Radiofrequency Ablation of the Renal Sympathetic Nerves as a Treatment for Resistant Hypertension - CAM 701136

Description
Radiofrequency ablation (RFA) of the renal sympathetic nerves 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 procedure decreases sympathetic activation, decreases vasoconstriction, and decreases activation of the renin-angiotensin system. RFA of the renal sympathetic nerves may act as a nonpharmacologic treatment for hypertension and has been proposed as a treatment option for patients with resistant hypertension.

For individuals who have hypertension resistant to standard medical management who receive RFA of the renal sympathetic nerves, the evidence includes at least 10 randomized controlled trials, numerous systematic reviews of the randomized controlled trials, as well as multiple nonrandomized 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, used a sham-controlled design to reduce the likelihood of placebo effect and demonstrated no significant differences between renal denervation and sham control patients in office-based or ambulatory blood pressure at 6-month follow-up. Results from Symplicity HTN-3 have been supported by a subsequent sham-controlled trial. The Symplicity HTN-3 results were in contrast to other studies, including Symplicity HTN-2 and the Renal Denervation for Hypertension (DENERHTN) trial, which reported efficacy in reducing blood pressure over a 6-month period compared with a control group. Additional smaller randomized controlled trials, 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 have reported improvements in blood pressure 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 strongest evidence comes from sham-controlled trials, the largest of which found no significant benefits with renal denervation. Meta-analyses of the systematic reviews have also reported inconsistent findings, with most analyses showing no significant benefit in blood pressure measurements following RFA. The evidence is insufficient to determine the effects of the technology on health outcomes. 

Background 
Resistant Hypertension
Hypertension is estimated to affect approximately 30% of the population in the United States.1 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, 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% to 30% of participants meet the definition for resistant hypertension, and in tertiary care hypertension clinics, the prevalence has been estimated to be 11% to 18%.1 Resistant hypertension is associated with a higher risk for adverse outcomes such as stroke, myocardial infarction, heart failure, and kidney failure.

A number of factors may contribute to uncontrolled hypertension, and they should be considered and addressed in all patients with hypertension before labeling a patient resistant. These include nonadherence to medications, excessive salt intake, inadequate doses of medications, excess alcohol intake, volume overload, drug-induced hypertension, and other forms of secondary hypertension.2 Also, sometimes it is necessary to address comorbid conditions (i.e., obstructive sleep apnea) to adequately control blood pressure.

Treatment for resistant hypertension is mainly intensified drug therapy, sometimes with the use of nontraditional 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. Nonpharmacologic interventions for resistant hypertension include modulation of the baroreflex receptor and/or radiofrequency (RF) denervation of the renal nerves. 

RF 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 adverse 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 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. 

The procedure is performed percutaneously with access at the femoral artery. A flexible catheter is threaded into the renal artery and controlled energy source, most commonly 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 RFA devices have been approved by the U.S. Food and Drug Administration (FDA) for ablation of the renal sympathetic nerves as a treatment for hypertension. Several devices have been developed for this purpose and are in various stages of application for the FDA approval (FDA product code: DQY):

  • Symplicity™ Renal Denervation System (Medtronic). In April 2018, the FDA approved an investigational device exemption pivotal trial, SPYRAL HTN (NCT02439749). The trial is randomized and sham-controlled and is designed to evaluate the RFA device as an alternative to exercise or lifestyle modification in patients with uncontrolled hypertension not treated with medication. Bohm et al. (2020) has already published the 3-month results.4 The trial remains ongoing, however, with planned follow-up for 3 years for evaluation of long-term efficacy and safety. An additional randomized trial in patients with uncontrolled hypertension despite antihypertensive medication is ongoing (SPYRAL HTN-ON MED, NCT02439775).
  • The EnligHTN™ Multi-Electrode Renal Denervation System (St. Jude Medical) is an RFA catheter using a 4-point multiablation basket design. In January 2014, the EnligHTN™ Renal Guiding Catheter was cleared for marketing by the FDA through the 510(k) process, based on substantial equivalence to predicate devices 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 Vessix™ Renal Denervation System (Boston Scientific; formerly the V2 renal denervation system, Vessix Vascular) is a combination of an RF balloon catheter and bipolar RF generator technologies, intended to permit a lower voltage intervention.
  • In 2020, the FDA granted breakthrough therapy designation to 2 renal artery denervation systems — SoniVie’s Therapeutic Intra-Vascular Ultrasound (TIVUS) System and Recor's Paradise Renal Denervation System — for treatment of patients with persistently elevated blood pressure.

Other RFA catheters (eg, Thermocouple Catheter™ [Biosense Webster]) used for other types of ablation procedures (e.g., cardiac electrophysiology procedures) have been used off-label for RFA of the renal arteries.

Related Policies
80157 Baroreflex Stimulation Devices

Policy
Radiofrequency ablation of the renal sympathetic nerves is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY for the treatment of resistant or uncontrolled hypertension.

Policy Guidelines 
See the Codes table for details.

Rationale
Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Radiofrequency Ablation
Clinical Context and Therapy Purpose

The purpose of radiofrequency ablation (RFA) in patients who have resistant or uncontrolled hypertension is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients with hypertension that is resistant to standard medical management with the use of 3 or more antihypertensive medications of complementary classes or that is otherwise uncontrolled. There is no widely accepted definition of uncontrolled hypertension. Furthermore, in real-world settings, it is difficult to distinguish uncontrolled hypertension from poor medication adherence.

Interventions
The therapy being considered is RFA. Radiofrequency ablation is a minimally invasive procedure performed percutaneously with access at the femoral artery. A flexible catheter is threaded into the renal artery and a controlled low-power energy is delivered to the arterial walls to ablate the renal sympathetic nerves. The updated Symplicity Spyral system employs a multielectrode RFA catheter intended to permit more complete, circumferential ablations.

Comparators
The following therapy is currently being used to treat those with resistant or uncontrolled hypertension: continued medical therapy.

Outcomes
The general short-term outcomes of interest (follow-up to at least 6 months) are a change in systolic and diastolic ) blood pressure (SBP and DBP) and medication use. Blood pressure measurements may include daytime ambulatory blood pressure, 24-hour average SBP, and office SBP.

A longer-term outcome of interest (follow-up to at least 3 years) is the effect on cardiovascular outcomes such as myocardial infarction and stroke.

Table 1. Outcomes of Interest for Individuals with Hypertension

Outcomes Details Timing
Morbid events Outcomes of interest include adverse events such as end-stage renal disease, and embolic events resulting in end-organ damage, renal artery or other vascular complications, or hypertensive crisis. ≥30 days
Treatment-related morbidity Outcomes of interest include decrease in daytime ambulatory SBP, nighttime SBP, and 24-hour average SBP ≥30 days

SBP: systolic blood pressure.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
  • Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Sham-controlled Randomized Controlled Trials
Characteristics and results of sham-controlled RCTs are summarized in Tables 2 through 4.

