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Renal Sympathetic Denervation for the Treatment of Refractory Hypertension Kui Toh Gerard Leong,1 Antony Walton,2 and Henry Krum3 1 Department of Cardiology, Changi General Hospital, Singapore 529889; email: [email protected] 2 Heart Centre, The Alfred Hospital, Melbourne, Victoria 3004, Australia; email: [email protected] 3
Annu. Rev. Med. 2014. 65:349–65 The Annual Review of Medicine is online at med.annualreviews.org This article’s doi: 10.1146/annurev-med-051812-145353 c 2014 by Annual Reviews. Copyright All rights reserved
Monash University, Melbourne, Victoria 3004, Australia; email: [email protected]
Keywords resistant hypertension, sympathetic nervous system, renal sympathetic denervation, renal disease, heart failure
Abstract Resistant hypertension poses significant health concerns. There are strong demands for new and safe therapies to control resistant hypertension while addressing its common causes, specifically poor compliance to lifelong polypharmacy, lifestyle modifications, and physician inertia. The sympathetic nervous system plays a significant pathophysiological role in hypertension. Surgical sympathectomy for blood pressure reduction is an old but extremely efficacious therapeutic concept, now abandoned with the dawn of a safer contemporary pharmacology era. Recently, clinical studies have revealed promising results for safe and sustained blood pressure reduction with percutaneous renal sympathetic denervation. This is a novel, minimally invasive, device-based therapy, specifically targeting and ablating the renal artery nerves with radiofrequency waves without permanent implantation. There are also reported additional benefits in related comorbidities, such as impaired glucose metabolism, renal impairment, left ventricular hypertrophy, heart failure, and others. This review focuses on how selective renal sympathetic denervation works, its present and potential therapeutic indications, and its future directions.
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INTRODUCTION
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Hypertension is a major global public health concern. An estimated 30–40% of the adult population in the developed world has hypertension (1, 2). Elevated blood pressure (BP) is strongly and directly related to increased cardiovascular risks (3). The association of hypertension with increased coronary heart disease cuts across national and ethnic boundaries (4). Each difference of 20 mm Hg above the usual systolic BP, or, approximately equivalently, 10 mm Hg above usual diastolic BP, is associated with more than a twofold difference in stroke, ischemic heart disease, and other vascular mortality rates (5). Fortunately, it has also been shown that if BP can be reduced with lifestyle and pharmacological management cardiovascular events can be reduced; this benefit is independent of age (6). However, the percentage of patients achieving adequate BP control according to the recommended guideline target values remains low (7). BP control rates in treated hypertensives range from 21% to 55% (8). There are multiple factors for this poor rate of hypertension control. They include poor compliance with lifelong multidrug medications (9) or with lifestyle modifications, and physician inertia (10). Compliance is made more difficult as hypertension is predominantly an asymptomatic disease. As for patients with BP above the target threshold levels, they are at high risk of major cardiovascular events (11). Resistant hypertension has been defined as BP that remains above goal in spite of the concomitant use of antihypertensive medications from at least three drug classes. Ideally, one of the three agents should be a diuretic, and all agents should be prescribed at optimal doses. Individuals with controlled BP using at least four drug classes are also considered to have resistant hypertension (11). The prevalence of resistant hypertension is variable, depending on the patient population and whether treatment is at a primary or specialized-care facility, such as a nephrology clinic. In one observational community study in the United States, using data
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from the National Health and Nutrition Examination Survey from 2003–2008 (12), the prevalence of US adults with resistant hypertension was 8.9% (SD 0.6%). With the failure of present strategies to adequately control BP in these patients with resistant hypertension, there is a strong demand for the development of new safe therapeutic strategies to treat resistant hypertension, overcoming poor compliance to lifelong multidrug regimens, lifestyle modifications, and physician inertia.
THE SYMPATHETIC NERVOUS SYSTEM IN KIDNEYS AND ITS ROLE IN HYPERTENSION The sympathetic nervous system (SNS) has an important regulatory role in the body. In its dysfunctional hyperexcitatory state, SNS activation can lead to multiple deleterious effects, including hypertension (Figure 1). The neural control of the kidney is of great significance for renin release, as well as volume and sodium homeostasis; all of these are key components in BP regulation. The renal SNS carries both afferent and efferent signals between the central nervous system and the kidneys (13). It includes a rich arborizing network of efferent and afferent nerves in the renal artery adventitia and kidneys. The afferent sensory nerves in the kidneys and renal arteries are both mechano- and chemosensitive. Afferent signals from the kidney to the central nervous system are increased in states of renal ischemia, renal parenchymal injury, and hypoxia, leading to increased efferent signals to the kidneys, heart, and peripheral blood vessels (13). The consequences of renal sympathetic-nerve activation are volume retention via activation of the reninangiotensin-aldosterone system through stimulation of the juxtaglomerular apparatus and subsequent renin release (14), sodium reabsorption (15), and reduction in renal blood flow (16, 17). These are mediated by the stimulation of the β-1 adrenoreceptors located in the juxtaglomerular granular cells resulting in an increased renin secretion rate, the stimulation
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Hypertrophy Heart failure Arrhythmia O2 consumption requirements increased
Vasoconstriction Atherosclerosis
Stroke Coronary artery disease Peripheral arterial disease Nephrosclerosis
Insulin resistance
Renal afferent nerves
Renal efferent nerves
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Afferent stimulators Renal ischemia Adenosine production Direct interaction Indirect interaction with significant intermediate steps
Renin release Renal angiotensin Aldosterone activation Sodium retention Renal blood flow
Elevated blood pressure
Outflowing efferents Inflowing afferents
Figure 1 Representation of the sympathetic nervous system, demonstrating the complex interaction between afferent sensory signaling from the kidney and efferent sympathetic outflow to the kidney, and the multiple deleterious consequences of a hyperexcitatory sympathetic nervous state. Adapted from Reference 19 with permission.
