Radiofrequency Ablation of the Renal Sympathetic Nerves as a Treatment for 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% to 30% of participants meet the definition for resistant hypertension, and in tertiary care hypertension clinics, the prevalence has been estimated to be 11% to 18%. (1) Resistant hypertension is associated with a higher risk for adverse outcomes such as stroke, myocardial infarction (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 before 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, 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.
RF denervation of the renal sympathetic nerves
Increased sympathetic nervous system activity has been linked to essential hypertension. Surgical sympathectomy has been shown to be effective in reducing BP 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 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.
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., Minneapolis, MN) 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 medical policy does not apply to Medicare Advantage.
This policy was created in July 2012 with literature update that covered the period of January 2000 through June 2012 and updated periodically with literature reviews, most recently through July 31, 2014.
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, because it would also control for any placebo effects, 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 several RCTs, the largest of which compared renal denervation with sham control for patients with treatment-resistant hypertension. Several other smaller RCTs have also been conducted, 1 that compared renal denervation with 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 next.
Results of the Symplicity HTN-3 trial, a multicenter, single-blinded, randomized, sham-controlled trial of renal denervation were published in 2014. (4) Included patients had severe, resistant hypertension, with a systolic BP of 160 mm Hg or higher, on maximally tolerated doses of at least 3 antihypertensive medications of complementary classes, 1 of which had to be a diuretic at an appropriate dose. Five-hundred thirty-five patients were randomized to renal denervation with the Medtronic Symplicity renal denervation catheter or to renal angiography only (sham control).
Changes in antihypertensive medication were not allowed during the 6-month follow-up period unless they were considered to be clinically necessary. The primary efficacy end point was the mean change in office systolic BP from baseline to 6 months in the denervation group, compared with the mean change in the sham control group. The secondary efficacy end point was the change in mean 24-hour ambulatory systolic blood pressure at 6 months. The primary safety end point was a composite of major adverse events, defined as death from any cause, end stage renal disease, an embolic event resulting in end-organ damage, renal-artery or other vascular complications, or hypertensive crisis within 30 days or new renal-artery stenosis of more than 70% within 6 months.
At the 6-month follow-up point, there was no significant between-group difference in the change in office BP. There was a change in systolic BP (SBP) of −14.13±23.93 mm Hg in the denervation group versus −11.74±25.94 mm Hg in the sham control group, for a difference of −2.39 mm Hg (95% CI: −6.89 to 2.12; p=0.26 with a superiority margin of 5 mm Hg). At 6-month follow-up, the change in ambulatory BP was −6.75±15.11 mm Hg in the denervation group versus −4.79±17.25 mm Hg in the sham control group, for a difference of −1.96 mm Hg (95% CI: −4.97 to 1.06; p=0.98 with a superiority margin of 2 mm Hg). Major adverse event rates were similar between the denervation and control groups 1.4% and 0.6%, respectively).
Strengths of this study include its large size and blinded, sham-controlled design, which reduce the likelihood of a placebo effect. A limitation of the present publication is that the follow-up period reported is relatively short, leading to an underdetection of a treatment benefit differences between the groups manifest over time. The study subjects, including those who do not cross over to renal denervation, will be followed for 5 years to assess longer term outcomes.
Bakris et al. reported more detailed ambulatory BP results from the Symplicity HTN-3 trial. (5) The change in average 24-hour ambulatory systolic and diastolic BP were as reported by Bhat et al. There were no significant differences in change in ambulatory BP between the renal denervation and control groups for any of the prespecified subgroup analyses, including the presence of coexisting diabetes mellitus; sex; race; body mass index of 30 kg/m2 or more; eGFR of 60 mL/min/1.73 m2 or more; age of 60 years or older; or any medication change during the study.
The Symplicity HTN-2 trial was a multicenter, unblinded RCT evaluating renal sympathetic denervation versus standard pharmacologic treatment for patients with resistant hypertension. (6) A total of 106 patients with a SBP 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 -month 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<0.001 for both 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 with 6% (3/51) in the control group (p<0.001). 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 with 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 Symplicity HTN-2 trial were reported in 2013. (7) 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 of 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 SBP and 9.7±10.6 mm Hg for diastolic BP (DBP). 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.