Table 2. Sham-Controlled RCT Characteristics

Trial N Intervention Eligibility Criteria Baseline Characteristics Primary Outcome
        RDN Sham  
SYMPLICITY HTN-34,5 535 Symplicity single-electrode RDN (n = 364) vs. sham (n = 171) Age 18 – 80 with office SBP ≥ 160 despite taking maximally tolerated doses of ≥ 3 medications of complementary classes, including a diuretic; 24-h SBP ≥ 135 Mean Age: 57.9
Sex: Male, 59.1%
Mean BMI: 34.2
Mean office BP: 180/97
Mean 24-h BP: 159/88
Medications: 5.1
Mean Age: 56.2
Sex: Male, 64.3%
Mean BMI: 33.9
Mean office BP: 180/99
Mean 24-h BP: 160/91
Medications: 5.2
Change in office SBP at 6 months; superiority margin 5 mmHg
SPYRAL HTN-OFF MED Pilot6 80 Symplicity Spyral multielectrode RDN (n = 38) vs. sham (n = 42) following 3-4 week medication wash-out Age 20 – 80 y with office SBP 150 – 180, DBP ≥ 90, and 24-h SBP 140 – 170; treatment-naïve individuals eligible Mean Age: 55.8
Sex: Male, 68.4%
Mean BMI: 29,8
Mean office BP: 162/100
Mean 24-h BP: 153/99
Prior Medications: NR
Mean Age: 52.8
Sex: Male, 68.4%
Mean BMI: 30.2
Mean office BP: 161/102
Mean 24-h BP: 152/99
Prior Medications: NR
Change in mean office and 24-h BP at 3 months and between groups (unpowered)
SPYRAL HTN-OFFMED Pivotal7 331 Symplicity Spyral multielectrode RDN (n = 166) vs. sham (n = 165) following 3 – 4 week medication wash-out Same as above Mean Age: 52.4
Sex: Male, 64%
Race: White, 28%; Black, 22%; NR, 44%
Mean BMI: 31.1
Mean office BP: 163/101
Mean 24-h BP: 151/98
Prior Medications: NR
Mean Age: 52.6
Sex: Male, 68%
Race: White, 30%; Black, 19%; NR, 48%
Mean BMI: 30.9
Mean office BP: 163/102
Mean 24-h BP: 151/99
Prior Medications: NR
Change in mean 24-h SBP at 3 months; superiority margin of -4.0 for 24-hr SBP and -6.5 for office SBP
SPYRAL HTN-ON MED Pilot8,9 80 Symplicity Spyral multielectrode RDN (n = 38) vs. sham (n = 42) on stable doses for at least 6 weeks Age 20 – 80 y with office SBP 150 – 180, DBP ≥ 90, 24-h SBP 140 – 170 despite use of 1 – 3 medications at ≥ 50% of maximum dose Mean Age: 53.9
Sex: Male, 87%
Race: White, 34%; Black, 11%; NR, 47%
Mean BMI: 31.4
Mean office BP: 165/100
Mean 24-h BP: 152/97
Medications: 2.13
Mean Age: 53.0
Sex: Male, 81%
Race: White, 36%; Black 12%; NR, 48%
Mean BMI: 32.5
Mean office BP: 164/103
Mean 24-h BP: 151/98
Medications: 1.98
Change in mean office and 24-h BP from baseline to 6 months and between groups (unpowered)

BP: blood pressure; BMI: body mass index; DBP: diastolic blood pressure; NR: not reported; RDN: renal denervation; SBP: systolic blood pressure.

Table 3. Primary Sham-Controlled RCT Results

Trial 24-h SBP Change (SD or 95% CI) 24-h DBP Change (SD or 95% CI) Office SBP Change (SD or 95% CI) Office DBP Change (SD or 95% CI)
SYMPLICITY HTN-34,5 6 months
RDN -6.8 (15.1) -4.1 (9.2) -14.1 (23.9) -6.6 (11.9)
Sham -4.8 (17.2) -3.1 (10.1) -11.7 (25.9) -4.6 (13.6)
MD (95% CI); p -2.0 (-5.0 to 1.1); 0.98 -1.0 (NR); 0.28 -2.4 (-6.9 to 2.1); 0.26 -2.0 (NR); 0.12
SPYRAL HTN-OFF MEDPilot6 3 months
RDN -5.5 (-9.1 to -2.0) -4.8 (-7.0 to -2.6) -10.0 (-15.1 to -4.9) -5.3 (-7.8 to -2.7)
Sham -0.5 (-3.9 to 2.9) -0.4 (-2.2 to 1.4) -2.3 (-6.1 to 1.6) -0.3 (-2.9 to 2.2)
MD (95% CI); p -5.0 (-9.9 to -0.2); 0.0414 -4.4 (-7.2 to -1.6); 0.0024 -7.7 (-14.0 to -1.5); 0.0155 -4.9 (-8.5 to -1.4); 0.0077
SPYRAL HTN-OFF MEDPivotal7 3 months
RDN -4.7 (-6.4 to -2.9) -3.7 (-4.8 to -2.6) -9.2 (-11.6 to -6.9) -5.1 (-6.4 to -3.8)
Sham -0.6 (-2.1 to 0.9) -0.8 (-1.7 to 0.1) -2.5 (-4.6 to -0.4) -1.0 (-2.3 to 0.3)
MD (95% CI); p -4.0 (-6.2 to -1.8); 0.0005 -3.1 (-4.6 to -1.7);< 0.0001 -6.6 (-9.6 to -3.5); < 0.0001 -4.4 (-6.2 to -2.6); < 0.0001
SPYRAL HTN-ON MED Pilot8,9 6 months
RDN -9.0 (-12.7 to -5.3) -6.0 (-8.5 to -3.5) -9.4 (-13.5 to -5.3) -5.2 (-7.7 to -2.7)
Sham -1.6 (-5.2 to 2.0) -1.9 (-4.7 to 0.9) -2.6 (-6.7 to 1.6) -1.7 (-4.2 to 0.9)
MD (95% CI); p -7.4 (-12.5 to -2.3); 0.0051 -4.1 (-7.8 to -0.4); 0.0292 -6.8 (-12.5 to -1.1); 0.0205 -3.5 (-7.0 to 0); 0.0478

CI: confidence interval; DBP: diastolic blood pressure; MD: mean difference; NR: not reported; RDN: renal denervation; SBP: systolic blood pressure; SD: standard deviation.

Table 4. Long-term and Subgroup Sham-controlled RCT Results

Trial 24-h SBP MD (95% CI); p 24-h DBP MD (95% CI); p Office SBP MD (95% CI); p Office DBP MD (95% CI); p
SYMPLICITY HTN-34,5  
6 months -2.0 (-5.0 to 1.1); 0.98 -1.0 (NR); 0.28 -2.4 (-6.9 to 2.1); 0.26 -2.0 (NR); 0.12
36 months -16.5 (-20.5 to -12.5); < 0.001 -11.2 (-13.6 to -8.7); < 0.0001 -22.1 (-27.2 to -17.0); < 0.0001 -12.0 (-14.6 to -9.3); < 0.0001
36 months (without imputation) -9.0 (NR); 0.53 NR -0.2 (NR); 0.74 NR
SPYRAL HTN-ON MED Pilot8,9  
3 months -4.6 (NR); 0.10 -3.7 (NR); 0.06 -1.6 (NR); 0.59 -1.5 (NR); 0.44
6 months -7.4 (-12.5 to -2.3); 0.0051 -4.1 (-7.8 to -0.4); 0.0292 -6.8 (-12.5 to -1.1); 0.0205 -3.5 (-7.0 to 0); 0.0478
6 months (adherent subgroup) -6.0 (NR); 0.99 -3.3 (NR); 0.249 -5.1 (NR); 0.144 -2.7 (NR); 0.241
6 months (non-adherent subgroup) -8.3 (NR); 0.029 -4.6 (NR); 0.062 -7.9 (NR); 0.087 -4.0 (NR); 0.135
12 months -1.9 (NR); 0.553 -0.8 (NR); 0.695 NR NR
24 months -11.2 (-18.4 to -4.0); 0.0031 -5.7 (-10.6 to -0.7); 0.025 -12.9 (-21.1 to -4.7); 0.0026 -8.5 (-15.0 to -2.1); 0.010
24 months (without imputation) -11.2 (-18.4 to -4.0); 0.003 NR -11.1 (-21.6 to -0.5); 0.11 NR
36 months -10.0 (-16.6 to -3.3); 0.0039 -5.9 (-10.1 to -1.8); 0.0055 -11.8 (-19.0 to -4.7); 0.0017 -3.9 (-9.8 to 1.9); 0.186
36 months (without imputation) -6.1 (-13.6 to 1.4); 0.11 NR 0.5 (-8.8 to 9.7); 0.92 NR

CI: confidence interval; DBP: diastolic blood pressure; MD: mean difference; NR: not reported; SBP: systolic blood pressure.

Symplicity HTN-3 Trial
Bhatt et al. (2014) published results of the Symplicity HTN-3 trial, a multicenter, single-blind, randomized, sham-controlled trial of renal denervation with a single-electrode RFA system.4 Included patients had severe, resistant hypertension, with a SBP of 160 mmHg or higher, on maximally tolerated doses of at least 3 antihypertensive medications of complimentary 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 Symplicity renal denervation catheter or to renal angiography only (sham control). Changes in antihypertensive medication were not allowed during the 6 month follow-up unless they were considered clinically necessary. The primary efficacy endpoint was the mean change in office SBP from baseline to 6 months in the denervation group compared with the sham control group. The secondary efficacy endpoint was the change in mean 24-hour ambulatory SBP at 6 months. The primary safety endpoint 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 blood pressure. Major adverse event rates were similar between the denervation (1.4%) and control (0.6%) groups. Strengths of this trial included its large size and blinded, sham-controlled design, which reduced the likelihood of a placebo effect. A limitation of the initial publication is that the blinded follow-up period reported was relatively short, potentially leading to an underdetection of a treatment benefit difference between the groups over time. Additionally, impacts of medication adherence could not be confirmed.