of the α-1B adrenoreceptors on the renal tubular epithelial cells causing increased renal tubular sodium reabsorption and decreased urinary sodium excretion, and the stimulation of the α-1A adrenoreceptors in the renal vasculature bringing about vasoconstriction and decreased renal blood flow (18). The renal sympathetic nerves play major roles in the complex pathophysiology of hypertension in both experimental models and in humans (20). Patients with essential hypertension generally have an increased efferent sympathetic drive to the kidneys, as evidenced by an elevated renal norepinephrine spillover rate, defined as the amount of transmitter that escapes neuronal uptake and local metabolism and thus “spills over” into the circulation (21, 22). Hypertension is also characterized by an increased rate of sympathetic-nerve firing (23). The renal afferent SNS directly influences sympathetic outflow to the kidneys and other or-
gans involved in cardiovascular control. The heightened sympathetic activity in patients with hypertension is possibly modulated by afferent signaling from renal sensory nerves (24). Disruption of the afferent nerves has been shown in animal models to reduce both BP (25) and renal end-organ damage (26). That the human kidney serves as an afferent limb in the sympathetic pathway is suggested by observational studies in which bilateral nephrectomy of native diseased kidneys in patients with end-stage renal disease who have undergone kidney transplants has been shown to improve or normalize BP (27, 28). In a study by Hausberg et al. (29), the SNS activity (measured by muscle sympatheticnerve activity) of 13 hemodialysis patients awaiting renal transplantation was compared with that of 32 renal transplantation recipient patients with good graft function and preserved diseased native kidneys, 16 renal transplantation recipient patients who had undergone www.annualreviews.org • Treatment of Refractory Hypertension
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bilateral nephrectomy, and 15 healthy volunteers. Despite good graft function with the correction of uremia with renal transplants, increased SNS activity was observed in renal transplantation recipients without nephrectomy of diseased native kidneys at a level not significantly different from chronic hemodialysis patients. However, in renal transplantation
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a
SYMPATHECTOMY FOR REFRACTORY HYPERTENSION
b
With knowledge of the above roles of SNS hyperactivity in hypertension, therapeutic denervation of the kidneys seems logical. Indeed, renal denervation has been applied successfully to prevent or ameliorate hypertension in a variety of experimental models (30–32). Nonselective surgical sympathectomy was effectively used for symptom relief and lowering of BP in the treatment of severe hypertension before antihypertensive drugs became generally available (33). However, although an improvement over lifestyle management or early pharmacological therapy for severe hypertension (34), surgical mortality rates were significant at 4% (35), and there were multiple long-term complications including significant hypotension, erectile dysfunction, bladder and bowel dysfunction, and Raynaud’s phenomenon (33–35).
c
Percutaneous RSDN catheter
PERCUTANEOUS RENAL SYMPATHETIC DENERVATION AS ANCILLARY THERAPY IN REFRACTORY HYPERTENSION
Treat distal to proximal Aorta Ablation sites
Spacing of, e.g., 5 mm Kidney
Figure 2 (a) Selective angiography of the right renal artery. (b) Fluoroscopic image of the renal sympathetic denervation (RSDN) catheter (below the 12-cm mark on the ruler) in the right renal artery. (c) Schematic illustration of the percutaneous RSDN catheter and ablation sites in the human renal artery (adapted from Reference 19 with permission). 352
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recipients who underwent bilateral native kidney nephrectomy, SNS activity was not significantly different from that measured in healthy volunteers. The observations suggest that the increased SNS activity in hypertension appears to be mediated by signals arising in the native kidneys that are independent of circulating uremia-related toxins.
