BlueCross and BlueShield of Montana Medical Policy/Codes
Radiofrequency Ablation of the Renal Sympathetic nerves as a Treatment for Resistant Hypertension
Chapter: Surgery: Administrative
Current Effective Date: March 15, 2014
Original Effective Date: March 15, 2014
Publish Date: January 15, 2014
Description

Radiofrequency ablation (RFA) of the renal sympathetic nerves is a non-pharmacologic treatment for hypertension. This treatment is intended to reduce sympathetic nerve activity in the renal system, thus leading to lower blood pressure. Patients with hypertension that is resistant to treatment with standard medications may derive benefit from this approach.

Resistant hypertension. Hypertension is a widely prevalent condition, which 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 (BP) despite treatment with at least 3 antihypertensive agents at optimal doses. Resistant hypertension is also a relatively common condition, given the large number of individuals with hypertension. In large clinical trials of hypertension treatment, up to 20-30% of participants meet the definition for resistant hypertension, and in tertiary care hypertension clinics, the prevalence has been estimated to be 11-18%. (1) Resistant hypertension is associated with a higher risk for adverse outcomes such as stroke, myocardial infarction (MI), heart failure, and kidney failure.

There are a number of factors that may contribute to uncontrolled hypertension, and these should be considered and addressed in all patients with hypertension prior to labeling a patient resistant. These include non-adherence to medications, excessive salt intake, inadequate doses of medications, excess alcohol intake, volume overload, drug-induced hypertension, and other forms of secondary hypertension. (2) Also, sometimes it is necessary to address comorbid conditions, i.e., obstructive sleep apnea, in order to adequately control BP.

Treatment for resistant hypertension is mainly intensified drug therapy, sometimes with the use of non-traditional antihypertensive medications such as spironolactone and/or minoxidil. However, control of resistant hypertension with additional medications is often challenging and can lead to high costs and frequent adverse effects of treatment. As a result, there is a large unmet need for additional treatments that can control resistant hypertension. Non-pharmacologic interventions for resistant hypertension include modulation of the baroreflex receptor, and/or radiofrequency (RF) denervation of the renal nerves.

Radiofrequency denervation of the renal sympathetic nerves. Increased sympathetic nervous system activity has been linked to essential hypertension. Surgical sympathectomy has been shown to be effective in reducing blood pressure but is limited by the side effects of surgery and was largely abandoned after effective medications for hypertension became available. The renal sympathetic nerves arise from the thoracic nerve roots and innervate the renal artery, the renal pelvis, and the renal parenchyma. Radiofrequency ablation (RFA) is thought to decrease both the afferent sympathetic signals from the kidney to the brain and the efferent signals from the brain to the kidney. This decreases sympathetic activation, decreases vasoconstriction, and decreases activation of the renin-angiotensin system. (3)

The procedure is performed percutaneously with access at the femoral artery. A flexible catheter is threaded into the renal artery and controlled, low-power RF energy is delivered to the arterial walls where the renal sympathetic nerves are located. Once adequate RF energy has been delivered to ablate the sympathetic nerves, the catheter is removed.

Regulatory Status

No RFA devices have been approved for ablation of the renal sympathetic nerves as a treatment for hypertension. There are several devices that have been developed for this purpose and are in various stages of application for U.S. Food and Drug Administration (FDA) approval. The Symplicity™ renal denervation device (Medtronic, Inc.) consists of a flexible catheter that is specifically intended for use in the renal arteries, and an external power generator. Other devices under development for this purpose include the Biosense Webster Thermocouple Catheter™, which has been used for cardiac electrophysiology procedures, and the St. Jude Medical EnligHTN™ multi-electrode renal denervation system.

Policy

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coverage

Radiofrequency ablation of the renal sympathetic nerves is considered experimental, investigational and/or unproven for the treatment of resistant hypertension.

Rationale

This technology requires high-quality randomized controlled trials (RCTs) to demonstrate efficacy. This is due to the natural variability in blood pressure (BP), the heterogeneity of the patient populations with increased BP, and the presence of many potential confounders of outcome. A sham-controlled RCT is ideal since it would also control for any placebo, or other non-specific, effects of BP treatment. Case series have limited utility for determining efficacy. They can be useful for demonstrating potential of the technique, for determining the rate of short- and long-term adverse effects of treatment, and to evaluate the durability of the treatment response.