Bakris et al. (2014) reported on more detailed ambulatory blood pressure results from the Symplicity HTN-3 trial.10, The change in average 24-hour ambulatory SBP and DBP were as reported by Bhatt et al.4 There were no significant differences in change in ambulatory blood pressure between the renal denervation and control groups for any of the prespecified subgroup analyses. Included among these prespecified subgroup analyses were the presence of coexisting diabetes, sex, race, body mass index of 30 kg/m2 or more, estimated glomerular filtration rate of 60 mL/min/1.73 m2 or more, age of 60 years or older, or any medication change during the study. Using pooled data from the Symplicity HTN-3 trial and the Global Symplicity Registry, Mahfoud et al. (2017) investigated the response to renal denervation in patients with isolated systolic hypertension and patients with combined systolic-diastolic hypertension.11 A total of 1,103 patients were included in the analysis, 429 with isolated systolic hypertension and 674 with combined hypertension. At 6 months, SBP reduction in patients with combined hypertension was -18.7 mmHg compared with -10.9 mmHg in patients with isolated systolic hypertension (p < .001).

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.12,13,14

Bhatt et al. (2022) reported on long-term follow-up data from the Symplicity HTN-3 trial, finding significant between-group differences in office SBP reductions from baseline in favor of renal denervation at 12, 24, and 36 months.5 However, the significance of these findings is limited due to unblinding and treatment of crossover data. Specifically, data from crossover patients were not pooled with data from patients originally assigned to renal denervation, and the most recent blood pressure measurements prior to crossover were used to impute data for the sham control group. Major adverse events were reported in 15%, 14%, and 14% of renal denervation, crossover, and non-crossover patients, respectively.

Symplicity Spyral OFF-MED Pilot and Pivotal Trials
In 2015, Kandzari and coworkers noted several shortcomings of the failed SYMPLICITY HTN-3 trial, including the use of complex antihypertensive medications regimens, heterogeneous study populations, procedure variability, and choice of primary endpoint.15 As a result, investigators first aimed to conduct a proof-of-concept trial of renal denervation in the absence of antihypertensive medications (SPYRAL HTN-OFF MED) utilizing the redesigned multielectrode Symplicity Spyral RFA catheter system. The multielectrode design was intended to provide more complete, circumferential treatments with automated 4-quadrant ablations, and operators were tasked with applying additional ablations in the branch and accessory renal arteries. Studies shifted to enroll patients with less severe and combined systolic-diastolic hypertension. Additionally, the primary endpoint now focused on 24-h ambulatory blood pressure measurements. Subsequent SPYRAL studies also monitored medication adherence.

In 2017, Townsend and coworkers published findings from the unpowered, proof-of-concept SPYRAL HTN-OFF MED pilot trial, in which 80 patients were randomized to renal denervation (n = 38) or sham treatment (n = 42).6 Patients were followed for 3 months following a 3 – 4 week medication washout period. Eligibility criteria included mild to moderate hypertension defined as office SBP ≥ 150 mmHg and < 180 mmHg and office DBP ≥ 90 mmHg in addition to mean 24-h ambulatory SBP ≥ 140 mmHg and < 170 mmHg. Both mean 24-h ambulatory and office blood pressure measurements significantly decreased from baseline in the renal denervation group at 3 months. No significant reductions in blood pressure were found in the sham control group. Between-group difference in blood pressure changes were also significant. Trial investigators concluded that these data provide biological proof of principle that renal denervation lowers blood pressure in untreated hypertensive patients, supporting prior data regarding the correlation between reduction in sympathetic tone and blood pressure reduction. No composite safety events were reported through 3 months of the pilot study, defined as the composite of all-cause mortality, end-stage renal disease, embolic event resulting in end-organ damage, renal artery perforation requiring reintervention, renal artery dissection requiring reintervention, vascular complications, hospitalization for hypertensive crisis or emergency, or new renal artery stenosis > 70%.

Utilizing a Bayesian study design, Bohm et al. (2020) published findings from the SPYRAL HTN-OFF MED Pivotal trial, in which pilot trial data (n = 80) was used as an informative prior and combined with data from an additional 251 subjects to constitute an overall primary analysis population (N = 331).7 Patients were randomly assigned to either renal denervation (n = 166) or sham procedure (n = 165). Significant between-group differences were found for the primary 24-h SBP and secondary office SBP endpoints in favor of renal denervation at 3 months. These primary and secondary endpoints were each met with a posterior probability of superiority greater than 0.999 with a treatment difference of -3.9 mmHg and -6.5 mmHg, respectively. Superiority of renal denervation was confirmed via both Bayesian and frequentist statistical methods. One composite safety event was reported in each study arm, neither of which were attributed to the device or trial procedures.

Symplicity Spyral ON-MED Pilot Trial
Kandzari et al. (2018) published initial findings from the unpowered SPYRAL HTN-ON MED pilot trial, in which 80 patients were randomized to renal denervation (n = 38) or sham treatment (n = 42).8 Eligibility criteria were consistent with those for the SPYRAL HTN-ON MED trial, but additionally required patients to be on 1 – 3 antihypertensive medications with stable doses at 50% or more of the maximum manufacturer's recommended dosage for at least 6 weeks. Patients were knowingly screened for antihypertensive drug adherence and medications changes were not permitted through 6 months unless patients met prespecified escape criteria (office SBP ≥ 180 mmHg or < 115 mmHg with symptoms of hypotension). Baseline patient characteristics were similar except for a 19% higher incidence of obstructive sleep apnea in the sham control group. At 6 months for the overall population, the key efficacy outcome of mean 24-h SBP was significantly reduced by -9.0 mmHg with renal denervation, with a statistically significant between-group difference of -7.4 mmHg in favor of renal denervation. Between-group differences were also statistically significant for 24-h DBP, office SBP, office DBP, daytime SBP and DBP, and night-time SBP and DBP in favor of renal denervation. In contrast to prior findings from the SPYRAL HTN-OFF MED trial, no significant between-group differences were noted at 3 months. Medication adherence at 6 months was 60.5% and 64.3% in renal denervation and sham control groups, respectively. Importantly, between-group differences for 24-h SBP and DBP were only significant for the subgroup of non-adherent patients. Additionally, between-group differences for office SBP and DBP were not statistically significant in either adherent or non-adherent subgroup analyses. On an individual patient level, 6-month 24-h SBP reductions were reported for 75% and 58% of patients in renal denervation and sham control groups, respectively.

Mahfoud et al. (2022) published long-term outcomes from the SPYRAL HTN-ON MED pilot trial through 36 months.9, Medication adjustments were permitted after 6 months and patients were unblinded and permitted to crossover after 12 months. No significant between-group differences were reported at 12 months, which investigators attributed to a higher medication burden in the sham control group as confirmed by 2 out of 4 post-hoc analyses. Progressive and sustained reductions in blood pressure were noted over time, with significant between-group differences at 24 and 36 months in favor of renal denervation. Between 6 and 36 months, mean 24-h SBP was reduced by an additional 5.9 mmHg with renal denervation. However, during this period, the mean number of antihypertensive medications prescribed for patients in both renal denervation and sham control groups increased by approximately 1 additional medication. Sham control measurements at 36 months included 13 imputed crossover patients' blood pressure measurements from the last observation prior to the renal denervation procedure. Between-group differences in mean office SBP lost statistical significance at 24 months without imputation. Additionally, both mean 24-h and office SBP between-group differences lost statistical significance without imputation at 36 months. At 36 months, 6 (20%) of 30 patients in the renal denervation group and 1 (3%) of 32 patients in the sham control group had mean 24-h SBP < 130 mmHg and DBP <80 mmHg (p = .05). However, between-group differences for the proportion of patients achieving target 24-h blood pressure were not statistically significant at 24 months. One composite safety event was reported in renal denervation and sham control arms through 36 months, occurring at 427 days and 693 days post-procedure, respectively. Changes in eGFR, serum creatinine, sodium levels, and potassium levels from baseline to 24 and 36 months were not significantly different between groups. Overall, study interpretation is complicated by short-term blinded follow-up and imputation of excluded crossover patient data. It is unclear which patients are most likely to derive benefit and whether such benefit is clinically meaningful in the context of increased medication use over time.