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Recently developed endovascular catheter technology now permits safer selective denervation of the renal sympathetic nerves located in the adventitia of the renal arteries. This is a minimally invasive procedure, without the need for a permanently implanted device, with access via the femoral artery using the well established Seldinger technique (36). Intra-arterial heparin is given, aiming for a target-activated clotting time >250 s. Both renal arteries are cannulated in sequence using a guide catheter (Figure 2a). Before treating each artery, the administration
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of intra-arterial nitroglycerine through the renal guide is recommended to reduce the risk of arterial spasm. A proprietary steerable radiofrequency (RF) ablation catheter, connected to a generator, is inserted into the renal arteries under fluoroscopic guidance (Figure 2b). Several discrete RF ablations (typically four to eight, depending on the individual renal artery anatomy) are then delivered onto the renal artery wall, denervating the nerves in the renal artery adventitia. Each RF ablation lasts up to 2 min and is 8 watts or less. These ablations are separated both longitudinally and rotationally within each renal artery (Figure 2c). The catheter tip temperature and impedance are monitored continuously during ablation, with RF energy delivery regulated according to a predetermined algorithm to ensure safety, avoiding unintentional damage to surrounding tissue (37). During RF ablation, there is diffuse visceral nonradiating loin pain of varying intensity. This localized visceral loin discomfort does not persist beyond the RF energy application and can be managed adequately with intravenous narcotics and amnesic sedatives. After the procedure, there may be some persistent mild loin discomfort. This requires at most a mild analgesic, such as paracetamol (acetaminophen) or an equivalent. The discomfort does not persist beyond four weeks.
THE CLINICAL EVIDENCE IN HUMANS: THE SYMPLICITY HTN-1 AND -2 TRIALS The Symplicity HTN trial series included the first human clinical studies that have shown promising data on the efficacy and safety of percutaneous RSDN for BP reduction in humans (see Table 1 for a summary).
Symplicity HTN-1 The first proof-of-concept nonrandomized open-label study was the Symplicity HTN-1 study (38). It included 45 patients with resistant essential hypertension without significant renal impairment [estimated glomerular filtration rate (GFR) of ≥45 mL/min/1.73 m2 ]. Resistant
hypertension was defined as office systolic BP of ≥160 mm Hg, despite being treated with at least three antihypertensive drugs (including one diuretic), or as confirmed intolerance to medications. They were analyzed for outcomes up to one year post RSDN. Their baseline mean office BP was 177/101 mm Hg (20/15). Office BPs after the procedure were reduced by −14/−10, −21/−10, −22/−11, −24/−11, and −27/−17 mm Hg at 1, 3, 6, 9, and 12 months, respectively. In the five nontreated patients, the mean rise in office BP was +3/−2, +2/+3, +14/+9, and +26/+17 mm Hg at 1, 3, 6, and 9 months, respectively. The responder rate (defined as systolic BP reduction ≥10 mm Hg) at 6 months was 87%. This was associated with reduction of renal sympathetic activity as evidenced from renal norepinephrine spillover measurements, diminished renin release with a parallel increase in renal plasma flow, and progressive and sustained reductions of central sympathetic outflow from microneurography measurements (39).
Symplicity HTN-2 This was the first randomized controlled clinical trial for percutaneous RSDN (40). Inclusion criteria included patients with office systolic BP of ≥160 mm Hg or ≥150 mm Hg in those with type 2 diabetes. Other inclusion criteria were similar to those in Symplicity HTN-1. The Symplicity HTN-2 study enrolled 106 patients. Patients were randomly assigned to undergo RSDN treatment (N = 52) or to continue with conventional drug treatment (the control group, N = 54). They were analyzed for outcomes up to six months post enrollment. The two groups had similar baseline characteristics and antihypertensive regimens. A similar follow-up protocol was used for both arms to counter the Hawthorne effect (41). At 6 months follow-up, three patients in each group were lost to follow-up. The remaining patients were analyzed. The office BP in the RSDN group (N = 49) was reduced by 32/12 (23/11) from 178/97 (18/16) at baseline (p < 0.0001 for systolic and diastolic www.annualreviews.org • Treatment of Refractory Hypertension
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Table 1 Summary of the Symplicity hypertension (HTN)-1 and -2 trials Symplicity HTN-1 study (38) and extended follow-up (47)
Symplicity HTN-2 study (40)
Design of study
First-in-man, proof-of-concept, international, multicenter, nonrandomized, open-label, efficacy, and safety study 12 months follow up for Symplicity HTN-1 24 months follow-up for extended follow-up study
Prospective, international, multicenter, randomized, open-label, efficacy, and safety study 6 month follow-up