Three-year follow-up data from the Symplicity HTN-2 trial were reported in 2014. (8) Follow-up was available for 40 of 52 subjects in the initial RFA group and for 30 of 37 subjects who were initially in the control group but who crossed over and received renal denervation 6 months after enrollment. After 30 months, the mean change in SBP was -34 mm Hg (95% CI: -40 to -27, p<0.01) and the mean change in DBP was -13 mm Hg (95% CI: -16 to -10, p<0.01). The degree of BP change was similar between the randomized and crossover subjects. Subjects in the initial RFA group had follow-up available at 36 months; at that point, the mean change in SBP was -33 mm Hg (95% CI: -40 to -25, p<0.01) and the mean change in DBP was -14 mm Hg (95% CI: -17 to -10, p<0.01). Beyond 12 months of follow-up, safety events included 5 hypertensive events requiring hospitalization; 1 case of mild transient acute renal failure due to dehydration; 2 episodes of atrial fibrillation requiring hospitalization; 1 case of acute renal failure due to acute interstitial nephritis that was deemed unrelated to renal denervation treatment; and 3 deaths that were deemed unrelated to the device or therapy.
The main limitations of this RCT are that it is small in size, unblinded, and has only a relatively short follow-up for the controlled portion of the trial. A trial with a sham control would allow better determination of whether the treatment effect was due to a placebo effect, or other non-specific effects of being in a trial. The 6-month follow-up reported for the controlled portion of the trial is too short to ascertain whether the reduction in BP is likely to reduce adverse cardiovascular outcomes such as myocardial infarction (MI) and stroke. The 12- and 36-month follow-up reports provide some insight into longer-term outcomes following the procedure, although comparison with a control group is no longer possible due to the crossover design.
It is unknown whether re-innervation of the renal sympathetic nerves occurs post-treatment. If reinnervation does occur, the efficacy of the procedure will diminish over time. The BP change appears to be stable over the longer-term follow-up studies, suggesting that re-innervation did not occur in the 36-month follow-up.
Fadl Elmula et al. reported results from a smaller RCT that compared renal denervation with clinically-adjusted drug treatment in treatment-resistant hypertension after patients with poor drug adherence were excluded. (9) The study enrolled patients with office SBP greater than 140 mm Hg, in spite of maximally tolerated doses of at least 3 antihypertensive drugs, including a diuretic, and required that patients had an ambulatory daytime SBP greater than 135 mm Hg after witnessed intake of antihypertensive drugs. Twenty patients were randomized, 10 to adjusted drug treatment and 10 to renal denervation with the Symplicity renal denervation catheter (1 of whom was subsequently excluded due to a diagnosis of secondary hypertension). In the drug-adjusted group, the office SBP changed from 160±14 mm Hg at baseline to 132±10 mm Hg at 6-month follow-up (p<0.000); in the renal denervation group, the office SBP changed from 156±13 mm Hg at baseline to 148±7 mm Hg at 6-month follow-up (p=0.42). SBP and DBP were significantly lower in the drug-adjusted group at 6-month follow-up.
An additional 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. (10) End points of this study included both BP control and recurrence of atrial fibrillation. Patients who received RFA of the renal arteries had significant reductions in SBP (181+7 mm Hg to 156+5 mm Hg) and DBP (96+6 mm Hg to 87+4 mm Hg), compared with 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% vs 29%, p=0.033).
Several RCTs have compared renal denervation with drug therapy for the treatment of resistant hypertension, with conflicting results. The most rigorous evidence about the efficacy of renal denervation comes from the largest of these trials, the Symplicity HTN-3 trial, which used a single-blinded, sham-controlled design to reduce the risk of placebo effect and showed no significant improvements in BP control with renal denervation at 6 months. The difference in findings between the Symplicity HTN-3 trial and earlier trials (i.e., Symplicity HTN-2) suggests that the treatment effect seen in nonblinded trials may have been due to a placebo effect, or other nonspecific effects of being in a trial. Alternatively, BP control in the control arm may have been better in Simplicity HTN-3 trial compared with earlier studies.