The powered SPYRAL HTN-ON MED Expansion trial incorporating pilot trial data is ongoing through 3 years with an estimated primary completion date of Oct. 2022 (NCT02439775) as of last update in April 2022.

Sham-controlled study relevance, design, and conduct limitations are summarized in Tables 5 and 6 below.

Table 5. Sham-Controlled Study Relevance Limitations

Study Populationa Interventionb Comparatorc Outcomesd Duration of Follow-upe
SYMPLICITY HTN-34,5   4. Study focused on prior generation single-electrode RFA catheter system.   6. Clinically significant difference not observed. 3. Short duration of blinded follow-up for primary efficacy outcome (6 months).
SPYRAL HTN-OFF MED Pilot6 3. Study population not representative of intended use; 4. Racial demographics of enrolled population not reported for over half of participants. 5. Number of ablations at main, branch, and accessory renal vessels not standardized and no practical methods to verify nerve destruction are available. 2. Not standard or optimal.   3. Short duration of follow-up (3 months).
SPYRAL HTN-OFF MED Pivotal7 3. Study population not representative of intended use; 4, Racial demographics of enrolled population not reported for nearly half of participants. 5. Number of ablations at main, branch, and accessory renal vessels not standardized and no practical methods to verify nerve destruction are available. 2. Not standard or optimal.   3. Short duration of blinded follow-up (3 months).
SPYRAL HTN-ON MED Pilot8,9 1. Intended use population is unclear as patients were permitted to take 1 – 3 medications at baseline with submaximal dosing, not meeting the standard definition of resistant hypertension; 4. Low enrollment of women (16%) and racial demographics of enrolled population not reported for nearly half of participants. 5. Number of ablations at main, branch, and accessory renal vessels not standardized and no practical methods to verify nerve destruction are available. 2. Not standard or optimal. 6. Clinically significant difference for mean 24-h blood pressure observed only in adherent subgroup population. No clinically significant difference for mean office blood pressure observed in either adherent or non-adherent subgroup analyses. 3. Short duration of blinded follow-up for primary efficacy outcome (6 months).

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. 
a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other.
b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other.
c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other.
d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not established and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other.
e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.
RFA: Radiofrequency ablation.

Table 6. Sham-controlled Study Design and Conduct Limitations

Study Allocationa Blindingb Selective Reportingc Data Completenessd Powere Statisticalf
SYMPLICITY HTN-34,5       4-5. Inadequate handling of crossovers with inappropriate exclusion of blood pressure measurements at crossover. LOCF may not be the most appropriate approach.    
SPYRAL HTN-OFF MED Pilot6         4. Unpowered pilot study.  
SPYRAL HTN-OFF MED Pivotal7            
SPYRAL HTN-ON MED Pilot8,9       4-5. Inadequate handling of crossovers with inappropriate exclusion of blood pressure measurements at crossover. LOCF may not be the most appropriate approach. 4. Unpowered pilot study. .

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias; 5. Other.
b Blinding key: 1. Participants or study staff not blinded; 2. Outcome assessors not blinded; 3. Outcome assessed by treating physician; 4. Other.
c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication; 4. Other.
d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials); 7. Other.
e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference; 4. Other.
f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated; 5. Other.
LOCF: last observation carried forward.

Unblinded Randomized Controlled Trials
DENERHTN Trial

Azizi et al. (2015) published results of the Renal Denervation for Hypertension (DENERHTN) trial, a prospective, open-label RCT with blinded endpoint evaluation.16 The trial 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 a cough), and amlodipine to either renal denervation or control. Both groups received standardized stepped-care antihypertensive treatment, which involved the sequential addition of spironolactone, bisoprolol, and sustained-release prazosin for SBP and DBP of 135 mmHg or higher or 85 mmHg or higher, respectively. Spironolactone could be started for home SBP and DBP of 170 mmHg or higher or 105 mmHg or higher, respectively. The analysis was conducted using a modified intention-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 SBP after 6 months of follow-up 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 mmHg; p = .033). 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 = .012), and 24-hour ambulatory blood pressure control was achieved in 39.6% of renal denervation patients (vs. 18.9% of controls; p = .013). Rates of daytime blood pressure control did not differ significantly between groups. The number of antihypertensive treatments at 6 months also did not differ significantly between groups (mean, 5.25 for renal denervation patients vs. 5.36 for control patients; p = .701). Three renal denervation-related adverse events were reported (lumbar pain in 2 patients, mild groin hematoma in 1 patient).

Courand et al. (2017) conducted a post hoc exploratory analysis using data from the DENERHTN trial to determine if abdominal aortic calcifications (AAC) had an impact on patients' response to renal denervation.17 Abdominal aortic calcification was measured in 90 patients. Analyses showed that patients with a lower AAC burden experienced larger decreases in daytime ambulatory SBP than patients who had a higher AAC burden.

Gosse et al. (2017) also conducted an analysis to evaluate factors that may predict response to renal denervation.18 Comparing responders and nonresponders in the renal denervation group, average nighttime SBP and standard deviation were predictors of response to renal denervation. However, in the control group, these 2 variables did not discriminate between responders and nonresponders.

Prague-15 Study
Rosa et al. (2015) reported on results of the Prague-15 study, an open-label RCT comparing renal sympathetic denervation with intensified pharmacologic treatment in patients who had resistant hypertension.19 Although trial enrollment was planned for 120 subjects with a 90% power in detecting a difference in treatment response between the 2 groups with an α of 0.05, the trial was prematurely halted after enrollment of 112 subjects (56 in each group), following the publication of the results of the Symplicity HTN-3 trial (discussed below). 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 mmHg, p < .001 [vs. baseline] for renal denervation patients; -8.1 mmHg, p = .001 [vs. baseline] for control patients). After 6 months, there were no significant differences in the absolute value or change in any of the blood pressure parameters reported between the renal denervation and control group.

Symplicity HTN-2 and Symplicity HTN-Japan
Symplicity HTN-2 was a multicenter, unblinded RCT (2010) evaluating renal sympathetic denervation and standard pharmacologic treatment for patients with resistant hypertension.20 A total of 106 patients with an SBP of at least 160 mmHg, despite 3 or more antihypertensive medications, were enrolled. Patients were followed for 6 months with the primary endpoint being the between-group difference in the change in blood pressure during the trial. Secondary outcomes included a composite outcome of adverse cardiovascular events and adverse events of treatment. Baseline blood pressure was 178/98 in the RFA group and 178/97 in the control group.

At 6-month follow-up, blood pressure reductions in the RFA group were 32 mmHg (standard deviation, 23) SBP and 12 mmHg (standard deviation, 11) DBP. In the control group, there was a 1-mmHg increase in SBP and no change for DBP (p < .001 for both SBP and DBP differences). The percentage of patients who achieved an SBP of 140 mmHg or less was 39% (19/49) in the RFA group compared with 6% (3/51) in the control group (p < .001). There was no difference in renal function, as measured by serum creatinine, between groups at the 6 month period. Three patients in the RFA group had adverse cardiovascular events compared with 2 in the control group (p = not significant). Other serious adverse events requiring admission in the RFA group included 1 case each of nausea/vomiting, hypertensive crisis, transient ischemic attack, and hypotension.

One-year follow-up data from the Symplicity HTN-2 trial were reported by Esler et al. (2012).21 This report included 47 of the 52 patients originally randomized to the RFA group, who were subsequently followed in an uncontrolled fashion after the 6-month follow-up. It also included 6 month follow-up of patients originally randomized to the control group, who were offered crossover to RFA after 6 months. Forty-six of 54 patients accepted crossover to RFA; 35 were available at 12 months. For the patients originally randomized to RFA, the decrease in blood pressure at 12 months was 28.1 mmHg for SBP and 9.7 mmHg for DBP. These decreases did not differ significantly from those reported at 6 months (31.7 mmHg systolic, 11.7 mmHg diastolic). For the crossover group, the decrease in blood pressure 6 months after renal denervation was 23.7 mmHg systolic and 8.4 mmHg diastolic. There were 2 procedural complications in the crossover group, 1 patient with a dissection of the renal artery and 1 patient with a hypotensive episode.