Inclusion criteria
Office systolic BP ≥160 mm Hg on ≥3 anti-HTN drugs, including a diuretic, or confirmed intolerance to medications
Office systolic BP ≥160 mm Hg or ≥150 mm Hg in type 2 diabetes, on ≥3 anti-HTN drugs
Main exclusion criteria
Secondary hypertension, significant heart valve disease, existing permanent pacemaker or implantable cardiac defibrillator, eGFR ≤45 mL/min/1.73 m2 , type 1 diabetes, unsuitable renal artery anatomy
Sample size
45
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Study details
153 (extended follow-up cohort)
52 RSDN group
54 Control
Age, years, mean (SD)
58 (9)
57 (11)
58 (12)
58 (12)
Number of antihypertension medications (mean SD)
4.7 (1.5)
5.1 (1.4)
5.2 (1.5)
5.3 (1.8)
Baseline BP, mm Hg, mean (SD)
177/101 (20/15)
176/98 (17/15)
178/97 (18/16)
178/98 (16/17)
Outcomes Change in office BP, mm Hg, mean
Office systolic and diastolic BP readings were significantly lower after RSDN compared to before RSDN (p ≤ 0.03 for all)
1 month 6 months 12 months 24 months
−14/−10 −22/−11 −27/−11 NA As follow up is only 12 months
Responder rate (systolic BP reduction ≥10 mm Hg) at 6 months
−20/−10 −25/−11 −23/−11 −32/−14
87% (92% in extended follow-up cohort)
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84%
35% (p < 0.0001)
BP). The responder rate at 6 months was 84%. Adequate BP control (defined as achieving systolic BP < 140 mm Hg) was successful in 39% of patients in the RSDN group and in 3% of patients in the control group (p < 0.0001). Home BP recordings confirmed the observed office BP changes with a reduction in home BP by 20/12 (17/11) mm Hg in the RSDN group (N = 49) and an increase of 2/0 (13/7) mm Hg in the control group (N = 51, p < 0.001). Left ventricular hypertrophy (LVH) is an indicator of cardiac end-organ damage 354
−20/−7 −32/−12 NA NA As follow up is only 6 months
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in arterial hypertension, and its presence is associated with an increased rate of cardiovascular events and death (42) independent of other cardiovascular risk factors and, notably, independent of BP values (43). Fortunately, it has been shown consistently that LVH regression was accompanied by favorable outcomes (44). In a Symplicity HTN-2 substudy, there was demonstration of significantly reduced LV mass and improved diastolic function in patients who had undergone the procedure for resistant hypertension (45). This might have
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important prognostic implications in patients with resistant hypertension and LVH. There was concern that the initial BPlowering effect would be temporary, diminishing after the renal sympathetic efferents regenerate and reinnervate the kidneys (46). However, the BP-lowering effect from percutaneous RSDN has been shown to be sustained for more than two years without significant adverse events. The Symplicity HTN-1 investigators reported longer-term follow-up data on their initial cohort (38) and a larger group of similar patients who were subsequently treated with RSDN in a nonrandomized manner (47). A total of 153 patients were treated with percutaneous RSDN. Baseline values included mean office BP of 176/98 (17/15) mm Hg and a mean of 5.1 (1.4) antihypertension medications. Postprocedure office BPs were reduced by 20/10, 24/11, 25/11, 23/11, 26/14, and 32/14 mm Hg at 1, 3, 6, 12, 18, and 24 months respectively. The procedure was without complication in 97% of patients (149 of 153). The four acute procedural complications included three groin pseudoaneurysms and one renal artery dissection, all managed without further complications. The persistent BP-lowering effect demonstrated (47) may be explained by the removal of renal afferent activity and the subsequent effects on central sympathetic outflow in contrast to efferent nerves; the afferent nerves do not appear to have the capacity to regrow (48).
Symplicity HTN-3 The Symplicity HTN-3 trial is an ongoing prospective randomized masked-procedure single-blind study with expected enrollment of 530 patients in the United States. Its aim is to evaluate the safety and effectiveness of catheter-based bilateral renal denervation for the treatment of uncontrolled hypertension as defined in the previous Symplicity HTN-1 and -2 trials. One criterion for inclusion is that candidates have a 24-h average systolic BP ≥135 mm Hg by ambulatory blood pressure monitoring (ABPM) to exclude patients with
white-coat hypertension. Unique to this trial are the single-blind sham procedures to look at placebo effects. Endpoints to be assessed (up to 6 months) include change in average 24-h systolic BP by ABPM and change in office-based systolic BP (49). In the Symplicity HTN-1 and -2 trials, the systolic and diastolic BP was reduced by 15– 30 mm Hg and 10–15 mm Hg, respectively. In contemporary pharmacology trials, the average systolic and diastolic BP drops were 4– 12 mm Hg and 4–9 mm Hg, respectively (6, 50). A significant proportion of patients discontinued their medications for various reasons (50). However, unlike pharmacological trials, the percutaneous RSDN trials do not have clinical outcome data at present.
