al, Kario et al, Rosa et al, and Azizi et al after the result of Symplicity HTN-3 were published (Fadl, 2015).  Across the 7 trials, a total of 985 patients were randomized to control (n=397) or renal denervation (n=588). In pooled analysis, for office systolic blood pressure, the effect size of renal denervation compared with control (defined as the treatment effect at 6 months in the renal denervation group subtracted from that in the control group) was -4.89 mm Hg (95% CI -20.9 to 11.1 mm Hg; P=0.47). For 24-hour SBP, the pooled effect size of renal denervation compared with control was -2.81 mm Hg
(95% CI -6.46 to 0.83 mm Hg; P=0.11). Safety measures did not differ significantly between groups.
 
Several systematic reviews that have included RCTs and nonrandomized studies have been published. In 2014, Kwok and colleagues published a systematic review of renal denervation that included 3 RCTs (the Symplicity HTN-3 trial, the Symplicity HTN-2 trial, and Pokushalov et al, described in the “Randomized Controlled Trials Section), 8 prospective observational studies, and 1 observational study with matched controls (Kwok, 2014).  Similarly, Pancholy et al published a systematic review of renal denervation that included the same 3 RCTs, along with 2 nonrandomized controlled trials. Previous systematic reviews and meta-analyses, including those by Davis et al and Shantha et al did not include the Symplicity HTN-3 trial or subsequently-reported RCTs.
 
Additional case series report safety and effectiveness outcomes after use of newer-generation renal denervation systems, including the OneShot Renal Denervation System (Verheye, 2015) and the Vessix Renal Denervation System (Sievert, 2015).
 
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this policy are listed below:
Ongoing
(NCT02439749) Global Clinical Study of Renal Denervation With the Symplicity Spyral™ Multi-electrode Renal Denervation System in Patients with Uncontrolled Hypertension in the Absence of Antihypertensive Medications (SPYRAL HTN-OFF MED): planned enrollment 120: projected completion date February 2020.
 
(NCT02439775) Global Clinical Study of Renal Denervation With the Symplicity Spyral™ Multi-electrode Renal Denervation System in Patients with Uncontrolled Hypertension on Standard Medical Therapy (SPYRAL HTN-ON MED): planned enrollment 100: projected completion date October 2019.
 
(NCT01366625) Effects of Renal Denervation on Blood Pressure and Clinical Course of Obstructive Sleep Apnea in Patients with Resistant Hypertension: planned enrollment 60: projected completion date December 2015.
 
(NCT01911078) Renal Sympathetic Denervation in Metabolic Syndrome (Metabolic Syndrome Study): planned enrollment 60: projected completion date June 2016.
 
(NCT01505010) Investigator-Steered Project on Intravascular Renal Denervation for Management of Drug-Resistant Hypertension: planned enrollment 240: projected completion date April 2016.
 
(NCT02016573) Renal Denervation for Uncontrolled Hypertension: planned enrollment 100: projected completion date December 2015.
 
(NCT01865240) Renal Denervation for Resistant Hypertension: planned enrollment 100: projected completion date February 2016.
 
(NCT02029885) Wave IV Study: Phase II Randomized Sham Controlled Study of Renal Denervation for Subjects with Uncontrolled Hypertension (an industry sponsored or cosponsored trial): planned enrollment 300: projected completion June 2016.
 
(NCT01901549) Renal Denervation in Patients after Acute Coronary Syndrome: planned enrollment 80: projected completion date June 2016.
 
(NCT02041130) Renal Sympathectomy in Heart Failure (the RESPECT-HF Study) – a Study of Renal Denervation for Heart Failure with Preserved Ejection Fraction: planned enrollment 144: projected completion date December 2016.
 
(NCT01459900) Renal Sympathectomy in Treatment Resistant Essential Hypertension, a Sham Controlled Randomized Trial: planned enrollment 70: projected completion date April 2015.
 
(NCT01523430) Denervation of Renal Sympathetic Activity and Hypertension Study: planned enrollment 120: projected completion date December 2016.
 
