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Catheter-Based Renal Sympathetic Nerve Ablation Controls Blood Pressure in More Difficult-to-Control Patients Taking Multi-Agent Pharmacologic Therapy

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  2. Catheter-Based Renal Sympathetic Nerve Ablation Controls Blood Pressure in More Difficult-to-Control Patients Taking Multi-Agent Pharmacologic Therapy
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About 75 million Americans and 1 billion people worldwide have hypertension (classified as blood pressure [BP] readings of ≥140/90 mm Hg). With up to 50% of adults from westernized societies projected to have hypertension by 2025, physicians will continue to be challenged with treating this major cardiovascular epidemic. Although BP control rates continue to improve, physicians still encounter large numbers of patients with resistant hypertension. Because many forms of hypertension have a significant neurogenic component, which is initiated and sustained in part by sympathetic nervous system overactivity, a minimally invasive, catheter-based means of reducing central sympathetic outflow has been developed for potential use in humans. Targeting excitatory renal sympathetic nerves located outside of the kidney adjacent to the renal artery, this procedure is designed to reduce BP by interrupting central sympathetic nervous system nerve traffic to the kidney. To evaluate whether BP control could be optimized more effectively in patients with treatment-resistant hypertension, a clinical trial was performed using this endovascular device.

The Renal Denervation in Patients With Uncontrolled Hypertension (Symplicity HTN-2) trial was an international, multicenter, randomized device manufacturer–sponsored study in patients aged 18 to 85 years with a systolic BP ≥160 mm Hg (or ≥150 mm Hg in patients with type 2 diabetes) despite taking ≥3 antihypertensive drugs. It was designed to evaluate whether device-based renal denervation used in addition to existing antihypertensive therapy was superior in controlling BP compared with maintaining antihypertensive drug treatment alone. Exclusion criteria included an estimated glomerular filtration rate (eGFR) <45 mL/min, type 1 diabetes, contraindications to magnetic resonance imaging (MRI), “substantial” aortic valvular stenosis, pregnancy or planned pregnancy during the study, or a history of myocardial infarction (MI), unstable angina, or cerebrovascular accident during the previous 6 months. Screening was completed at 24 centers (16 of which were designated as centers of excellence) in Europe, Australia, and New Zealand, with no US centers involved. To be eligible, patients were required to record automated home BP measurements twice daily and to document compliance for 2 weeks. In addition, patients underwent renal artery anatomical screening before randomization with either duplex ultrasonography, MRI, computerized tomography, or renal angiography to confirm anatomical eligibility. Patients were excluded if they had hemodynamically significant renal artery stenosis, previous renal artery intervention, or renal artery anatomy that precluded treatment (defined as a renal artery <4 mm diameter, <20 mm length, or more than one main renal artery). Patients also underwent 24-hour ambulatory BP monitoring (ABPM), and baseline creatinine, cystatin C, and spot urine albumin-to-creatinine ratio prior to randomization.

In a one-to-one ratio, patients were randomly assigned to undergo catheter-based renal denervation with the Simplicity Catheter System (Ardian, Mountain View, CA) or to the control group. Background antihypertensive use was similar in both groups. Data analyzers were not masked to treatment group assignment. For patients assigned to renal denervation, the Simplicity catheter was advanced through the femoral artery with the tip of the catheter placed in the distal renal artery. Low-power radiofrequency energy treatments were applied to the vascular wall of the renal artery to provide heat to its outer layer and the sympathetic nerves located in the adventitia. The catheter was then drawn back 1 to 2 cm and rotated circumferentially. The procedure was then repeated 4 to 6 times in this and the contralateral renal artery. Heparin was given before the procedure to achieve effective anticoagulation, and intravenous anxiolytics and narcotics were used for visceral pain that sometimes occurs at the time of ablation.

Follow-up occurred at 1, 3, and 6 months when the average of 3 measurements of office BP using the Omron HEM-705 monitor (Omron Healthcare, Vernon Hills, IL) was measured. In addition, serum creatinine and cystatin C and a spot urine albumin-to-creatinine ratio were assessed as well as any adverse effects that occurred. Adherence to medication and daily automated seated home BP measurement performed 3 times in the morning and 3 times in the evening was monitored 2 weeks before the 6-month appointment. At the 6-month visit, 24-hour ABPM was performed, with readings taken every 15 minutes in the daytime and every 30 minutes at nighttime (Spacelabs 90207 monitor; Spacelabs Healthcare, Issaqua, WA). Renal imaging occurred in the renal denervation group by duplex ultrasonography with computed tomographic (CT) angiography or magnetic resonance angiography used only if a clinically significant abnormality was detected by ultrasonography.