Safety Profile of Percutaneous Radiofrequency Renal Denervation in the Treatment of Resistant Hypertension In the evaluation of any novel therapy, safety is a major concern. Preclinical animal studies have shown percutaneous RSDN to be safe (51). In the Symplicity HTN-1 trial (38), there was one intraprocedural renal artery dissection. This occurred before RF energy delivery without further sequelae. There were no other renovascular complications. GFR was not significantly affected. This good renal safety profile was also seen in the expanded and extended Symplicity HTN-1 cohort study (47). Up to 24 months, there were no long-term significant renovascular complications and no deterioration of renal function. In the Symplicity HTN-2 trial (40), renal safety was demonstrated again. There were no renal artery complications. Transient intraprocedural bradycardia occurred in seven (13%) patients who had RSDN. They responded to atropine without complications. There were no significant changes in the mean estimated glomerular filtration rate (eGFR) as defined in reference paper 37, serum creatinine, and cystatin C concentrations between the treatment and control groups at 6-month follow-up. www.annualreviews.org • Treatment of Refractory Hypertension
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NEWER RENAL SYMPATHETIC DENERVATION SYSTEMS
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At present, most clinical experience has been with percutaneous RSDN catheters that have a single electrode, mounted on the terminal end of a steerable catheter utilizing RF waves as the ablation modality. Numerous newer RSDN systems are emerging; these are undergoing human safety and efficacy trials (Table 2). All these new devices allow for simultaneous application of ablation energy at multiple different points in the renal artery lumen to denervate the renal sympathetic nerves. This allows for shorter procedure time and, more importantly for the patient, fewer and shorter periods of pain during the application of the ablation energy on the renal sympathetic nerves. There is also a theoretically reduced volume of nephrotoxic contrast used. This allows a greater pool of patients to undergo this procedure safely. The newer multi-electrode radiofrequency renal denervation (RSDN) catheters can allow smaller and shorter renal arteries to be ablated. There is also a race to develop safer ablation energy modalities.
Radiofrequency as a Renal Denervation Modality The new RSDN systems employ multiple RF ablation electrodes mounted on steerable basket-like shaped catheters as in the St. Jude Medical EnligHTNTM system or spiral-shaped catheters as in the Medtronic Multi-Electrode Radiofrequency Renal Denervation System. Preliminary (unpublished) 6-month data on the EnligHTN system (N = 46) have shown efficacious BP reduction, with 76% of patients achieving systolic BP reduction of ≥10 mm Hg at 6 months postprocedure. The mean BP reduction at 6 months was −26/−10 mm Hg, from 176/96 mm Hg at baseline to 150/86 mm Hg. The Covidien OneShotTM system employs a saline-irrigated balloon catheter, with a spiral RF electrode on the balloon. It permits a single RF energy application lasting only 2 min per renal artery. The application of saline irrigation in RF ablation is reported to produce 356
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deeper and wider ablation zones while reducing the amount of char formation and minimizing damage to nontarget tissue. The Vessix V2 Renal Denervation SystemTM is an over-thewire low-pressure balloon catheter with multiple RF electrodes mounted on the exterior of the balloon. It claims to offer treatment times of 30 s. The balloon catheter also accommodates smaller arterial diameters (3.0 mm). The St. Jude Medical EnligHTNTM , Covidien OneShotTM , and Vesix V2 systems have obtained Conformit´e Europ´eenne (CE) approval.
Ultrasound as a Renal Sympathetic Denervation Modality There is another CE-approved percutaneous ablation catheter that uniquely employs ultrasound as the denervation modality. The R RSDN System ReCor Medical PARADISE employs a catheter with a cylindrical transducer within a low-pressure balloon that emits ultrasound energy circumferentially, effecting renal denervation. It is claimed that this allows complete circumferential denervation more consistently and efficiently than the standard RF ablation catheter. In a small study (N = 11), this ultrasound RSDN method appeared to be a safe and effective treatment for resistant hypertension (52).
PRESENT INDICATIONS FOR PERCUTANEOUS RENAL SYMPATHETIC DENERVATION TREATMENT OF HYPERTENSION On the basis of current clinical evidence (38, 40), RSDN is indicated for resistant severe essential hypertension with no significant renal impairment (estimated GFR ≥45 mL/min/1.73 m2 ) and suitable renal artery anatomy. Resistant severe hypertension is defined as office systolic BP of ≥160 mm Hg, or ≥150 mm Hg in type 2 diabetes, despite treatment with at least three antihypertensive drugs (including one diuretic) or confirmed intolerance to
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Table 2 New renal sympathetic denervation (RSDN) systems
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RSDN system
Device features
Clinical evidence
St. Jude Medical EnligHTNTM multi-electrode system (CE Mark approval in May 2012)
Steerable catheter, with multiple electrodes at the distal basket-like end RF generator
Safety and efficacy study of Renal Artery Ablation in Resistant Hypertension Patients (EnligHTN I), NCT01438229. Completed enrollment number 47 Papademetriou V. 2012. EnligHTN I: safety and efficacy of a novel multi-electrode renal denervation catheter in patients with resistant hypertension: a first-in-human multicenter study. Presented at Am. Heart Assoc. Congress, Los Angeles, Nov 3–7 International Long-Term Follow-Up Study of Patients With Uncontrolled Hypertension (EnligHTN II), NCT01705080 Expected enrollment number 500 Enrollment period January to December 2013