The literature review identified one small, short-term RCT, a few non-randomized controlled trials, and several case series. These relevant studies are reviewed below.

Randomized, controlled trials

Simplicity HTN-2. The Simplicity HTN-2 trial was a multicenter, unblinded RCT evaluating renal sympathetic denervation versus standard pharmacologic treatment for patients with resistant hypertension. (4) A total of 106 patients with a systolic blood pressure of at least 160 mm Hg despite 3 or more antihypertensive medications were enrolled. The trial was unblinded, and clinicians ascertaining outcomes were not blinded to treatment assignment. Patients were followed for 6 months with the primary endpoint being the between-group difference in the change in BP over the course of the trial. Secondary outcomes included a composite outcome of adverse cardiovascular events and adverse effects of treatment. Baseline BP was 178/98 in the RFA group and 178/97 in the control group.

At 6 months’ follow-up, the BP reductions in the RFA group were 32 mm Hg systolic (SD 23) and 12 mm Hg diastolic (SD 11). In the control group, there was a 1 mm Hg increase in systolic BP and no change for diastolic BP (p<0.0001 for both systolic blood pressure (SBP) and SBP differences). The percent of patients who achieved an SBP of 140 or less was 39% (19/49) in the radiofrequency ablation (RFA) group compared to 6% (3/51) in the control group (p<0.0001). There was no difference in renal function, as measured by serum creatinine, between groups at the 6-month time period. There were 3 patients in the RFA group who had adverse cardiovascular events compared to 2 in the control group (p=NS). Other serious adverse events requiring admission in the RFA group included one case each of nausea/vomiting, hypertensive crisis, transient ischemic attack (TIA), and hypotension.

The main limitations of this RCT are that it is small in size, unblinded, and has only a relatively short follow-up. A trial with a sham control would allow better determination of whether the treatment effect was due to a placebo effect, or other non-specific effects of being in a trial. The 6-month follow-up is too short to ascertain whether the reduction in BP is likely to reduce adverse cardiovascular outcomes such as myocardial infarction (MI) and stroke. It is unknown whether re-innervation of the renal sympathetic nerves occurs post-treatment. If re-innervation does occur, the efficacy of the procedure will diminish over time. Trials with longer term follow-up are needed to determine whether this is the case.

Non-randomized, comparative studies

Several nonrandomized studies with a control group have been published. The populations from some of these studies overlap to a large extent with the Simplicity HTN-2 trial. Additional cases may have been added to the study population using the same eligibility criteria, and only a small number of control patients were included in the analyses. Thus, these comparisons are not considered randomized. These studies examine different physiologic outcomes in addition to changes in blood pressure.

An echocardiographic sub-study was published in 2012. (5) This trial compared 46 patients who underwent RFA to 18 control patients from the larger control group in the trial. The selection of patients for the control group was not specified. The main endpoints of this trial were echocardiographic measures of left ventricular hypertrophy (LVH) and diastolic dysfunction at 6 months post-treatment. There was a significant decrease in the LV mass index for the treatment group at 6 months, from a baseline of 112.4 ± 33.9 g/m2 to 94.9 ± 29.8 g/m2. In the control group, there was a slight increase in LV mass index from 114.8 ± 41.6 g/m2 to 118.7 ± 30.1 g/m2 (p=0.009 for comparison with RFA group). There was also a significant improvement in measures of diastolic dysfunction for the RFA group compared to controls at 6 months.

Another sub-study published in 2011 evaluated the response to exercise in 46 patients treated with RFA compared to 9 patients in the control group at 3 months post-treatment. (6) There were significant improvements in the achieved workload, and recovery from exercise in heart rate and blood pressure compared to controls. There were no differences in maximum oxygen uptake or maximum heart rate during exercise.

A third study that enrolled 50 patients measured parameters of glucose metabolism in treated and control patients. This population included a subset of patients from the Simplicity trial (n=17 treated and n=9 control patients) and also included another 20 treated patients and 4 control patients who met the same eligibility criteria used in the Simplicity HTN-2 trial. Outcomes at 3 months showed that there was an improvement in fasting glucose for the treated patients from a baseline of 118 ± 3.4 mg/dL to 108 ± 3.8 mg/dL (p=0.039). There was no change in the control group. Insulin levels and C-peptide levels were also reduced in the treatment group, as were peak glucose levels at 2 hours on a glucose tolerance test.

