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. Radiofrequency ablation of the renal sympathetic nerves may act as a nonpharmacologic treatment for hypertension and has been proposed as a treatment option for patients with uncontrolled hypertension despite the use of anti-hypertensive medications.

For individuals who have uncontrolled hypertension, despite the use of anti-hypertensive medications, who receive RFA of the renal sympathetic nerves, the evidence includes several RCTs, numerous systematic reviews of the RCTs, and a multinational registry study. Relevant outcomes are symptoms, change in disease status, morbid events, medication use, and treatment-related morbidity. 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 Pilot 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 non-adherent 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. The SPYRAL HTN-ON MED Expansion study failed to meet its primary efficacy endpoint and found only 0.03 mmHg difference between renal denervation and sham control groups at 6 months follow-up. A significant reduction in office blood pressure was noted at 6 months (-4.1 mmHg). Confounding of these outcome estimates by unbalanced medication changes, missing 24-h SBP outcome data, and timing of antihypertensive medications related to 24-h SBP assessment may explain the discordant results between the pilot and expansion phases of this trial. Study interpretation is also 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. Evidence from systematic reviews and meta-analyses are conflicting, but all available studies included evidence from both first and second-generation Symplicity catheters as well as multiple renal denervation methodologies such as ultrasound. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. 

Background 
Uncontrolled Hypertension
Hypertension is estimated to affect approximately 30% of the population in the U.S.¹ It accounts for a high burden of morbidity related to stroke, ischemic heart disease, kidney disease, and peripheral arterial disease. An estimated 1 in 4 adults with hypertension have their hypertension under control, but the remaining 77% (93 million) remain uncontrolled.² Uncontrolled hypertension is diagnosed when an individual's blood pressure remains above targeted levels when a patient either is not using, or unable to use, treatments to control blood pressure or when hypertension persists despite antihypertensive therapies.³ The definition of uncontrolled hypertension is inclusive of resistant hypertension in which blood pressure remains above the targeted range despite the use of 3 or more antihyperensive medications, including a diuretic, with complementary mechanisms of action.³ A number of factors may contribute to uncontrolled hypertension including nonadherence to medications, excessive salt intake, inadequate doses of medications, excess alcohol intake, volume overload, drug-induced hypertension, and other forms of secondary hypertension.⁴ Also, sometimes it is necessary to address comorbid conditions (i.e., obstructive sleep apnea) to control blood pressure adequately.

Treatment
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 adverse events 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 procedure decreases sympathetic activation, decreases vasoconstriction, and decreases activation of the renin-angiotensin system.⁵

The procedure is performed percutaneously with access at the femoral artery. A flexible catheter is threaded into the renal artery, and a 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 FDA approval (FDA product code: DQY):

• The Symplicity Spyral™ Renal Denervation System (Medtronic) is a multielectrode RFA catheter system designed to deliver 4-quadrant ablations. On Aug. 23, 2023, the FDA Advisory Committee for Circulatory System Devices voted that the Symplicity Spyral system met its safety endpoint as well as its efficacy endpoint, but after a tied vote in which the chairperson cast the final vote, the committee determined that the device did not achieve a positive balance of benefits and harms.
• 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.

Other RFA catheters (e.g., 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.

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 the treatment of patients with persistently elevated blood pressure. However, ultrasound-based renal denervation systems are outside of the scope of this evidence review.

Policy
Radiofrequency ablation of the renal sympathetic nerves is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY for the treatment of 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 Treatment for hypertension consists of behavioral modifications and antihypertensive medications. For individuals with uncontrolled hypertension despite the use of antihypertensive medications, treatment is mainly intensified drug therapy, sometimes with the use of nontraditional antihypertensive medications such as spironolactone and/or minoxidil. However, treatment of hypertension which has not been adequately controlled with additional medications is often challenging and can lead to high costs and frequent adverse events of treatment. As a result, there is a large unmet need for additional treatments that can control uncontrolled hypertension. Nonpharmacologic interventions for uncontrolled hypertension despite medical management include modulation of the baroreflex receptor and/or radiofrequency (RF) denervation of the renal nerves.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.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., people of color [African American, Asian, Black, Latino and Native American]; LGBTQIA [lesbian, gay, bisexual, transgender, queer, intersex, asexual]; women; and people with disabilities [physical and invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Radiofrequency Ablation
Clinical Context and Therapy Purpose
The purpose of radiofrequency ablation (RFA) in individuals who have 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 individuals with hypertension that is uncontrolled despite the use of antihypertensive medications or who poorly tolerate blood pressure lowering therapy. 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, spiral-shaped RFA catheter intended to permit more complete, circumferential ablations.