Medtronic Multi-Electrode Radiofrequency System
Steerable catheter with multiple electrodes at the distal helical coil end RF generator
Multi-Electrode Radiofrequency Renal Denervation System Feasibility Study, NCT01699529 Expected enrollment number 50 Enrollment period September 2012 to September 2013
Covidien OneShotTM system (CE Mark approval in February 2012)
A saline-irrigated balloon catheter with a helical electrode on its surface RF generator
Ormiston J. 2012. OneShot. Feasibility study to evaluate the Maya Renal Hypertension Ablation System for chronic hypertension. RHAS Trial. TCT2012, Miami. The Rapid Renal Sympathetic Denervation for Resistant Hypertension (RAPID I) trial, NCT01520506 Expected enrollment number 40 Enrollment period May 2012 to November 2013
Vessix V2 (CE Mark approval in May 2012)
Low-pressure balloon catheter with multiple electrodes mounted on the exterior of the balloon RF generator
Treatment of resistant hypertension using a RF percutaneous transluminal angioplasty catheter (REDUCE-HTN), NCT01541865 Expected enrollment number 150 Enrollment period February 2012 to March 2013
ReCor Medical PARADISE (CE Mark approval in February 2012)
Catheter with a distal cylindrical transducer, within a low-pressure balloon that emits ultrasound energy circumferentially, effecting renal denervation Ultrasound generator
Bonan R. 2012. PARADISE: first-in-man results of a novel circumferential catheter-based ultrasound technology for renal denervation. Abstr. presented at Annu. Sci. Sess. Eur. Assoc. Percutaneous Cardiovascular Interventions, Paris, May 16 Renal Denervation by Ultrasound Transcatheter Emission (REALIZE), NCT01529372. A single-arm, open-label, prospective, first-in-man study with a 12-month follow-up period Estimated enrollment 20 Enrollment period May 2012 to July 2014 Transcatheter Intravascular Ultrasound Energy Delivery for Renal Denervation (ACHIEVE), NCT01789918. A single-arm, open-label, prospective, postmarket follow-up study to be conducted with a 12-month follow-up period Estimated enrollment 50 Enrollment period February 2013 to February 2015
Abbreviations: CE approval, Conformit´e Europ´eenne approval; HTN, hypertension.
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medications. Diuretics that are useful for treatment of poorly controlled hypertension include long-acting thiazides, long-acting loop diuretics, and mineralocorticoid receptor antagonists (11). Addition of spironolactone to existing multi-antihypertension drug regimens (inclusive of diuretics) has been shown to be efficacious in reducing BP in resistant hypertension. In the nonrandomized post hoc analysis of the Anglo-Scandinavian Cardiac Outcomes TrialBlood Pressure Lowering Arm, the addition of spironolactone to a triple-drug treatment led to a significant decrease of systolic BP of 21.9 mm Hg and diastolic BP of 9.5 mm Hg (53). A subsequent randomized double-blind, placebocontrolled, multicenter trial yielded similar but more modest BP reductions (54). In this study, patients with resistant hypertension while on ≥3 antihypertension medications (inclusive of a long-acting loop diuretic) were given either spironolactone or a placebo. At eight weeks, the ABPM nighttime systolic, 24-h ABPM systolic, and office systolic BP values were significantly decreased by spironolactone (differences of −8.6, −9.8, and −6.5 mm Hg, respectively; p = 0.011, 0.004, and 0.011, respectively), whereas the fall of the respective diastolic BP values was not significant (−3.0, −1.0, and −2.5 mm Hg, respectively; p = 0.079, 0.405, and 0.079, respectively). The adverse events in both groups were comparable. Suitable renal artery anatomy at present means the presence of solitary renal arteries without significant renal stenosis (
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Renal Sympathetic Denervation for the Treatment of Refractory Hypertension Kui Toh Gerard Leong,1 Antony Walton,2 and Henry Krum3 1 Department of Cardiology, Changi General Hospital, Singapore 529889; email: [email protected] 2 Heart Centre, The Alfred Hospital, Melbourne, Victoria 3004, Australia; email: [email protected] 3
Annu. Rev. Med. 2014. 65:349–65 The Annual Review of Medicine is online at med.annualreviews.org This article’s doi: 10.1146/annurev-med-051812-145353 c 2014 by Annual Reviews. Copyright All rights reserved
Monash University, Melbourne, Victoria 3004, Australia; email: [email protected]
Keywords resistant hypertension, sympathetic nervous system, renal sympathetic denervation, renal disease, heart failure
Abstract Resistant hypertension poses significant health concerns. There are strong demands for new and safe therapies to control resistant hypertension while addressing its common causes, specifically poor compliance to lifelong polypharmacy, lifestyle modifications, and physician inertia. The sympathetic nervous system plays a significant pathophysiological role in hypertension. Surgical sympathectomy for blood pressure reduction is an old but extremely efficacious therapeutic concept, now abandoned with the dawn of a safer contemporary pharmacology era. Recently, clinical studies have revealed promising results for safe and sustained blood pressure reduction with percutaneous renal sympathetic denervation. This is a novel, minimally invasive, device-based therapy, specifically targeting and ablating the renal artery nerves with radiofrequency waves without permanent implantation. There are also reported additional benefits in related comorbidities, such as impaired glucose metabolism, renal impairment, left ventricular hypertrophy, heart failure, and others. This review focuses on how selective renal sympathetic denervation works, its present and potential therapeutic indications, and its future directions.