Mahfoud et al. (7) enrolled 100 patients in a study that evaluated the impact of RFA on renal function and renal hemodynamics, 87 treated with RFA and 13 control patients. This population also overlapped with the Simplicity HTN-2 trial and all patients met the eligibility criteria used in Simplicity HTN-2. There was no discernable impact of RFA on the glomerular filtration rate or mean urinary albumin excretion at 6 months’ follow-up. There were significant improvements for the treated patients on the incidence of microalbumineria and the renal resistive index. There were no instances of renal artery stenosis, dissections, or aneurysms at the 6-month time point.

Case series

The largest case series was the Simplicity HTN-1 study, which was a multicenter, single-arm trial sponsored by the manufacturer. (8, 9) A total of 153 patients with resistant hypertension were treated at 19 clinical centers in the US, Europe and Australia. The mean baseline BP was 176/98, and participants were taking a mean of 5 antihypertensive drugs. Patients were followed for up to 24 months with the main endpoint being reduction in BP. Procedural complications occurred in 4 patients (3%), including 3 cases of groin pseudoaneurysms and one renal artery dissection. The mean BP reductions at 6 months, 12 months, and 24 months were 25/11, 23/11, and 32/14 respectively. There was no evidence for a diminution of the treatment effect over time.

A few other very small case series have been published, reporting BP outcomes and adverse events from the procedure. (10-14) The numbers of patients in these case series ranged from 2-12, which is generally too small to provide meaningful group outcome data.

Ongoing trials

A search of ClinicalTrials.Gov with the terms “renal artery denervation” yielded 24 relevant trials. Most of these were single-arm series of different types of renal artery denervation in various patient populations. There were 5 RCTs listed of renal denervation as a treatment for resistant hypertension, these are described briefly below.

Simplicity HTN-3 trial (NCT01418261). The Simplicity HTN-3 trial is a larger randomized, controlled trial of renal denervation with similar methodology as the Simplicity HTN-2 trial. (15) Enrollment is planned for approximately 500 patients, who will be randomized to renal denervation or standard care. The primary efficacy endpoint is reduction in BP from baseline to 6 months. Other efficacy endpoints include the percent of patients achieving target BP and medication use. Safety endpoints include overall mortality, change in renal function, renal perforation, renal artery dissection, vascular complications, and hospitalizations for hypertension. The trial is expected to be completed in 2013-2014.

ReSET trial (NCT01459900). The Renal Sympathectomy in Treatment of Resistant Essential Hypertension (ReSET) trial is a sham-controlled, double-blind RCT of patients with elevated BP despite treatment with at least 3 medications. The primary endpoint is change in daytime systolic BP at 6 months of follow-up. Enrollment is planned for 70 patients, with an estimated study completion date of May 2013.

DEPART trial (NCT01522430). The Study of Catheter-based Renal Denervation Therapy in Hypertension (DEPART) trial is a sham-controlled, double-blind RCT of patients with elevated BP despite treatment with at least 3 medications. The primary endpoints are changes in systolic/diastolic BP and glomerular filtration rate at 6 months of follow-up. Enrollment is planned for 120 patients, with an estimated study completion date of December 2016.

DENER-HTN trial (NCT01570777). The Renal Denervation in Hypertension (DENER-HTN) trial is a multicenter, unblinded RCT of patients with elevated BP despite treatment with at least 3 medications. The primary endpoint is change in daytime systolic BP at 6 months of follow-up. Enrollment is planned for 120 patients, with an estimated study completion date of July 2014.

RELIEF trial (NCT01628172). The Renal Sympathetic Denervation for the Management of Chronic Hypertension (RELIEF) trial is a single-blind RCT of patients with elevated BP despite treatment with at least 3 medications. The primary endpoint is change in 24-hour ambulatory BP at 6 months of follow-up. Enrollment is planned for 100 patients, with an estimated study completion date of January 2014.

Summary

RFA of the renal sympathetic nerves is a non-pharmacologic treatment for hypertension and has been proposed as a treatment option for patients with resistant hypertension. There are currently no devices that have FDA-approval for this indication. This is an active area of research, with numerous ongoing RCTs, including at least 2 double-blind, sham-controlled RCTs.