Comparators
The following therapy is currently being used to treat those with 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.
• Studies of the Symplicity Spyral catheter were reviewed, but evidence from the first-generation Symplicity Flex catheter was 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
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)
SPYRAL HTN-ON MED Expansion3	257	Symplicity Spyral multielectrode RDN (n = 168) vs. sham (n = 89) on stable doses for at least 6 weeks	Same as above	Mean Age: 55.5 Sex: Male, 80% Race: White, 36%; Black, 12%; NR, 37% Mean BMI: 31.4 Mean office BP: 163/102 Mean 24-h BP: 149/97 Medications: NR	Mean Age: 55 Sex: Male, 78% Race: White, 37%; Black 17%; NR, 39% Mean BMI: 32 Mean office BP: 163/101 Mean 24-h BP: 148/95 Medications: NR	Change in mean 24-h BP from baseline to 6 months and between groups

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)
SPYRAL HTN-OFF MED Pilot6	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); .0414	-4.4 (-7.2 to -1.6); .0024	-7.7 (-14.0 to -1.5); .0155	-4.9 (-8.5 to -1.4); .0077
SPYRAL HTN-OFF MED Pivotal7	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); .0005	-3.1 (-4.6 to -1.7); < .0001	-6.6 (-9.6 to -3.5); < .0001	-4.4 (-6.2 to -2.6); < .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); .0051	-4.1 (-7.8 to -0.4); .0292	-6.8 (-12.5 to -1.1); .0205	-3.5 (-7.0 to 0);.0478
SPYRAL HTN-ON MED Expansion3	6 months
RDN	-5.9	NR	-10.1	NR
Sham	-5.8	NR	-6.2	NR
MD (95% CI); p	0.0 (-2.8 to 2.9); .974	NR	-4.0 (-7.6 to 0.4); .028	NR
SPYRAL HTN-ON MED Expansion (Full Cohort)3	6 months
RDN	-6.5	NR	-9.9	NR
Sham	-4.5	NR	-5.1	NR
MD (95% CI); p	-1.9 (-4.4 to 0.5); .110	NR	-4.9 (-7.9 to -1.9); .001	NR

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 OFF MED (Full-Cohort)3
3 months ± SD, N, p-value	RDN: -4.5 ± 10.8, N = 153; p < .001 Sham: -0.6 ± 8.7, N = 147	NR	RDN: -9.4 ± 14.8, N = 170; p<.001 Sham: -2.3 ±12.7, N = 164	NR
6 months ± SD, N, p-value	RDN: -15.3 ± 13.7, N = 150 Sham:-17.1 ± 12.3, N = 159	NR	RDN: -20.8 ± 13.9, N = 174 Sham: -21.9 ± 14.3, N = 177	NR
12 months ± SD, N, p-value	RDN: -14.3 ± 11.9, N = 146 Sham: -19.2 ± 12.l, N = 92; p = .03	NR	RDN: -21.3 ± 14.2, N = 171 Sham: -22.4 ± 13.6, N = 104	NR
SPYRAL HTN-ON MED Pilot8,9
3 months	-4.6 (NR); .10	-3.7 (NR); .06	-1.6 (NR); 0.59	-1.5 (NR); .44
6 months	-7.4 (-12.5 to -2.3); .0051	-4.1 (-7.8 to -0.4); .0292	-6.8 (-12.5 to -1.1); .0205	-3.5 (-7.0 to 0); .0478
6 months (adherent subgroup)	-6.0 (NR); .99	-3.3 (NR); .249	-5.1 (NR); .144	-2.7 (NR); .241
6 months (non-adherent subgroup)	-8.3 (NR); .029	-4.6 (NR); .062	-7.9 (NR); .087	-4.0 (NR); .135
12 months	-1.9 (NR); .553	-0.8 (NR); .695	NR	NR
24 months	-11.2 (-18.4 to -4.0); .0031	-5.7 (-10.6 to -0.7); .025	-12.9 (-21.1 to -4.7); .0026	-8.5 (-15.0 to -2.1); .010
24 months (without imputation)	-11.2 (-18.4 to -4.0); .003	NR	-11.1 (-21.6 to -0.5); .11	NR
36 months	-10.0 (-16.6 to -3.3); .0039	-5.9 (-10.1 to -1.8); .0055	-11.8 (-19.0 to -4.7); .0017	-3.9 (-9.8 to 1.9); .186
36 months (without imputation)	-6.1 (-13.6 to 1.4); .11	NR	0.5 (-8.8 to 9.7); .92	NR