Unpublished
(NCT01932450) A Randomized, Open-label Study Investigating the Effect of Bilateral Renal Artery Sympathetic Denervation by Catheter-based Radiofrequency Ablation on Blood Pressure and Disease Progression in Autosomal Dominant Polycystic Kidney Disease: planned enrollment 100: projected completion date July 2015.
 
(NCT01628172) Renal Sympathetic Denervation for the Management of Chronic Hypertension (an industry sponsored or cosponsored trial): planned enrollment 100: projected completion date January 2015.
 
(NCT01895140) A Pragmatic Randomized Clinical Evaluation of Renal Denervation for Treatment Resistant Hypertension (an industry sponsored or cosponsored trial): planned enrollment 104: terminate date October 2014.
 
The evidence for the use of radiofrequency ablation (RFA) of the renal sympathetic nerves for individuals with resistant hypertension includes 8 randomized controlled trials (RCTs), along with multiple on randomized comparative studies and case series. Relevant outcomes are symptoms, change in disease status, morbid events, medication use, and treatment-related morbidity. The largest trial, the Symplicity HTN-3 trial, which used a sham-controlled design to reduce the likelihood of placebo effect, demonstrated no significant differences between renal denervation and sham-control patients in office-based or ambulatory blood pressure (BP) at 6-month follow-up. The Symplicity HTN-3 results were in contrast to additional studies, including Symplicity HTN-2 and DENERHTN, which reported efficacy in reducing BP over a 6-month time period compared with a control group. Additional smaller RCTs, some of which were stopped early after results of the Symplicity HTN-3 trial became available, did not demonstrate significantly improved outcomes with renal denervation. Single-arm studies with overlapping populations also report improvements in BP and related physiologic parameters, such as echocardiographic measures of left ventricular hypertrophy that appear to be durable up to 24-months of follow-up. The body of evidence for the use of renal denervation to treat hypertension consists of RCTs that have conflicting results. The strongest evidence comes from sham-controlled trials, the largest of which found no significant benefits with renal denervation. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
 
2016 Update
A literature search conducted through August 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Additional analyses from Symplicity HTN-3 have reported on the effects of renal denervation on nocturnal blood pressure and cardiac physiology and analyses of population subgroups (Kario, 2015; Lu, 2016; Flack, 2015).
 
In 2016, Mathiassen and colleagues reported results of an additional sham controlled, doubled-blind, randomized, controlled trial to evaluate the efficacy of renal denervation in patients with treatment-resistant refractory hypertension (Matiassen, 2016).  In this study, 69 patients with treatment-resistant hypertension were randomized to renal denervation (N=36) or sham treatment (N=33). For the study’s primary efficacy endpoint, reduction in daytime systolic ambulatory blood pressure (after adjustment for changes in antihypertensive medications), there were no significant between-group differences between at 3 months (-6.1 mmHg in the renal denervation group vs -4.7 mmHg in the sham group, P=0.73) or at 6 months (-6.9 mmHg in the renal denervation group vs -2.6 in the sham group, P=0.35).
 
In 2015, Schneider and colleagues published the ISAR-denerve study, which evaluated the results of renal denervation in patients following renal transplantation. A total of 18 patients were randomized 1:1 to renal denervation or best medical therapy alone (Schneider, 2015). The study was not blinded. Office BPs was measured at 30 days and 6 months post-procedure. For the primary efficacy endpoint of mean change in office BP from baseline to 6 months post-randomization, a difference of 24/11 in reduction in office-based BP was noted between groups (P<0.001 for SBP and P=0.09 for DBP; CIs not reported) at 6 month follow up. There was no change in mean 24-h ABPM for either group.
 
In the DENERVHTA study, 27 patients with hypertension resistant to 3 drugs were randomized in a 1:1 ratio to renal denervation (n=13) or the addition of spironolactone (n=14) (Oliveras, 2016) Subjects and investigators were unblended. A total of 11 and 12 subjects in the renal denervation and spironolactone groups, respectively, completed the study; analysis was intention-to-treat. At 6 months, after adjustment for age, sex, and baseline 24-hour SBP, there was a significantly greater improved reduction in 24-hour ambulatory SBP in the spironolactone group of -17.9 mmHg (95% CI -30.9 to -4.9 mmHg, P=0.01), with similar reductions in 24-hour ambulatory DBP. There were no statistically significant differences in office BP between groups.
 