Three-year follow-up data from the Symplicity HTN-2 trial were reported by Esler et al. (2014).22 Follow-up was available for 40 of 52 subjects in the initial RFA group and for 30 of 37 subjects in the initial control group who crossed over to renal denervation 6 months after enrollment. After 30 months, the mean change in SBP was -34 mmHg (95% CI, -40 to -27 mmHg; p < .01) and the mean change in DBP was -13 mmHg (95% CI, -16 to -10 mmHg; p < .01). The degree of blood pressure 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 mmHg (95% CI, -40 to -25 mmHg; p < .01) and the mean change in DBP was -14 mmHg (95% CI, -17 to -10 mmHg; p < .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 deemed unrelated to renal denervation treatment; and 3 deaths deemed unrelated to the device or therapy.

The main limitations of the Symplicity HTN-2 trial were its small size, unblinded design, and a relatively short follow-up for the controlled portion of the trial. A trial with a sham control would have allowed a 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 was too short to ascertain whether the reduction in blood pressure would reduce adverse cardiovascular outcomes such as myocardial infarction and stroke. The 12- and 36-month follow-up reports provided some insight into longer-term outcomes following the procedure, although comparison with a control group was no longer possible due to the crossover design.

It is unknown whether reinnervation of the renal sympathetic nerves occurs post-treatment. If it does, the efficacy of the procedure will diminish over time. The blood pressure change appears to be stable over the longer-term follow-up studies, suggesting that reinnervation did not occur in the 36-month follow-up.

Kario et al. (2015) reported on results of the Symplicity HTN-Japan trial, which was an RCT comparing renal sympathetic denervation with standard pharmacotherapy in subjects with treatment-resistant hypertension.23 Enrollment was initially planned for 100 subjects, but the trial was halted early after results of the Symplicity HTN-3 trial were published, at which time 41 subjects (22 to renal denervation, 19 to control) had been randomized. At 6 months, the change in SBP in renal denervation subjects did not differ significantly from the change in SBP in control subjects (between-group difference, -8.6 mmHg; 95% CI, -21.1 to 3.8 mmHg; p = .169). No major adverse events occurred. The authors noted that the trial was underpowered due to the early termination.

SYMPATHY
De Jager et al. (2017) conducted a trial in which patients with resistant hypertension were randomized to usual care based on European Society Hypertension guidelines (n = 44) or usual care plus renal denervation (n = 95): the Renal Sympathetic Denervation as a New Treatment for Therapy Resistant Hypertension (SYMPATHY) trial.24 Six-month follow-up analyses showed no significant difference between groups in daytime SBP (2.0 mmHg; 95% CI, -6.1 to 10.2 mmHg), 24-hour SBP (1.0 mmHg; 95% CI, -7.1 to 9.1 mmHg), or office SBP (-8.2 mmHg; 95% CI, -17.1 to 0.7 mmHg).

De Jager et al. (2018) evaluated medication adherence as a post hoc analysis of data from the SYMPATHY trial.25, Serum screening for blood pressure-lowering drugs was conducted on samples taken at baseline (n = 98) and at the 6-month follow-up (n = 83). Most patients (68%) were found to be nonadherent. Factors related to nonadherence were a higher number of prescribed blood pressure-lowering drugs, higher baseline blood pressure, and younger age. As adherence decreased, office blood pressure increased significantly.

Other Randomized Controlled Trials
Several smaller RCTs (N range, 18 to 81 patients) have compared renal denervation with drug therapy for the treatment of resistant hypertension, with inconsistent results.26,27,28,29,30,31,32 Although the majority of the unblinded trials demonstrated some significant improvements in blood pressure control with renal denervation,27,30,31,32 small earlier trials that used a double-blind, sham-controlled design to reduce the risk of a placebo effect showed no significant improvements with renal denervation.26,28,29

Section Summary: Randomized Controlled Trials
Several RCTs have compared single-electrode renal denervation with drug therapy for the treatment of resistant hypertension, with inconsistent results. The most rigorous evidence about the efficacy of renal denervation comes from the largest of these trials, the Symplicity HTN-3 trial, which used a single-blind, sham-controlled design to reduce the risk of a placebo effect and showed no significant improvements in blood pressure control with renal denervation at 6 months. Other smaller trials that used sham controls also showed no significant improvements in SBP for patients treated with single-electrode renal denervation compared with controls. Other trials not using a sham control design, including the DENERHTN and Symplicity HTN-2 trials, did find a significant benefit in patients treated with single-electrode renal denervation. Potential explanations for the differences in the treatment effect between the Symplicity HTN-3 trial and the unblinded trials may be a placebo effect or other nonspecific effects of participating in a trial. Alternatively, blood pressure control in the control arm might have been better in Symplicity HTN-3 trial than in earlier studies. While long-term follow-up for the SYMPLICITY HTN-3 trial found significant between-group differences in favor of renal denervation at 12, 24, and 36 months, the clinical significance of these findings is limited due to unblinding and treatment of crossover data. Specifically, data from crossover patients were not pooled with data from patients originally assigned to renal denervation, and the most recent blood pressure measurements prior to crossover were used to impute data for the sham control group.

Several RCTs have compared multielectrode renal denervation to sham with or without concomitant antihypertensive drug therapy for the treatment of a broader population of individuals with mild to moderate uncontrolled and combined systolic-diastolic hypertension. The SPYRAL HTN-OFF MED Pivotal trial found significant between-group differences of -4.0 mmHg for 24-h SBP and -6.6 mmHg for office SBP at 3 months, each meeting a posterior probability of superiority greater than 0.999. Investigators noted that these data provide biological proof of principle that renal denervation lowers blood pressure in untreated hypertensive patients, supporting prior data regarding the correlation between reduction in sympathetic tone and blood pressure reduction. It is unclear whether these trials results are generalizable to a real-world population. The SPYRAL HTN-ON MED pilot trial also found significant between-groups differences of -7.4 mmHg for 24-h SBP and -6.8 mmHg for office SBP at 6 months for the overall population in favor of renal denervation. However, the 24-h SBP results were only significant for the subgroup of medication non-adherent patients. Subgroup analyses of both the non-adherent and adherent populations failed to find a significant between-group difference for office SBP and DBP. Long-term data from the SPYRAL HTN-ON MED study suggest that blood pressure reductions with multielectrode renal denervation are progressive and sustained over time, with between-group differences of -10.0 mmHg for 24-h SBP and -11.8 for office SBP for the overall population at 36 months. These differences lost significance without imputation. Therefore, study interpretation is complicated by short-term blinded follow-up and imputation of excluded crossover patient data, and it is unclear which patients are most likely to derive benefit. Currently, there is no practical method to verify nerve destruction following ablation. The powered SPYRAL HTN-ON MED Expansion study is ongoing.

Systematic Reviews
Multiple systematic reviews with overlapping studies, 1 of which is a Cochrane review by Coppolino et al. (2017),33, have summarized the key RCTs evaluating renal denervation. The characteristics of the systematic reviews are summarized in Table 7, and the key results are summarized in Table 8. The overall results vary depending on the inclusion of earlier, unblinded studies and controlled but nonrandomized studies, with some systematic reviews reporting significant improvements with renal denervation and some reporting no significant improvement.

The Cochrane review reported that none of the trials was designed to evaluate clinical endpoints as primary outcomes.33 The evidence for clinical endpoints (e.g., all-cause mortality, hospitalization, cardiovascular events) was of low-quality. Comparisons of clinical outcomes in sham versus renal denervation groups showed no significant differences between groups in myocardial infarction (relative risk, 1.3; 95% CI, 0.5 to 3.8), ischemic stroke (relative risk, 1.1; 95% CI, 0.4 to 3.7), or unstable angina (relative risk, 0.6; 95% CI, 0.1 to 5.1).

Most analyses included 6-month follow-up measurements, while a review by Chen et al. (2017),34 calculated change in blood pressure for subgroups at 12-month follow-up. The 12-month analysis showed no difference at the longer follow-up.

