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.
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.
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.
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.
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