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

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.¹⁰ 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. Longer-term follow-up for the full cohort of pilot plus pivotal trial patients found that at 6 months, significant differences in 24-h SBP and office SBP were no longer observed, likely as a result of trial participants beginning or resuming antihypertensive medications at 3 months follow-up.³ By 12 months, the sham control group had a superior 24-h SBP, although no between-group differences were reported at 1 year post-treatment for office SBP (Table 4).

Symplicity Spyral ON-MED Pilot and Expansion Trials
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 HTN-ON MED Expansion trial has yet to be published, but results are available from material from the FDA Aug. 23, 2023, Meeting of the Circulatory System Devices Panel for the Medtronic, Inc. Symplicity Spyral Renal Denervation System at the time of drafting this health assessment.³ The eligibility criteria and primary efficacy endpoint were identical to the HTN-ON MED pilot study described above, with similar baseline characteristics (Table 2). The expansion trial randomized participants 2:1 to renal denervation (n = 168) or sham treatment (n = 89) and assessed patients as part of the expansion study alone or as part of a merged full cohort incorporating pilot data. A total of 12 patients in the renal denervation group and 13 in the sham group met escape criteria. Additionally, few patients from the pilot cohort were able to be incorporated into the full analysis due to large discrepancies outcome effects. Medtronic postulated that these differences might be due to unbalanced antihypertensive medication changes between groups, which showed that a higher proportion of sham control patients increased BP medications (17% in the renal denervation group vs. 30% in the sham group), non-evaluable 24-h SBP data (11.5% in the sham group vs. 6.8% in the renal denervation group), or confounding due to timing of BP medication use in relation to 24-h ambulatory monitoring.

The primary efficacy endpoint of baseline adjusted change in 24-h SBP from baseline to 6-months post-procedure, compared between renal denervation and sham groups did not show a significant difference in the expansion cohort or the full cohort of patients on Baysesan analysis (mean Bayesian posterior treatment effect, -0.03 mmHg; 95% CI, -2.92 to 2.76, posterior probability of superiority, = 0.51). However, 6 month office SBP did show a significant difference favoring the renal denervation group (mean Bayesian posterior treatment effect, -4.1 mmHg; 95% CI, -7.4 to 0.75, posterior probability of superiority, = 0.99), but the outcome assessment was non-powered. These results were mirrored in the frequentist ANCOVA analysis in both the expansion and full cohorts, which showed no differences in 24-h SBP but favored renal denervation for office SBP (Table 3). Between-group differences were also statistically significant for night-time SBP at 6 months (mean difference, -3.7; 95% CI, -6.5 to -0.9; p = .0095) in favor of renal denervation, but no differences were noted for daytime or 24-h SBP. At 6 months, the expansion cohort was unblinded, and the addition of medications was permitted; however, a high proportion of participants did not remain on stable medication usage during the trial. The FDA performed an assessment of differences in medication burden between groups at baseline, 3 months, and 6 months follow-up and did not find a significant between-group difference at any time point between groups. A subgroup analysis found that at 6 months follow-up 24-h SBP was significantly different between patients based on geography (United States vs. outside United States, p-value for interaction = .011). Patients in the U.S. sham control group had a greater absolute 24-h SBP reduction (6.7 mmHg) compared to those outside the U.S. (2.6 mmHg). Patients in the HTN-ON MED trial reported few major adverse events at 6 months, with only 2 (1%) in the renal denervation group and 1 (0.8%) event in the sham control group.