Table 7. Characteristics of Systematic Review of Controlled Trials Assessing Renal Denervation

Study Dates Trials N (Range) Design Duration, mo
Pappaccogli et al. (2018)35 2010 – 2016 11 1236 (19 – 535) RCT, CT 6
Coppolino et al. (2017)33 2010 – 2016 12 1149 (16 – 535) RCT, CT 6
Chen et al. (2017)34 2010 – 2016 9 1068 (19 – 535) RCT 6
Fadl Elmula et al. (2017)36 2010 – 2017 10 1174 (19 – 524) RCT, CT 6
Sun et al. (2016)37 2010 – 2015 9 2932 (67 – 622) RCT, CT 6
Zhang et al. (2016)38 2013 – 2015 11 1160 (19 – 535) RCT, CT 6
Yao et al. (2016)39 2010 – 2015 8 1059 (19 – 535) RCT 6
Fadl Elmula et al. (2015)40 2010 – 2015 7 985 (20 – 535) RCT 6

CT: controlled trial; RCT: randomized controlled trial.

Table 8. Systematic Review Results at 6-Month Follow-Up for Controlled Trials Assessing Renal Denervation

Study Treatment Comparator Trials Outcomes SMD, mmHg 95% CI,
mmHg
p I2, %
Pappaccogli et al. (2018)35 RD Control 9
9
10
10
Office SBP
Office DBP
ASBP
ADBP
-3.5
-2.8
-1.8
-0.6
-13.0 to 6.1
-6.0 to 0.4
-4.5 to 0.9
-2.3 to 1.2
NS
NS
NS
NS
90
74
47
63
Coppolino et al. (2017)33 RD Control 5
4
6
5
24-h SBP
24-h DBP
Office SBP
Office DBP
0.3
0.9
-4.1
-1.3
-3.7 to 4.3
-4.5 to 6.4
-15.3 to 7.1
-7.3 to 4.7
NS
NS
NS
NR
NR
NR
NR
NR
Chen et al. (2017)34 RD Control 9
7
24-h SBP
Office SBP
-1.1
-2.5
-4.7 to 2.5
-12.9 to 7.8
.55
.63
67
90
Fadl Elmula et al. (2017)36 RD Control 8
10
Office SBP
24-h SBP
-3.6
-1.0
-12.8 to 5.6
-4.3 to 2.3
.45
.54
NR
NR
Sun et al (2016)37 RD Control 9
8
Office SBP
Office DBP
-12.81
-5.56
-22.77 to -2.85
-8.15 to -2.97
.01
< .001
92
63
Zhang et al (2016)38 RD Control 11 Office SBP -13.9 -21.17 to -6.63 < .001 93
Yao et al (2016)39 RD Control 8
8
Office SBP
Office DBP
-8.23
-3.77
-16.86 to 0.39
-7.21 to -0.32
NR
NR
93
90
Fadl Elmula et al. (2015)40 RD Control 15 Office SBP -4.89 -20.9 to 11.1 .47 91.7

ADBP: ambulatory diastolic blood pressure; ASBP: ambulatory systolic blood pressure; CI: confidence interval; DBP: diastolic blood pressure; NR: not reported; NS: not significant; RD: renal denervation; SBP: systolic blood pressure; SMD: standardized mean difference.

Several other systematic reviews have also included RCTs and nonrandomized studies. Kwok et al. (2014) published a systematic review on renal denervation that included 3 RCTs (the Symplicity HTN-3 trial, the Symplicity HTN-2 trial, and Pokushalov et al. (2012), described in the Randomized Controlled Trials section), 8 prospective observational studies, and 1 observational study with matched controls.41 Similarly, Pancholy et al. (2014) published a meta-analysis of renal denervation that included the same 3 RCTs, along with 2 non-RCTs.42 Other systematic reviews and meta-analyses, including those by Davis et al. (2013)43 and Shantha et al. (2015),44, did not include the Symplicity HTN-3 trial or subsequently reported RCTs.

Nonrandomized Comparative Studies
Several nonrandomized studies with a control group have been published. Populations from some of these studies overlap to a large extent with the Symplicity 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 examined different physiologic outcomes in addition to changes in blood pressure.

Other nonrandomized comparative studies exist. Given the multiple randomized studies, these studies add little to the overall body of evidence and are not discussed further here.45,46,47,48

Summary of Evidence
For individuals who have hypertension resistant to standard medical management or uncontrolled hypertension who receive RFA of the renal sympathetic nerves, the evidence includes numerous RCTs, numerous systematic reviews of the RCTs, as well as multiple nonrandomized comparative studies and case series. Relevant outcomes are symptoms, change in disease status, morbid events, medication use, and treatment-related morbidity. The Symplicity HTN-3 trial used a sham-controlled design to reduce the likelihood of placebo effect and demonstrated no significant differences between single-electrode renal denervation and sham control patients in office-based or ambulatory blood pressure at 6-month follow-up. The Symplicity HTN-3 results were in contrast to other studies not using a sham control design but were supported by a number of early smaller sham-controlled trials. Meta-analyses of the RCTs have also reported inconsistent findings, with most analyses showing no significant benefit in blood pressure measurements following single-electrode RFA. Recent evidence focuses on the use of next generation multielectrode RFA catheters. The proof of principle SPYRAL HTN-OFF MED study found that multielectrode renal denervation was superior to sham in the absence of background antihypertensive medication therapy, with between-group differences of -4.0 mmHg for 24-h SBP and -6.6 for office SBP at 3 months. The unpowered SPYRAL HTN-ON MED study also found significant between-group differences of -7.4 mmHg for 24-h SBP and -6.8 mmHg for office SBP at 6 months; however, results were only significant for the subgroup of patients nonadherent to medications. Long-term data from the SPYRAL HTN-ON MED study suggest that blood pressure reductions with multielectrode renal denervation are progressive and sustained over time. However, study interpretation is complicated by short-term blinded follow-up and imputation of excluded crossover patient data. It is unclear which patients are most likely to derive benefit, and currently, there is no practical method to verify nerve destruction following ablation. The powered SPYRAL HTN-ON MED Expansion study is ongoing. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Heart Association et al
The American Heart Association (AHA), American College of Cardiology (AHA), and American Society of Hypertension (ASH; 2015) issued joint guidelines on the treatment of hypertension in patients with coronary artery disease.49 The guidelines noted the Symplicity HTN-3 trial did not find a significant benefit from renal denervation and stated that additional randomized controlled trials would be needed.

The AHA, ACC, and 9 additional specialty societies (2018) published joint guidelines on the prevention, detection, evaluation, and management of high blood pressure in adults.50 In discussing resistant hypertension, the guidelines indicated that studies using catheter ablation of renal sympathetic nerves "have not provided sufficient evidence to recommend the use of these devices."

The AHA (2018) published a Scientific Statement on the detection, evaluation, and management of resistant hypertension.51 The AHA Statement discussed the lack of benefit found in the Symplicity HTN-3 trial, as well as its methodological limitations. The statement also referred to the more recent positive data from the SPYRAL HTN-OFF MED trial, but noted that because the enrolled patients did not have resistant hypertension, "at best, this represents a proof-of-principle study demonstrating the role of the renal sympathetic nervous system in hypertension." The statement concluded that "the role of device-based sympatholytic treatments, as with renal denervation and baroreceptor stimulation, awaits clarification."

Eighth Joint National Committee
The Eighth Joint National Committee (2014), which was appointed to provide recommendations on hypertension treatment, published an evidence-based guideline on the management of hypertension in adults.52 These recommendations did not discuss the use of renal denervation.

National Institute for Health and Care Excellence
In 2012, the National Institute for Health and Care Excellence (NICE) published an interventional procedures guidance on the use of percutaneous transluminal radiofrequency sympathetic denervation of the renal artery for resistant hypertension, recommending that the procedure should only be used with special arrangements for clinical governance, consent, and audit or research due to limited evidence.53 This guidance is currently being updated with expected publication in March 2023.54

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently ongoing and unpublished trials that might influence this review are listed in Table 9.