The primary effectiveness end point was the between-group change in average office-based measurements in systolic BP from baseline to 6 months post-randomization. Secondary end points included procedural safety (reduction of eGFR >25% or new stenosis >60% confirmed by angiography at 6 months), a composite cardiovascular end point (MI, sudden cardiac death, new-onset heart failure, death from progressive heart failure, stroke, aortic or lower limb revascularization procedure, lower limb amputation, death from aortic or peripheral arterial disease, dialysis, death because of renal failure, hospital admission for hypertensive emergency unrelated to nonadherence to drugs, and hospital admission for atrial fibrillation), and additional measurement of BP reduction at 6 months after randomization. These secondary BP end points included the occurrence of ≥10 mm Hg systolic response, achievement of target systolic BP, change in 24-hour ABPM, and change in home BP measurements. With a planned sample size of 50 patients in each group, the study was 80% powered to show benefit of renal denervation with respect to the primary end point assuming at least a 12-mm Hg difference between groups and a 21-mm Hg standard deviation of the change in systolic BP from baseline to 6 months. Data were monitored, collected, and managed by the industry sponsor but the principle author had full access to all the data and the final responsibility to submit for publication.

From June 9, 2009, to January 15, 2010, 106 (56%) of 190 patients screened were eligible for inclusion and were assigned randomly to either the renal denervation or the control group. Patients were equally matched by age (mean age, 58 years), sex, mean baseline systolic/diastolic BP (178/97 mm Hg), race (97% white), most comorbidities, and the number taking antihypertensive therapy for more than 5 years (75%) as well as the number of antihypertensive medications (mean, 5.2). Patients in the renal denervation group had a lower baseline renal function than the control group as assessed by eGFR (77 mL/min vs 86 mL/min; P=.013) although baseline cystatin C concentrations were similar. Antihypertensive drug classes were used similarly in both groups, with diuretics, including aldosterone antagonists, used in more than 89% of patients.

Three patients in each randomized group were lost to follow-up, leaving a total of 100 patients analyzed for the primary end point (49 who underwent renal denervation and 51 controls). Six months after randomization, office-based BP measurements in the renal denervation group were reduced by 32/12 mm Hg (from 178/96 mm Hg at baseline [P<.0001 for systolic and diastolic BP]), while they increased 1/0 mm Hg in the control group (P=.77 for systolic BP, P=.83 for diastolic BP). A similar change was seen in home BP measurements as BP fell 22/11 mm Hg in the renal denervation group (n=32) compared with a rise of 2/0 mm Hg in the control group (n=40) (absolute difference between groups 22/12 mm Hg [P=.0001 for systolic and diastolic BP]). Similarly, averaged 24-hour ABPM at 6 months was reduced in the renal denervation group (n=20) by a mean of 11/7 mm Hg (P=.006 for systolic BP and 0.014 for diastolic BP), whereas averages did not change in the control group (n=25) (−3/−1 mm Hg [P=.51 for systolic, P=.75 for diastolic BP]). More patients at 6 months who underwent renal denervation had reductions in systolic BP of ≥10 mm Hg than did controls (84% vs 35%) and achieved a target BP <140 mm Hg (19% vs 3.6%) (P<.001 for both). Ten of 49 (20%) patients who underwent renal denervation had drug reactions prior to the 6-month follow-up compared with 3 of 51 (6%) controls (P=.04). There was no difference between groups in the number who required drug increases prior to the 6-month follow-up.

No immediate serious complications occurred related to the device or the procedure. Less serious initial complications occurring in the procedure group included 1 femoral artery pseudoaneurysm that was effectively treated with manual compression, 1 post-procedural drop in BP resulting in a reduction in antihypertensive drugs, 1 urinary tract infection, 1 extended hospital admission for paresthesias, and 1 case of back pain treated with analgesics that resolved after 1 month. Additionally, 7 of 52 (13%) patients undergoing renal denervation had transient bradycardia during the procedure, which resolved after being treated with atropine. No difference in renal function at 6 months occurred between groups. In addition, no patients had a decrease in eGFR >50%, although 2 renal denervation patients and 3 controls had a decrease >25% in eGFR. There was no clinically or statistically significant difference in protein excretion at 6 months as measured by the albumin-to-creatinine ratio.

At 6 months, 43 of 49 patients who underwent renal denervation had imaging (37 duplex ultrasonography, 5 MRI, and 5 CT angiography). Of these, only 1 patient had a possible progression of an underlying atherosclerotic lesion, which required no intervention. In terms of the composite cardiovascular end points assessed at 6 months, 5 hospital admissions for hypertensive emergency occurred (3 patients who had renal denervation and 2 controls). During follow-up, serious adverse events occurred in 4 denervation patients (1 with nausea and edema possibly related to underlying hypertension, 1 with a hypertensive crisis after abruptly stopping clonidine, 1 transient ischemic attack [TIA], and 1 patient who received a coronary stent for angina) and 2 controls (1 TIA, 1 coronary stent for angina).