The published evidence consists of one small, short-term RCT that reports efficacy in reducing blood pressure over a 6-month time period. Other small studies with overlapping populations also report improvements in related physiologic parameters, such as echocardiographic measures of LVH. One case series suggests that improvements may be durable up to 24-months’ follow-up. There is no evidence that reports improvements in health outcomes as a result of treatment with RFA of the renal sympathetic nerves. Potential complications of this procedure include vascular access problems, perforation of the renal artery, and renal artery stenosis, but rates of complications have not been well-established. This evidence is insufficient to determine whether health outcomes are improved, and therefore radiofrequency ablation of the renal sympathetic nerves is considered experimental, investigational and/or unproven.

Practice Guidelines and Position Statements

None

Coding

Disclaimer for coding information on Medical Policies

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.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.  

ICD-9 Codes

401.0-405.99

ICD-10 Codes

I10-I15.9, 015L4ZZ, 015M4ZZ, 015N4ZZ

Procedural Codes: 0338T, 0339T
References
  1. Acelajado MC, Calhoun DA. Resistant hypertension, secondary hypertension, and hypertensive crises: diagnostic evaluation and treatment. Cardiol Clin 2010; 28(4):639-54.
  2. Doumas M, Papademetriou V, Douma S et al. Benefits from treatment and control of patients with resistant hypertension. Int J Hypertens 2010; 2011:318549.
  3. Zile MR, Little WC. Effects of autonomic modulation: more than just blood pressure. J Am Coll Cardiol 2012; 59(10):910-2.
  4. 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 2010; 376(9756):1903-9.
  5. Brandt MC, Mahfoud F, Reda S et al. Renal sympathetic denervation reduces left ventricular hypertrophy and improves cardiac function in patients with resistant hypertension. J. Am. Coll. Cardiol. 2012; 59(10):901-9.
  6. 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 2011; 58(11):1176-82.
  7. 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 2012.
  8. Symplicity HTN-1 Investigators. Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months. Hypertension 2011; 57(5):911-7.
  9. Krum H, Schlaich M, Whitbourn R et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 2009; 373(9671):1275-81.
  10. Tsioufis C, Dimitriadis K, Tsiachris D et al. Catheter-based renal sympathetic denervation for the treatment of resistant hypertension: first experience in Greece with significant ambulatory blood pressure reduction. Hellenic J Cardiol 2012; 53(3):237-41.
  11. Mabin T, Sapoval M, Cabane V et al. First experience with endovascular ultrasound renal denervation for the treatment of resistant hypertension. EuroIntervention 2012; 8(1):57-61.
  12. Simonetti G, Spinelli A, Gandini R et al. Endovascular radiofrequency renal denervation in treating refractory arterial hypertension: a preliminary experience. Radiol Med 2012; 117(3):426-44.
  13. Prochnau D, Lucas N, Kuehnert H et al. Catheter-based renal denervation for drug-resistant hypertension by using a standard electrophysiology catheter. EuroIntervention 2012; 7(9):1077-80.
  14. Witkowski A, Prejbisz A, Florczak E et al. Effects of renal sympathetic denervation on blood pressure, sleep apnea course, and glycemic control in patients with resistant hypertension and sleep apnea. Hypertension 2011; 58(4):559-65.
  15. Kandzari DE, Bhatt DL, Sobotka PA et al. Catheter-based renal denervation for resistant hypertension: rationale and design of the SYMPLICITY HTN-3 trial. Clin Cardiol 2012 [Epub ahead of print].
  16. Radiofrequency Ablation of the Renal Sympathetic Nerves as a Treatment for Resistant Hypertension. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2012 August) Surgery 7.01.136.
History
March 2014  New medical document. Radiofrequency ablation of the renal sympathetic nerves is considered experimental, investigational and/or unproven for the treatment of resistant hypertension. 
BCBSMT Home
®Registered marks of the Blue Cross and Blue Shield Association, an association of independent Blue Cross and Blue Shield Plans. ®LIVE SMART. LIVE HEALTHY. is a registered mark of BCBSMT, an independent licensee of the Blue Cross and Blue Shield Association, serving the residents and businesses of Montana.
CPT codes, descriptions and material only are copyrighted by the American Medical Association. All Rights Reserved. No fee schedules, basic units, relative values or related listings are included in CPT. The AMA assumes no liability for the data contained herein. Applicable FARS/DFARS Restrictions Apply to Government Use. CPT only © American Medical Association.
Radiofrequency Ablation of the Renal Sympathetic nerves as a Treatment for Resistant Hypertension