Several systematic reviews that have included RCTs and nonrandomized studies have been published, although none include the Symplicity HTN-3 trial. In 2013, Davis et al. (11) published a systematic review and meta-analysis of renal denervation that included 2 RCTs (the Symplicity HTN-2 trial (6,7) and Pokushalov et al., (10) described in the “Randomized Controlled Trials” section), 1 observational study with a control group, and 9 observational studies without a control group. In the 3 controlled studies, compared with medical treatment at 6 month follow-up, renal denervation was associated with a reduction in mean SBP of -28.9 mm Hg (95% CI: -37.2 to -20.6; p<0.000) and in mean DBP of -11 mm Hg (95% CI: -16.4 to -5.7; p<0.000). In uncontrolled studies, compared with prerenal denervation values, at 6 months of follow-up, SBP and DBP changed by -25.0 mm Hg (95% CI: -29.9 to -20.1) and -10.0 mm Hg (95% CI: -12.5 to -7.5) respectively.
Shantha et al. conducted a systematic review and meta-analysis to evaluate the effects of renal denervation on obstructive sleep apnea.12 In a pooled analysis of 5 noncontrolled studies that included 49 patients, renal denervation was associated with a reduction in mean apnea-hypopnea index at 6 months post-procedure (weighted mean difference, -9.61, 95% CI: -15.43 to -3.79, p=0.001.
Nonrandomized Comparative Studies
Several nonrandomized studies with a control group have been published. The populations from some of these studies overlap to a large extent with the Symplicity HTN-2 trial. Additional cases may have been added to the study population using the same eligibility criteria, and only a small number of control patients were included in the analyses. Thus, these comparisons are not considered randomized. These studies examine different physiologic outcomes in addition to changes in BP.
An echocardiographic sub-study was published in 2012. (13) This trial compared 46 patients who underwent RFA with 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 with controls at 6 months.
Another sub-study published in 2011 evaluated the response to exercise in 46 patients treated with RFA compared with 9 patients in the control group at 3 months post-treatment. (14) There were significant improvements in the achieved workload, and recovery from exercise in heart rate and blood pressure compared with 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 Symplicity trial (n=17 treated, 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. (15) 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 Symplicity HTN-2 trial and all patients met the eligibility criteria used in Symplicity HTN-2. There was no discernable impact of RFA on the glomerular filtration rate or mean urinary albumin excretion at 6 -month follow-up. There were significant improvements for the treated patients on the incidence of microalbuminuria and the renal resistive index. There were no instances of renal artery stenosis, dissections, or aneurysms at the 6-month time point.
Ewen et al. evaluated the impact of renal denervation on BP, heart rate, and chronotropic index at rest, during exercise, and at recovery in 60 patients with resistant hypertension (50 who underwent renal denervation and 10 control patients). (16) At 6-month follow-up, office BP was reduced by 26/7 mm Hg to 138±3/84±2 mm Hg in the renal denervation group (p<0.001 for both), whereas there was no significant change in BP in the control group (BP reduced by 2/0 mm Hg to 153±5/87±1 mm Hg; p=0.750/p=0.611). At 6- month follow-up, the intervention group demonstrated a significant reduction in percent of maximum systolic BP from baseline during exercise and recover.
The largest case series was the Symplicity HTN-1 study, which was a multicenter, single-arm trial sponsored by the manufacturer. (17, 18) 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.