The authors conclude that in patients with medically treated resistant hypertension, bilateral renal denervation using a catheter-based approach substantially reduces BP, without serious procedure-related or device-related complications.—Esler MD, Krum H, Sobotka PA, et al, for the Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. 2010;376:1903–1909.

Comment

  1. Top of page
  2. Catheter-Based Renal Sympathetic Nerve Ablation Controls Blood Pressure in More Difficult-to-Control Patients Taking Multi-Agent Pharmacologic Therapy
  3. Comment

The Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines define resistant hypertension as BP above target despite use of at least 3 antihypertensive drugs, one of which is a diuretic, taken at maximal (or highest tolerated) doses. Most observational studies suggest that resistant hypertension affects between 15% and 30% of patients with hypertension. Although not well-studied, poor BP control in patients with resistant hypertension likely leads to excessive cardiovascular risk and is associated with high health care costs. Current treatment of resistant hypertension generally involves multiple antihypertensive agents, and these complicated medical regimens increase the risk of tolerability issues and drug interactions, often without optimal effect on BP control.

The pathophysiology of resistant hypertension is complex and not completely understood. Activation of the sympathetic nervous system appears to be one of the main contributors to BP elevation. Specifically, renal sympathetic efferent and afferent nerves that lie within and immediately adjacent to the renal artery appear to be involved in the initiation and maintenance of systemic hypertension through multiple mechanisms, including increasing renin secretion and volume retention. It has been hypothesized that removing the kidneys from sympathetic input through renal denervation will lead to substantial and sustained BP reduction. Early studies in animal models have provided support for this hypothesis. However, previous surgical methods aimed at decreasing sympathetic tone in patients with hypertension were associated with variable efficacy and with high perioperative morbidity as well as a greater risk of long-term complications, including postural hypotension and bowel, bladder, and erectile dysfunction.

Recently, a novel investigational procedure has been developed that aims to reduce the BP-raising effect of central sympathetic nervous system output by locally interrupting renal sympathetic signaling. This technology uses a catheter-based system threaded through the femoral artery into both distal renal arteries, where radiofrequency ablation is used to disrupt the renal sympathetic nerves while sparing other abdominal and pelvic nervous enervation. While in theory, this device could be used in any hypertensive patient, given the cost and inconvenience of undergoing a percutaneous procedure, patients with resistant hypertension would seem a logical use of this technology. As such, this device was first clinically evaluated in humans in 2009 in a small uncontrolled proof-of-concept study of 45 patients. The same investigators have now performed a larger, well-constructed and implemented, randomized, controlled study of 100 patients with resistant hypertension.

The Symplicity HTN-2 trial demonstrates that office BP, home BP, and 24-hour ABPM are all favorably reduced with endovascular radiofrequncy renal sympathetic denervation. Specifically, at 6-month follow-up, office-based BP measurements were reduced by 32/12 mm Hg among those who underwent renal denervation, while BP did not differ from baseline among those who maintained previous drug treatment alone. At 6 months, 84% of patients who underwent renal denervation had a reduction in systolic BP of ≥10 mm Hg compared with 35% of those who maintained previous treatment. Ten (20%) of 49 patients who underwent renal denervation had reductions in the number of antihypertensive drug classes required compared with 3 (6%) of 51 controls. Of note, 39% (n=19) of the renal denervation group but only 3.6% (n=3) of the control group achieved a BP <140/90 mm Hg. While the procedure did require an overnight stay in the hospital, there were only few minor initial procedural complications. During follow-up, there was no difference between the groups in serious procedure-related or device-related complications or the occurrence of clinical adverse events. Imaging of the renal arteries showed no evidence of renal artery stenosis or aneurysmal dilatation during the 6-month follow-up. There was no effect on measured renal function with denervation even in those who entered the trial with an eGFR of 45 mL/min/m2 to 60 mL/min/m2.

This trial suggests that catheter-based renal denervation may be a viable new method for the treatment of drug-resistant hypertension. Currently available in Europe at a cost of around $12,000, the procedure is not technically difficult, appears to be safe, takes about 40 minutes to perform, and only requires pre-procedure analgesia. Concerns with the present study include the relatively small sample size, relatively short duration of follow-up, use of only a handful of experienced operators, and a study design that did not require the placebo group to undergo a sham procedure, which would have made the study double-blind. Additionally, patients with secondary and white-coat hypertension were not excluded, which may have biased the results. Future studies should be conducted in more patients, with more operators, and with longer follow-up to more fully evaluate the long-term safety and efficacy of the procedure. Specific populations of individuals with resistant hypertension, including those of older age, obesity, diabetes, chronic kidney disease, sleep apnea, as well as patients taking specific classes of antihypertensive drugs commonly associated with increased sympathetic nervous system activity need to be specifically studied. A large-scale US study of renal denervation is set to begin early in 2012. This will enable us to better identify those specific populations of patients, including a more diverse ethnic population, who will respond best to this novel and potentially paradigm-shifting procedure.