Radiofrequency Ablation of the Renal Sympathetic Nerves as a Treatment for Resistant Hypertension
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
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.
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.
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.
Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply.
This policy was created in July 2012 with literature update that covered the period of January 2000 through June 2012. The most recent literature search was performed for the period of June 2012 through August 2013.
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 two small, short-term RCTs, one which compared renal denervation to standard care for patients with resistant hypertension, and a second that compared renal denervation plus cardiac ablation versus cardiac ablation alone for patients with resistant hypertension and atrial fibrillation. There were also a number of non-randomized controlled trials and case series. These relevant studies are reviewed below.
Randomized Controlled Trials
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.
One-year follow-up data from the Simplicity HTN-2 trial were reported in 2013. (5) 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 then offered crossover to RFA after 6 months. A total of 46/54 patients accepted crossover to RFA; 35 were available at the 12-month time point. For the patients originally randomized to RFA, the decrease in BP at 12 months was 28.1 + 24.9 mm Hg for systolic BP and 9.7 + 10.6 mm Hg for diastolic BP. These decreases in BP were not significantly different from those reported at the 6-month time point (31.7 + 23.1 mm Hg systolic and 11.7 + 11.2 mm Hg diastolic). For the crossover group, the decrease in BP 6 months after renal denervation was 23.7 + 27.5 mm Hg systolic and 8.4 + 12.1 mm Hg diastolic. There were 2 procedural complications in the crossover group, one patient with a dissection of the renal artery and one patient with a hypotensive episode.
The main limitations of this RCT are that it is small in size, unblinded, and has only a relatively short follow-up for the controlled portion of the trial. A trial with a sham control would allow better determination of whether the treatment effect was due to a placebo effect, or other 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.
A second randomized study compared RFA of the renal arteries plus cardiac ablation for atrial fibrillation (pulmonary vein isolation) with ablation for atrial fibrillation alone in 27 patients with refractory atrial fibrillation and resistant HTN. (6) Endpoints of this study included both BP control and recurrence of atrial fibrillation. Patients who received RFA of the renal arteries had significant reductions in systolic BP (181+7 mm Hg to 156+5 mm Hg) and diastolic BP (96+6 mm Hg to 87+4 mm Hg), compared to no reduction in the control group (p<0.001). The percentage of patients who were free of atrial fibrillation at 12 months post-treatment was higher in the group receiving renal artery denervation (69% versus 29%, p=0.033).
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. (7) 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. (8) 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. (9) 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.
The largest case series was the Simplicity HTN-1 study, which was a multicenter, single-arm trial sponsored by the manufacturer. (10, 11) A total of 153 patients with resistant hypertension were treated at 19 clinical centers in the U.S., 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.
Numerous other small non-randomized studies and case series have been published, reporting BP outcomes and adverse events from the procedure. (9, 12-20) these case series generally report similar BP reductions, as do the controlled studies with few complications. Some studies have reported on different populations such as those with moderately resistant HTN (18) and in patients with chronic kidney disease. (19) Other studies report additional outcomes, including improvements in quality of life (QOL) (17) favorable changes in renal hemodynamics (9) and improvements in measures of vascular function. (20)
A search of ClinicalTrials.Gov with the terms “renal artery denervation” AND “hypertension” yielded 50 relevant trials. Most of these were single-arm series of different types of renal artery denervation in various patient populations. There were 8 ongoing RCTs listed of renal denervation as a treatment for resistant hypertension, these are described briefly below. There were also several RCTs of renal denervation plus cardiac ablation for atrial fibrillation versus cardiac ablation alone; these studies are not included on this list.
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. (21) 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.
Renal Denervation in Treatment Resistant Hypertension (NCT01762488). This is a randomized, double-blind trial of renal denervation in patients with resistant hypertension. The primary endpoint is change in 24-hour ambulatory BP. Planned enrollment is for 70 patients, study completion date not listed.
Renal Denervation by Allegro System in Patients with Resistant Hypertension (NCT01874470). This is a randomized, open-label study of renal denervation compared to standard medication in patients with resistant hypertension. The primary endpoint is change in systolic BP measured by 24-hour ambulatory monitor. Planned enrollment is for 160 patients with estimated completion date of April 2014.
Renal Denervation by MDT-2211 System in Patients with Uncontrolled Hypertension (NCT01644604). This is a randomized, open-label study of renal denervation versus standard care in patients with uncontrolled hypertension. The primary endpoint is change in office blood pressure. Planned enrollment is for 100 patients, with an estimated study completion date of December 2017.
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.
Clinical Input Received through Physician Specialty Societies and Academic Medical Centers
Radiofrequency ablation (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, RCT in patients with resistant hypertension. This trial reported efficacy in reducing blood pressure over a 6-month time period compared to a control group, and an extension study reported 12-month BP follow-up for treated patients in an uncontrolled fashion. This trial reported a decrease in SBP of approximately 30 mm Hg and a decrease in diastolic blood pressure (DBP) of approximately 10 mm Hg at 6 months and that this reduction was largely maintained at 12 months. Another small RCT that compared renal denervation plus cardiac ablation to cardiac ablation alone for patients with atrial fibrillation and resistant hypertension reported a similar decrease in BP and a reduced rate of recurrent atrial fibrillation for the patients receiving renal denervation.
Single-arm 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 clinical outcomes as a result of treatment with RFA of the renal sympathetic nerves. Potential complications of this procedure include vascular access problems, perforation of the renal artery, and renal artery stenosis, but rates of complications have not been well-established. This evidence is insufficient to determine whether health outcomes are improved, and therefore radiofrequency ablation of the renal sympathetic nerves is considered investigational.
Practice Guidelines and Position Statements
Medicare National Coverage
There is no national coverage determination.
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 (effective 01/01/14)
Bilateral (effective 01/01/14)
Unlisted procedure, nervous system
401.0 - 405.99
Hypertensive disease code section (there is no specific ICD-9-CM code for resistant hypertension)
ICD-10-CM (effective 10/01/14)
I10 - I15.9
Hypertensive disease code range
ICD-10-PCS (effective 10/01/14)
014L4ZZ, 015M4ZZ, 015N4ZZ
Surgical, destruction, sympathetic nerve code range (thoracic, abdominal, lumbar – the renal sympathetic nerves come from T10-L1)
New Policy. Radiofrequency ablation of the renal sympathetic nerves is considered investigational for the treatment of resistant hypertension.
Replace policy. Policy updated with literature review through July 31, 2013. References 5, 6, 17-21 added. No change in policy statement. Codes 0338T and 0339T added to policy; codes 36251-36254 removed from policy; they are no specific to the procedure.
Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).