Table 9. Summary of Key Trials

NCT No. Trial Name Planned Enrollment Completion Date
Ongoing      
NCT04722159 Clinical Outcome of Patients With Resistant Hypertension Undergoing Renal Denervation: A Report From the Swedish Registry for Renal Denervation 300 Aug 2021
(recruiting)
NCT04311086a Global Clinical Study of Renal Denervation in the Distal Main and First Order Branch Renal Arteries Using the Symplicity Spyral™ Multi-electrode Renal Denervation System (SPYRAL DYSTAL) 56 Jan 2023
(ongoing)
NCT02439749a 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) 366 Dec 2023
(ongoing)
NCT04307836a A Prospective, Multicenter, No-treatment Controlled, Randomized, Open-label, Pivotal Study to Evaluate the Safety and Efficacy of DENEX, Renal Denervation Therapy, in Patients with Hypertension on no or 1-3 Antihypertensive Medications 140 Jan 2024 (recruiting)
NCT04535050a A Prospective, Multicenter, Sham-controlled, Single-blinded, Randomized, Pilot Study to Evaluate the Safety and Effectiveness of DENEX Renal Denervation System in Patients With Uncontrolled Hypertension Not Treated With Antihypertensive Medication 100 Mar 2026
(not yet recruiting)
NCT02439775a 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) 337 Jul 2026 (ongoing)
NCT05198674a The SPYRAL AFFIRM Global Clinical Study of Renal Denervation With the Symplicity Spyral Renal Denervation System in Subjects With Uncontrolled Hypertension (SPYRAL AFFIRM) 1200 Jun 2027
(recruiting)
NCT05563337 Renal Denervation in Hypertensive Women Planning to Become Pregnant (WHY-RDN) 80 Aug 2027
(not yet recruiting)
NCT01534299a Global SYMPLICITY Registry (GSR) Denervation Findings in Real World (DEFINE) 5000 Oct 2027
(recruiting)

NCT: national clinical trial.
a Denotes industry-sponsored or cosponsored trial.

References 

  1. Acelajado MC, Calhoun DA. Resistant hypertension, secondary hypertension, and hypertensive crises: diagnostic evaluation and treatment. Cardiol Clin. Nov 2010; 28(4): 639-54. PMID 20937447
  2. Doumas M, Papademetriou V, Douma S, et al. Benefits from treatment and control of patients with resistant hypertension. Int J Hypertens. Dec 22 2010; 2011: 318549. PMID 21234402
  3. Zile MR, Little WC. Effects of autonomic modulation: more than just blood pressure. J Am Coll Cardiol. Mar 06 2012; 59(10): 910-2. PMID 22381426
  4. Bhatt DL, Kandzari DE, O'Neill WW, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. Apr 10 2014; 370(15): 1393-401. PMID 24678939
  5. Bhatt DL, Vaduganathan M, Kandzari DE, et al. Long-term outcomes after catheter-based renal artery denervation for resistant hypertension: final follow-up of the randomised SYMPLICITY HTN-3 Trial. Lancet. Sep 16 2022. PMID 36130612
  6. Townsend RR, Mahfoud F, Kandzari DE, et al. Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomised, sham-controlled, proof-of-concept trial. Lancet. Nov 11 2017; 390(10108): 2160-2170. PMID 28859944
  7. Bohm M, Kario K, Kandzari DE, et al. Efficacy of catheter-based renal denervation in the absence of antihypertensive medications (SPYRAL HTN-OFF MED Pivotal): a multicentre, randomised, sham-controlled trial. Lancet. May 02 2020; 395(10234): 1444-1451. PMID 32234534
  8. Kandzari DE, Bohm M, Mahfoud F, et al. Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept randomised trial. Lancet. Jun 09 2018; 391(10137): 2346-2355. PMID 29803589
  9. Mahfoud F, Kandzari DE, Kario K, et al. Long-term efficacy and safety of renal denervation in the presence of antihypertensive drugs (SPYRAL HTN-ON MED): a randomised, sham-controlled trial. Lancet. Apr 09 2022; 399(10333): 1401-1410. PMID 35390320
  10. Bakris GL, Townsend RR, Liu M, et al. Impact of renal denervation on 24-hour ambulatory blood pressure: results from SYMPLICITY HTN-3. J Am Coll Cardiol. Sep 16 2014; 64(11): 1071-8. PMID 24858423
  11. Mahfoud F, Bakris G, Bhatt DL, et al. Reduced blood pressure-lowering effect of catheter-based renal denervation in patients with isolated systolic hypertension: data from SYMPLICITY HTN-3 and the Global SYMPLICITY Registry. Eur Heart J. Jan 07 2017; 38(2): 93-100. PMID 28158510
  12. Kario K, Bhatt DL, Brar S, et al. Effect of Catheter-Based Renal Denervation on Morning and Nocturnal Blood Pressure: Insights From SYMPLICITY HTN-3 and SYMPLICITY HTN-Japan. Hypertension. Dec 2015; 66(6): 1130-7. PMID 26558819
  13. Lu D, Wang K, Liu Q, et al. Reductions of left ventricular mass and atrial size following renal denervation: a meta-analysis. Clin Res Cardiol. Aug 2016; 105(8): 648-656. PMID 26838292
  14. Flack JM, Bhatt DL, Kandzari DE, et al. An analysis of the blood pressure and safety outcomes to renal denervation in African Americans and Non-African Americans in the SYMPLICITY HTN-3 trial. J Am Soc Hypertens. Oct 2015; 9(10): 769-779. PMID 26362830
  15. Kandzari DE, Kario K, Mahfoud F, et al. The SPYRAL HTN Global Clinical Trial Program: Rationale and design for studies of renal denervation in the absence (SPYRAL HTN OFF-MED) and presence (SPYRAL HTN ON-MED) of antihypertensive medications. Am Heart J. Jan 2016; 171(1): 82-91. PMID 26699604
  16. Azizi M, Sapoval M, Gosse P, et al. Optimum and stepped care standardised antihypertensive treatment with or without renal denervation for resistant hypertension (DENERHTN): a multicentre, open-label, randomised controlled trial. Lancet. May 16 2015; 385(9981): 1957-65. PMID 25631070
  17. Courand PY, Pereira H, Del Giudice C, et al. Abdominal Aortic Calcifications Influences the Systemic and Renal Hemodynamic Response to Renal Denervation in the DENERHTN (Renal Denervation for Hypertension) Trial. J Am Heart Assoc. Oct 10 2017; 6(10). PMID 29018027
  18. Gosse P, Cremer A, Pereira H, et al. Twenty-Four-Hour Blood Pressure Monitoring to Predict and Assess Impact of Renal Denervation: The DENERHTN Study (Renal Denervation for Hypertension). Hypertension. Mar 2017; 69(3): 494-500. PMID 28115517
  19. Rosa J, Widimsky P, Tousek P, et al. Randomized comparison of renal denervation versus intensified pharmacotherapy including spironolactone in true-resistant hypertension: six-month results from the Prague-15 study. Hypertension. Feb 2015; 65(2): 407-13. PMID 25421981
  20. Esler MD, Krum H, Sobotka PA, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. Dec 04 2010; 376(9756): 1903-9. PMID 21093036
  21. Esler MD, Krum H, Schlaich M, et al. Renal sympathetic denervation for treatment of drug-resistant hypertension: one-year results from the Symplicity HTN-2 randomized, controlled trial. Circulation. Dec 18 2012; 126(25): 2976-82. PMID 23248063
  22. Esler MD, Bohm M, Sievert H, et al. Catheter-based renal denervation for treatment of patients with treatment-resistant hypertension: 36 month results from the SYMPLICITY HTN-2 randomized clinical trial. Eur Heart J. Jul 2014; 35(26): 1752-9. PMID 24898552
  23. Kario K, Ogawa H, Okumura K, et al. SYMPLICITY HTN-Japan - First Randomized Controlled Trial of Catheter-Based Renal Denervation in Asian Patients -. Circ J. 2015; 79(6): 1222-9. PMID 25912693
  24. de Jager RL, de Beus E, Beeftink MM, et al. Impact of Medication Adherence on the Effect of Renal Denervation: The SYMPATHY Trial. Hypertension. Apr 2017; 69(4): 678-684. PMID 28264922
  25. de Jager RL, van Maarseveen EM, Bots ML, et al. Medication adherence in patients with apparent resistant hypertension: findings from the SYMPATHY trial. Br J Clin Pharmacol. Jan 2018; 84(1): 18-24. PMID 28815689
  26. Schmieder RE, Ott C, Toennes SW, et al. Phase II randomized sham-controlled study of renal denervation for individuals with uncontrolled hypertension - WAVE IV. J Hypertens. Mar 2018; 36(3): 680-689. PMID 29035942
  27. Oliveras A, Armario P, Clara A, et al. Spironolactone versus sympathetic renal denervation to treat true resistant hypertension: results from the DENERVHTA study - a randomized controlled trial. J Hypertens. Sep 2016; 34(9): 1863-71. PMID 27327441
  28. Mathiassen ON, Vase H, Bech JN, et al. Renal denervation in treatment-resistant essential hypertension. A randomized, SHAM-controlled, double-blinded 24-h blood pressure-based trial. J Hypertens. Aug 2016; 34(8): 1639-47. PMID 27228432
  29. Desch S, Okon T, Heinemann D, et al. Randomized sham-controlled trial of renal sympathetic denervation in mild resistant hypertension. Hypertension. Jun 2015; 65(6): 1202-8. PMID 25824248
  30. Schneider S, Promny D, Sinnecker D, et al. Impact of sympathetic renal denervation: a randomized study in patients after renal transplantation (ISAR-denerve). Nephrol Dial Transplant. Nov 2015; 30(11): 1928-36. PMID 26333545
  31. Fadl Elmula FE, Hoffmann P, Larstorp AC, et al. Adjusted drug treatment is superior to renal sympathetic denervation in patients with true treatment-resistant hypertension. Hypertension. May 2014; 63(5): 991-9. PMID 24591332
  32. Pokushalov E, Romanov A, Corbucci G, et al. A randomized comparison of pulmonary vein isolation with versus without concomitant renal artery denervation in patients with refractory symptomatic atrial fibrillation and resistant hypertension. J Am Coll Cardiol. Sep 25 2012; 60(13): 1163-70. PMID 22958958
  33. Coppolino G, Pisano A, Rivoli L, et al. Renal denervation for resistant hypertension. Cochrane Database Syst Rev. Feb 21 2017; 2: CD011499. PMID 28220472
  34. Chen XH, Kim S, Zeng XX, et al. Account for Clinical Heterogeneity in Assessment of Catheter-based Renal Denervation among Resistant Hypertension Patients: Subgroup Meta-analysis. Chin Med J (Engl). Jul 05 2017; 130(13): 1586-1594. PMID 28639575
  35. Pappaccogli M, Covella M, Berra E, et al. Effectiveness of Renal Denervation in Resistant Hypertension: A Meta-Analysis of 11 Controlled Studies. High Blood Press Cardiovasc Prev. Jun 2018; 25(2): 167-176. PMID 29752703
  36. Fadl Elmula FEM, Feng YM, Jacobs L, et al. Sham or no sham control: that is the question in trials of renal denervation for resistant hypertension. A systematic meta-analysis. Blood Press. Aug 2017; 26(4): 195-203. PMID 28443356
  37. Sun D, Li C, Li M, et al. Renal Denervation vs Pharmacotherapy for Resistant Hypertension: A Meta-Analysis. J Clin Hypertens (Greenwich). Aug 2016; 18(8): 733-40. PMID 26619813
  38. Zhang X, Wu N, Yan W, et al. The effects of renal denervation on resistant hypertension patients: a meta-analysis. Blood Press Monit. Aug 2016; 21(4): 206-14. PMID 26901340
  39. Yao Y, Zhang D, Qian J, et al. The effect of renal denervation on resistant hypertension: Meta-analysis of randomized controlled clinical trials. Clin Exp Hypertens. 2016; 38(3): 278-86. PMID 27018652
  40. Fadl Elmula FE, Jin Y, Yang WY, et al. Meta-analysis of randomized controlled trials of renal denervation in treatment-resistant hypertension. Blood Press. 2015; 24(5): 263-74. PMID 26194721
  41. Kwok CS, Loke YK, Pradhan S, et al. Renal denervation and blood pressure reduction in resistant hypertension: a systematic review and meta-analysis. Open Heart. NA 2014; 1(1): e000092. PMID 25332808
  42. Pancholy SB, Shantha GP, Patel TM, et al. Meta-analysis of the effect of renal denervation on blood pressure and pulse pressure in patients with resistant systemic hypertension. Am J Cardiol. Sep 15 2014; 114(6): 856-61. PMID 25084693
  43. Davis MI, Filion KB, Zhang D, et al. Effectiveness of renal denervation therapy for resistant hypertension: a systematic review and meta-analysis. J Am Coll Cardiol. Jul 16 2013; 62(3): 231-241. PMID 23644092
  44. Shantha GP, Pancholy SB. Effect of renal sympathetic denervation on apnea-hypopnea index in patients with obstructive sleep apnea: a systematic review and meta-analysis. Sleep Breath. Mar 2015; 19(1): 29-34. PMID 24839239
  45. 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. Mar 06 2012; 59(10): 901-9. PMID 22381425
  46. Mahfoud F, Cremers B, Janker J, et al. Renal hemodynamics and renal function after catheter-based renal sympathetic denervation in patients with resistant hypertension. Hypertension. Aug 2012; 60(2): 419-24. PMID 22733462
  47. Ukena C, Mahfoud F, Kindermann I, et al. Cardiorespiratory response to exercise after renal sympathetic denervation in patients with resistant hypertension. J Am Coll Cardiol. Sep 06 2011; 58(11): 1176-82. PMID 21884958
  48. Ewen S, Mahfoud F, Linz D, et al. Effects of renal sympathetic denervation on exercise blood pressure, heart rate, and capacity in patients with resistant hypertension. Hypertension. Apr 2014; 63(4): 839-45. PMID 24420550
  49. Rosendorff C, Lackland DT, Allison M, et al. Treatment of hypertension in patients with coronary artery disease: a scientific statement from the American Heart Association, American College of Cardiology, and American Society of Hypertension. Circulation. May 12 2015; 131(19): e435-70. PMID 25829340
  50. Whelton PK, Carey RM, Aronow WS, et al. 2017 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. Hypertension. Jun 2018; 71(6): 1269-1324. PMID 29133354
  51. Carey RM, Calhoun DA, Bakris GL, et al. Resistant Hypertension: Detection, Evaluation, and Management: A Scientific Statement From the American Heart Association. Hypertension. Nov 2018; 72(5): e53-e90. PMID 30354828
  52. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. Feb 05 2014; 311(5): 507-20. PMID 24352797
  53. National Institute for Health and Care Excellence (NICE). Interventional procedures guidance: Percutaneous transluminal radiofrequency sympathetic denervation of the renal artery for resistant hypertension [IPG418]. January 2012; https://www.nice.org.uk/guidance/ipg418. Accessed September 29, 2022.
  54. National Institute for Health and Care Excellence (NICE). In development: Percutaneous transluminal radiofrequency sympathetic denervation of the renal artery for resistant hypertension [GID-IPG10221]. 2022; https://www.nice.org.uk/guidance/indevelopment/gid-ipg10221. Accessed September 28, 2022