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INTRODUCTION
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Hypertension is a major global public health concern. An estimated 30–40% of the adult population in the developed world has hypertension (1, 2). Elevated blood pressure (BP) is strongly and directly related to increased cardiovascular risks (3). The association of hypertension with increased coronary heart disease cuts across national and ethnic boundaries (4). Each difference of 20 mm Hg above the usual systolic BP, or, approximately equivalently, 10 mm Hg above usual diastolic BP, is associated with more than a twofold difference in stroke, ischemic heart disease, and other vascular mortality rates (5). Fortunately, it has also been shown that if BP can be reduced with lifestyle and pharmacological management cardiovascular events can be reduced; this benefit is independent of age (6). However, the percentage of patients achieving adequate BP control according to the recommended guideline target values remains low (7). BP control rates in treated hypertensives range from 21% to 55% (8). There are multiple factors for this poor rate of hypertension control. They include poor compliance with lifelong multidrug medications (9) or with lifestyle modifications, and physician inertia (10). Compliance is made more difficult as hypertension is predominantly an asymptomatic disease. As for patients with BP above the target threshold levels, they are at high risk of major cardiovascular events (11). Resistant hypertension has been defined as BP that remains above goal in spite of the concomitant use of antihypertensive medications from at least three drug classes. Ideally, one of the three agents should be a diuretic, and all agents should be prescribed at optimal doses. Individuals with controlled BP using at least four drug classes are also considered to have resistant hypertension (11). The prevalence of resistant hypertension is variable, depending on the patient population and whether treatment is at a primary or specialized-care facility, such as a nephrology clinic. In one observational community study in the United States, using data
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from the National Health and Nutrition Examination Survey from 2003–2008 (12), the prevalence of US adults with resistant hypertension was 8.9% (SD 0.6%). With the failure of present strategies to adequately control BP in these patients with resistant hypertension, there is a strong demand for the development of new safe therapeutic strategies to treat resistant hypertension, overcoming poor compliance to lifelong multidrug regimens, lifestyle modifications, and physician inertia.
THE SYMPATHETIC NERVOUS SYSTEM IN KIDNEYS AND ITS ROLE IN HYPERTENSION The sympathetic nervous system (SNS) has an important regulatory role in the body. In its dysfunctional hyperexcitatory state, SNS activation can lead to multiple deleterious effects, including hypertension (Figure 1). The neural control of the kidney is of great significance for renin release, as well as volume and sodium homeostasis; all of these are key components in BP regulation. The renal SNS carries both afferent and efferent signals between the central nervous system and the kidneys (13). It includes a rich arborizing network of efferent and afferent nerves in the renal artery adventitia and kidneys. The afferent sensory nerves in the kidneys and renal arteries are both mechano- and chemosensitive. Afferent signals from the kidney to the central nervous system are increased in states of renal ischemia, renal parenchymal injury, and hypoxia, leading to increased efferent signals to the kidneys, heart, and peripheral blood vessels (13). The consequences of renal sympathetic-nerve activation are volume retention via activation of the reninangiotensin-aldosterone system through stimulation of the juxtaglomerular apparatus and subsequent renin release (14), sodium reabsorption (15), and reduction in renal blood flow (16, 17). These are mediated by the stimulation of the β-1 adrenoreceptors located in the juxtaglomerular granular cells resulting in an increased renin secretion rate, the stimulation
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Hypertrophy Heart failure Arrhythmia O2 consumption requirements increased
Vasoconstriction Atherosclerosis
Stroke Coronary artery disease Peripheral arterial disease Nephrosclerosis
Insulin resistance
Renal afferent nerves
Renal efferent nerves
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Afferent stimulators Renal ischemia Adenosine production Direct interaction Indirect interaction with significant intermediate steps
Renin release Renal angiotensin Aldosterone activation Sodium retention Renal blood flow
Elevated blood pressure
Outflowing efferents Inflowing afferents
Figure 1 Representation of the sympathetic nervous system, demonstrating the complex interaction between afferent sensory signaling from the kidney and efferent sympathetic outflow to the kidney, and the multiple deleterious consequences of a hyperexcitatory sympathetic nervous state. Adapted from Reference 19 with permission.