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed below:
 
Ongoing:
(NCT01583881) Sympathetic Renal Denervation in Heart Failure with Normal LV Ejection Fraction: Denervation of the renal sympathetic nerves in Heart Failure With normal LV Ejection Fraction; planned enrollment 60; completion date July 2016
 
(NCT02021019) Renal Denervation to Improve Outcomes in Patients with End-stage Renal; planned enrollment 100; completion date – December 2016
 
(NCT02439775) Global Clinical Study of Renal Denervation with the Symplicity Spyral™ Multi-electrode Renal Denervation System in Patients with Uncontrolled Hypertension on Standard Medical Therapy (SPYRAL HTN-ON MED); planned enrollment 100; completion date September 2020
 
Unpublished
(NCT02039492) Sympathetic Renal Denervation Versus Increment of Pharmacological Treatment in Resistant Arterial Hypertension; planned enrollment 50; completion date December 2015
 
(NCT01366625) Effects of Renal Denervation on Blood Pressure and Clinical Course of Obstructive Sleep Apnea in Patients With Resistant Hypertension; planned enrollment 60; completion date December 2015
 
(NCT09911078) Renal Sympathetic Denervation in Metabolic Syndrome (Metabolic Syndrome Study); planned enrollment 60 (stopped after 20); completion date June 2016
 
(NCT01850901) an industry sponsored or cosponsored trial. Renal Sympathetic Denervation as a New Treatment for Therapy Resistant Hypertension - A Multicenter Randomized Controlled Trial; planned enrollment 300; completion date June 2016
 
Eighth Joint National Committee
In 2014, the Eighth Joint National Committee, which was appointed to provide recommendations about hypertension treatment, published an evidence-based guideline for the management of hypertension in adults (James, 2014). This guideline does not discuss the use of renal denervation.
  
2017 Update
A literature search conducted using the Medline database through August 2017. There was no information identified that would prompt a change in the coverage statement.
  
2018 Update
A literature search was conducted through August 2018.  There was no new information identified that would prompt a change in the coverage statement.   

CPT/HCPCS:
0338TTranscatheter renal sympathetic denervation, percutaneous approach including arterial puncture, selective catheter placement(s) renal artery(ies), fluoroscopy, contrast injection(s), intraprocedural roadmapping and radiological supervision and interpretation, including pressure gradient measurements, flush aortogram and diagnostic renal angiography when performed; unilateral
0339TTranscatheter renal sympathetic denervation, percutaneous approach including arterial puncture, selective catheter placement(s) renal artery(ies), fluoroscopy, contrast injection(s), intraprocedural roadmapping and radiological supervision and interpretation, including pressure gradient measurements, flush aortogram and diagnostic renal angiography when performed; bilateral
36251Selective catheter placement (first-order), main renal artery and any accessory renal artery(s) for renal angiography, including arterial puncture and catheter placement(s), fluoroscopy, contrast injection(s), image postprocessing, permanent recording of images, and radiological supervision and interpretation, including pressure gradient measurements when performed, and flush aortogram when performed; unilateral
36252Selective catheter placement (first-order), main renal artery and any accessory renal artery(s) for renal angiography, including arterial puncture and catheter placement(s), fluoroscopy, contrast injection(s), image postprocessing, permanent recording of images, and radiological supervision and interpretation, including pressure gradient measurements when performed, and flush aortogram when performed; bilateral
36253Superselective catheter placement (one or more second order or higher renal artery branches) renal artery and any accessory renal artery(s) for renal angiography, including arterial puncture, catheterization, fluoroscopy, contrast injection(s), image postprocessing, permanent recording of images, and radiological supervision and interpretation, including pressure gradient measurements when performed, and flush aortogram when performed; unilateral
36254Superselective catheter placement (one or more second order or higher renal artery branches) renal artery and any accessory renal artery(s) for renal angiography, including arterial puncture, catheterization, fluoroscopy, contrast injection(s), image postprocessing, permanent recording of images, and radiological supervision and interpretation, including pressure gradient measurements when performed, and flush aortogram when performed; bilateral
64999Unlisted procedure, nervous system

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