Coding Section

Codes Number Description
CPT 

0338T

Transcatheter 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 (new code effective 01/01/14)

 

0339T

Same as code above but bilateral (new code effective 01/01/14)

ICD-9-CM

 

Investigational for all relevant diagnoses

 

401.0-405.99

Hypertensive disease code section (there is no specific ICD-9-CM code for resistant hypertension)

ICD-10-CM (effective 10/01/15)

 

Investigational for all relevant diagnoses

 

I10-I15.9

Hypertensive disease code range

ICD-10-PCS (effective 10/01/15)

 

ICD-10-PCS codes are only used for inpatient services. There is no specific ICD-10-PCS code for this procedure.

 

015L4ZZ, 015M4ZZ, 015N4ZZ

Surgical, destruction, sympathetic nerve code range (thoracic, abdominal, lumbar the renal sympathetic nerves come from T10-L1)

Type of Service

Surgery  

Place of Service

Outpatient/Inpatient  

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2014 Forward     

10/02/2023 Annual review, no change to policy intent, but, verbiage updated for clarity. Also updating Rationale and References.
10/05/2022 Annual review, no change to policy intent. Updating regulatory status, rationale and references

10/01/2021 

Annual review, no change to policy intent. Updating rationale and references. 

10/01/2020 

Annual review, no change to policy intent. Updating rationale and references. 

10/01/2019 

Annual review, policy statement revised to say :Radiofrequency ablation of the renal sympathetic nerves is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY for the treatment of resistant hypertension. No other changes made. 

10/08/2018 

Annual review, no change to policy intent. Updating description, regulatory status, guidelines, rationale and references. 

10/12/2017 

Annual review, no change to policy intent. Updating regulatory status and rationale. No other changes made. 

10/10/2016 

Annual review, no change to policy intent. Updating background, description, rationale and references. Adding guidelines.

10/08/2015 

Annual reivew, no change to policy intent. Updated background, description, regulatory status, rationale and references.

08/04/2014

Annual review. Added related policy. Updated regulatory status, rationale and references. No change to policy intent.

Complementary Content
${loading}