The primary safety analysis pooled patients from both the HTN-OFF MED and HTN-ON MED trials (n = 253) and was defined as the composite incidence of major adverse events at 1-month post-randomization as adjudicated by a clinical events committee. Adverse events of interest included all-cause mortality, end-stage renal disease, significant embolic events resulting in end-organ damage, renal artery perforation requiring intervention, renal artery dissection requiring intervention, vascular complications, hospitalization for a hypertensive crisis not related to non-adherence with BP medications or study protocol as well as the 6-month incidence of renal artery stenosis (> 70 diameter stenosis by angiography). The primary safety endpoint result was met with only a single vascular complication of a pseudo aneurysm being reported (event rate, 0.4%; 95% CI, 0% to 1.9%, p < .001) and is lower than the pre-specified performance goal of 7.1%. No renal artery stenoses were identified in the first 6 months of analysis; a sub-study using data from 180 renal denervation patients with CTA or MRA studies at 12 months found that potential stenoses were identified in 31 subjects at 12 months follow-up. Of these, 2 had stenoses of 51% – 75%, and 5 had stenoses of > 76%; on follow-up angiography, 5 reported no stenosis 1 had confirmed 60% diameter stenosis, and 1 had no follow-up imaging.

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
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; 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).
SPYRAL HTN-ON MED Expansion3	4. Low enrollment of women 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. Different rates of hypertension medication changes in renal denervation and sham groups post-randomization.	6. Clinically significant difference for mean office blood pressure only observed; no difference in primary 24-hr blood pressure. Sub-group analysis shows discordant BP reductions for US and non-US participants on primary outcome.	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
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.	.
SPYRAL HTN-ON MED Expansion3				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 key secondary endpoint of change in office BP.

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.

Global Symplicity Registry
The Global Symplicity Registry (GSR) is a prospective, multi-center, single-arm, non-interventional and open-label registry that aims to document the long-term safety and effectiveness of renal denervation in a real-world population.³ Since 2012, a total of 3,077 patients have been enrolled in the GSR, but this includes a larger proportion of patients with the first-generation Symplicity Flex catheter. A subset of patients treated with the second-generation Symplicity Spyral device (n = 846) was considered for this review. However, only a small group of these patients have 24-h SBP measurements, and fewer still have longer-term follow-ups. Patients generally had more co-morbidities and a greater baseline level of anti-hypertensive medications (mean 4.8) than those included in the Symplicity HTN-ON MED and HTN-OFF MED trials. Significant improvements from baseline in 24-hour ambulatory SBP and office SBP were observed at 6 months, 12 months, 24 months, and 36 months follow-up (Table 7). The magnitude of change in blood pressure from baseline was greater than that observed in sham-controlled trials, which may be suggestive of a potential placebo effect.

Table 7. Outcomes of Global Symplicity Registry

Outcome	Baseline Blood Pressure	6 Months	12 Months	24 Months	36 Months
24-h SBP MD ± SD, N	155.20 ± 20.10, N = 542	-7.69 ± 18.72, N = 289	-8.77 ± 18.04, N = 242	-8.83 ± 17.96, N = l32	-14.39 ± 2 1.93, N = 74
24-h DBP MD ± SD, N	88.10 ± 15.18, N = 542	-4.88 ± 10.76, N = 289	4.90 ± 10.62, N = 242	-4.42 ± 10.05, N = l32	-6.12 ± 12.33, N = 74
Office SBP MD ± SD, N	165.83 ± 24.82, N = 792	-14.23 ± 25.76, N = 517	-15.18 ± 26.54, N = 475	-13.99 ± 27.59, N = 331	-18.07 ± 26.76, N = 200
Office DBP MD ± SD, N	91.19 ± 17.44, N = 792	-5.52 ± 14.07, N = 515	-6.42 ± 14.77, N = 473	-7.67 ± 15.06, N = 326	-7.79 ± 15.68, N = 195

MD: mean difference; SBP: systolic blood pressure; SD: standard deviation

Section Summary: Randomized Controlled Trials
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-group 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. The SPYRAL HTN-ON MED Expansion study did not meet its primary effectiveness endpoint. No difference in 24-h SBP (0.03 mmHg) between the renal denervation and sham groups in HTN-ON MED was observed, although there was a significant difference in reduction for office SBP (4.1 mmHg), which favored the renal denervation group. Several confounders may have impacted the HTN-ON MED outcomes, including unbalanced medication changes between the 2 treatment groups, unbalanced missing 24-h SBP data, and timing of antihypertensive medication related to ABPM monitoring. Study interpretation is also 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. A safety analysis on a subset of HTN-ON and HTN-OFF MED participants found only 0.4% had a major adverse event at 1 month follow-up and met its pre-specified performance goal.