Krum et al reported 3-year follow-up for patients in the Symplicity HTN-1 study in 2014. (19) Among 88 patients who had complete follow-up data at 36 months, the mean change in SBP was -32 mm Hg (95% CI, -35.7 to -28.2) and DBP was -14.4 mm Hg (95% CI: -16.9 to -11.9). The proportion of patients with a SBP decrease of 10 mm Hg or more was stable over time: 69% at 1 month; 81% at 6 months; 85% at 12 months; 83% at 24 months; and 93% at 36 months. Adverse events included 4 cases of possible or suspected renal artery stenosis, 1 of which required stenting; 3 deaths that were deemed unrelated to the device or procedure; 2 hospitalizations for acute renal failure in the setting of other illnesses; and 13 hospitalizations for hypertensive episodes.
Numerous other small non-randomized studies and case series have been published, reporting BP outcomes and adverse events from the procedure. (15,20-35) these case series generally report similar BP reductions, as do the controlled studies with few complications. Some studies have reported on different populations such as the elderly population, (36) those with moderately resistant HTN, (26) with chronic kidney disease, (27,37) or with an accessory renal artery. (38) Other studies report additional outcomes, including improvements in quality of life,25 favorable changes in renal hemodynamics,15 changes in neurohormonal measurements,39 improvements in LV mass and function, (40,41) changes in PR interval and heart rate, (42) reduction in microalbuminuria, (43) and improvements in measures of vascular function. (28)
Ongoing and Unpublished Clinical Trials
A search of online database ClinicalTrials.gov with the terms “renal denervation” AND “hypertension” yielded 58 interventional studies actively recruiting patients. There were a number of ongoing RCTs listed of renal denervation as a treatment for resistant hypertension which are described briefly next. There were also several RCTs of renal denervation plus cardiac ablation for atrial fibrillation versus cardiac ablation alone; these studies are not included on this list.
Summary of Evidence
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 randomized controlled trials (RCTs)
The published evidence consists of 4 RCTs, along with multiple nonrandomized comparative studies and case series. The largest and most recent trial, the Symplicity HTN-3 trial, which used a sham-controlled design to reduce the likelihood of placebo effect, demonstrated no significant differences between renal denervation and sham-control patients in office-based or ambulatory blood pressure (BP) at 6-month follow-up. The Symplicity HTN-3 results were in contrast to earlier studies, the largest of which, Symplicity HTN-2, reported efficacy in reducing BP over a 6-month time period compared with a control group, and an extension study reported 12-month BP follow-up for treated patients in an uncontrolled fashion. Symplicity HTN-2 reported a decrease in SBP of approximately 30 mm Hg and a decrease in DBP of approximately 10 mm Hg at 6 months and that this reduction was largely maintained at 12 months.
Single-arm studies with overlapping populations also report improvements in BP and related physiologic parameters, such as echocardiographic measures of LV hypertrophy, that appear to be durable up to 24-months of follow-up. There is no evidence that reports improvements in clinical outcomes as a result of treatment with RFA of the renal sympathetic nerves. Potential complications of this procedure include vascular access problems, perforation of the renal artery, and renal artery stenosis, but rates of complications have not been well-established. Given the findings from the Symplicity HTN-3 trial and evidence from earlier studies, it is uncertain whether RFA improves health outcomes compared with continued medical therapy, and therefore RFA of the renal sympathetic nerves is considered investigational.
Practice Guidelines and Position Statements
In 2013, the European Society of Cardiology issued an expert consensus statement45 on catheter-based renal denervation that makes the following conclusions:
“Current evidence from the available clinical trials strongly support the notion that catheter-based radiofrequency ablation of renal nerves reduces blood pressure and improves blood pressure control in patients with drug-treated resistant hypertension, with data now extending out to 36 months. Accordingly, renal denervation can be considered as a therapeutic option in patients with resistant hypertension, whose blood pressure cannot be controlled by a combination of lifestyle modification and pharmacological therapy according to current guidelines.”
The statement outlined the following criteria patients should meet before renal denervation is considered:
U.S. Preventive Services Task Force Recommendations
RFA of renal sympathetic nerves is not a preventive service.
Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.
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
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.
Annual Review. Policy updated with literature review through July 31, 2014. References 4-5, 8-9, 11-12, 16, 19, 29-36, 38-43, and 45 added. No change to policy statement.
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).