Systematic Reviews
Multiple systematic reviews with overlapping studies, 1 of which is a Cochrane review by Coppolino et al. (2017),¹¹ have summarized the key RCTs evaluating renal denervation. The characteristics of the systematic reviews are summarized in Table 8, and the key results are summarized in Table 9. 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.¹¹ 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),¹² calculated change in blood pressure for subgroups at 12-month follow-up. The 12-month analysis showed no difference at the longer follow-up. A network meta-analysis by Silverwatch et al. (2022) pooled the results of 20 RCTs of varying approaches to renal denervation compared to sham or antihypertensive medications or one another.¹³ Trials enrolled participants with uncontrolled hypertension treated with radiofrequency main renal artery denervation (n = 10 studies), radiofrequency of the main renal artery plus branches (n = 4), radiofrequency of main renal artery plus antihypertensive therapy (n = 5), ultrasound of the main renal artery (n = 3), sham control (n = 8), and antihypertensive therapy alone (n = 9). The authors found that radiofrequency renal denervation had the greatest improvement in 24 ambulatory, daytime, and nighttime BPs compared to other interventions (p-scores ranging from 0.83 to 0.97), with significant effects found versus both sham and antihypertensive therapies.

Table 8. Characteristics of Systematic Review of Controlled Trials Assessing Renal Denervation

Study	Dates	Trials	N (Range)	Design	Duration, mo
Silverwatch et al. (2022)13	2010 – 2020	20	2,152 (20 – 535)	RCT	2 – 6
Ogoyama et al. (2021)14	2014 – 2021	9	1,555 (51 – 535)	RCT, CT	2 – 6
Pappaccogli et al. (2018)15	2010 – 2016	11	1,236 (19 – 535)	RCT, CT	6
Coppolino et al. (2017)11	2010 – 2016	12	1,149 (16 – 535)	RCT, CT	6
Chen et al. (2017)12	2010 – 2016	9	1,068 (19 – 535)	RCT	6
Fadl Elmula et al. (2017)16	2010 – 2017	10	1,174 (19 – 524)	RCT, CT	6
Sun et al. (2016)17	2010 – 2015	9	2,932 (67 – 622)	RCT, CT	6
Zhang et al. (2016)18	2013 – 2015	11	1,160 (19 – 535)	RCT, CT	6
Yao et al. (2016)19	2010 – 2015	8	1,059 (19 – 535)	RCT	6
Fadl Elmula et al. (2015)20	2010 – 2015	7	985 (20 – 535)	RCT	6

CT: controlled trial; RCT: randomized controlled trial.

Table 9. Systematic Review Results at 6-Month Follow-Up for Controlled Trials Assessing Renal Denervation

Study	Treatment	Comparator	Trials	Outcomes	SMD, mm Hg	95% CI, mm Hg	p	I2, %
Silverwatch et al. (2022)13	RD (radiofrequency of main renal artery, main renal artery plus branch, main renal artery plus antihypertensive treatment or ultrasound of main renal artery)	Sham or AHT (network meta-analysis)	20	Outcome: Group 24-h SBP: rfMRA+B 24-h SBP: rfMRA 24-h SBP: rfMRA+AHT 24-h SBP: usMRA 24-h SBP: rfMRA+B 24-h SBP: rfMRA 24-h SBP: rfMRA+AHT 24-h SBP: usMRA Office SBP: rfMRA+B Office SBP: rfMRA Office SBP: rfMRA+AHT Office SBP: usMRA Office SBP: rfMRA+B Office SBP: rfMRA Office SBP: rfMRA+AHT Office SBP: usMRA	-7.2 0.6 -4.7 -1.2 -12.9 5.9 -1 -6.9 -6.9 -0.2 -10.5 2.3 -7.3 -0.7 -10.1 -1.8	-13.6 to -0.8 -4.4 to 5.5 -5.5 to 14.8 -8.6 to 6.2 -22.6 to -3.2 -11.4 to 1.3 -7.2 to 5.2 -17.8 to 4.1 -19.9 to 6.3 -13.4 to 13.1 -30.7 to 9.7 -12.9 to 17.5 -26.4 to 11.8 -11.7 to 10.4 -21.4 to -0.6 -21.2 to 24.8	SS NS NS NS SS NS NS NS NS NS NS NS NS NS SS NS	Comparison*: Sham Sham Sham Sham AHT AHT AHT AHT Sham Sham Sham Sham AHT AHT AHT AHT
Ogoyama et al. (2021)14	rf RD (1st or 2nd generation device)	Control	6	24-h SBP (N = 1137) 24-h DBP (N = 1137) Office SBP (N = 997) Office DBP (N = 997)	-3.17 -1.58 -4.93 -3.33	-5.22 to -1.11 -3.11 to -0.04 -7.81 to -2.06 -4.88 to -1.78	SS SS SS SS	30 47 26 16
Pappaccogli et al. (2018)15	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)11	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)12	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)16	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)17	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)18	RD	Control	11	Office SBP	-13.9	-21.17 to -6.63	<.001	93
Yao et al (2016)19	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)20	RD	Control	15	Office SBP	-4.89	-20.9 to 11.1	.47	92

*Value reflects comparison group for network meta-analysis not I2
ADBP: ambulatory diastolic blood pressure; ASBP: ambulatory systolic blood pressure; AHT: antihypertensive therapy; B: branch of renal artery; CI: confidence interval; DBP: diastolic blood pressure; MRA: main renal artery; NR: not reported; NS: not significant; RD: renal denervation; rf: radiofrequency: SBP: systolic blood pressure; SMD: standardized mean difference; SS: statistically significant; usMRA: ultrasound deneveration of main renal artery. 

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.²¹ 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.²² 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.²³ 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.²⁴ These recommendations did not discuss the use of renal denervation.

European Society for Hypertension (ESH)
The ESH, with endorsement by the European Renal Association and the International Society of Hypertension, issued guidance on the management of arterial hypertension in 2023.²⁵ The following recommendations were issued concerning renal denervation:

• Renal denervation can be considered as a treatment option in patients with an eGFR of > 40 ml/min/1.73m2 who have uncontrolled blood pressure despite the use of anti-hypertensive drug combination therapy or if drug treatment elicits serious side effects. (Class of Recommendation: II, Level of Evidence: B)
• Renal denervation can be considered as an additional treatment option in patients with resistant hypertension if eGFR is > 40 ml/min/1.73m2. (Class of Recommendation: II, Level of Evidence: B)
• Selection of patients to whom renal denervation is offered should be done in a shared decision-making process after objective and complete patient information is collected. (Class of Recommendation: I, Level of Evidence: C)
• Renal denervation should only be performed in experienced specialized centers to guarantee appropriate selection of eligible patients and completeness of the denervation procedure. (Class of Recommendation: I, Level of Evidence: C)

A class of recommendation I indicates a general consensus that the measure is useful, and a class II recommendation reflects that there is no general consensus and that only doubtful evidence exists. An 'A' level of evidence indicates that RCTs or meta-analyses with cardiovascular disease outcomes are available for this recommendation, a level 'B' suggests RCTs with surrogate measures, observational studies with cardiovascular disease outcomes or meta-analyses are available, and a C recommendation reflects either expert opinion or only observational or lower quality experimental evidence.

ESH recommendations did not discuss the specific use of radiofrequency renal denervation and included evidence from other modalities, such as ultrasound, in their evidence appraisal.

National Institute for Health and Care Excellence
In 2023, 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.²⁶

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 10.

Table 10. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
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)
Unpublished
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 (completed)
NCT04722159	Clinical Outcome of Patients With Resistant Hypertension Undergoing Renal Denervation: A Report From the Swedish Registry for Renal Denervation	300	Aug 2021 (unknown)

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

References 

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15. 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
16. 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
17. 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
18. 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
19. 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
20. 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
21. 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
22. 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
23. 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
24. 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
25. Mancia G, Kreutz R, Brunström M, et al. 2023 ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension Endorsed by the International Society of Hypertension (ISH) and the European Renal Association (ERA). J Hypertens. Jun 21 2023. PMID 37345492
26. National Institute for Health and Care Excellence (NICE). Interventional procedures guidance: Percutaneous transluminal radiofrequency sympathetic denervation of the renal artery for resistant hypertension [IPG418]. March 2023; https://www.nice.org.uk/guidance/ipg754. Accessed August 29, 2023.

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 2024 Forward     

10/30/2024 Annual review, title, description, background, rationale, references and regulatory status updated. Policy continues to maintain a not medically necessary position, but, has had resistant hypertension removed and addresses uncontrolled hypertension.

01012024  NEW POLICY