of the α-1B adrenoreceptors on the renal tubular epithelial cells causing increased renal tubular sodium reabsorption and decreased urinary sodium excretion, and the stimulation of the α-1A adrenoreceptors in the renal vasculature bringing about vasoconstriction and decreased renal blood flow (18). The renal sympathetic nerves play major roles in the complex pathophysiology of hypertension in both experimental models and in humans (20). Patients with essential hypertension generally have an increased efferent sympathetic drive to the kidneys, as evidenced by an elevated renal norepinephrine spillover rate, defined as the amount of transmitter that escapes neuronal uptake and local metabolism and thus “spills over” into the circulation (21, 22). Hypertension is also characterized by an increased rate of sympathetic-nerve firing (23). The renal afferent SNS directly influences sympathetic outflow to the kidneys and other or-
gans involved in cardiovascular control. The heightened sympathetic activity in patients with hypertension is possibly modulated by afferent signaling from renal sensory nerves (24). Disruption of the afferent nerves has been shown in animal models to reduce both BP (25) and renal end-organ damage (26). That the human kidney serves as an afferent limb in the sympathetic pathway is suggested by observational studies in which bilateral nephrectomy of native diseased kidneys in patients with end-stage renal disease who have undergone kidney transplants has been shown to improve or normalize BP (27, 28). In a study by Hausberg et al. (29), the SNS activity (measured by muscle sympatheticnerve activity) of 13 hemodialysis patients awaiting renal transplantation was compared with that of 32 renal transplantation recipient patients with good graft function and preserved diseased native kidneys, 16 renal transplantation recipient patients who had undergone www.annualreviews.org • Treatment of Refractory Hypertension
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bilateral nephrectomy, and 15 healthy volunteers. Despite good graft function with the correction of uremia with renal transplants, increased SNS activity was observed in renal transplantation recipients without nephrectomy of diseased native kidneys at a level not significantly different from chronic hemodialysis patients. However, in renal transplantation
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a
SYMPATHECTOMY FOR REFRACTORY HYPERTENSION
b
With knowledge of the above roles of SNS hyperactivity in hypertension, therapeutic denervation of the kidneys seems logical. Indeed, renal denervation has been applied successfully to prevent or ameliorate hypertension in a variety of experimental models (30–32). Nonselective surgical sympathectomy was effectively used for symptom relief and lowering of BP in the treatment of severe hypertension before antihypertensive drugs became generally available (33). However, although an improvement over lifestyle management or early pharmacological therapy for severe hypertension (34), surgical mortality rates were significant at 4% (35), and there were multiple long-term complications including significant hypotension, erectile dysfunction, bladder and bowel dysfunction, and Raynaud’s phenomenon (33–35).
c
Percutaneous RSDN catheter
PERCUTANEOUS RENAL SYMPATHETIC DENERVATION AS ANCILLARY THERAPY IN REFRACTORY HYPERTENSION
Treat distal to proximal Aorta Ablation sites
Spacing of, e.g., 5 mm Kidney
Figure 2 (a) Selective angiography of the right renal artery. (b) Fluoroscopic image of the renal sympathetic denervation (RSDN) catheter (below the 12-cm mark on the ruler) in the right renal artery. (c) Schematic illustration of the percutaneous RSDN catheter and ablation sites in the human renal artery (adapted from Reference 19 with permission). 352
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recipients who underwent bilateral native kidney nephrectomy, SNS activity was not significantly different from that measured in healthy volunteers. The observations suggest that the increased SNS activity in hypertension appears to be mediated by signals arising in the native kidneys that are independent of circulating uremia-related toxins.
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Recently developed endovascular catheter technology now permits safer selective denervation of the renal sympathetic nerves located in the adventitia of the renal arteries. This is a minimally invasive procedure, without the need for a permanently implanted device, with access via the femoral artery using the well established Seldinger technique (36). Intra-arterial heparin is given, aiming for a target-activated clotting time >250 s. Both renal arteries are cannulated in sequence using a guide catheter (Figure 2a). Before treating each artery, the administration
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of intra-arterial nitroglycerine through the renal guide is recommended to reduce the risk of arterial spasm. A proprietary steerable radiofrequency (RF) ablation catheter, connected to a generator, is inserted into the renal arteries under fluoroscopic guidance (Figure 2b). Several discrete RF ablations (typically four to eight, depending on the individual renal artery anatomy) are then delivered onto the renal artery wall, denervating the nerves in the renal artery adventitia. Each RF ablation lasts up to 2 min and is 8 watts or less. These ablations are separated both longitudinally and rotationally within each renal artery (Figure 2c). The catheter tip temperature and impedance are monitored continuously during ablation, with RF energy delivery regulated according to a predetermined algorithm to ensure safety, avoiding unintentional damage to surrounding tissue (37). During RF ablation, there is diffuse visceral nonradiating loin pain of varying intensity. This localized visceral loin discomfort does not persist beyond the RF energy application and can be managed adequately with intravenous narcotics and amnesic sedatives. After the procedure, there may be some persistent mild loin discomfort. This requires at most a mild analgesic, such as paracetamol (acetaminophen) or an equivalent. The discomfort does not persist beyond four weeks.
THE CLINICAL EVIDENCE IN HUMANS: THE SYMPLICITY HTN-1 AND -2 TRIALS The Symplicity HTN trial series included the first human clinical studies that have shown promising data on the efficacy and safety of percutaneous RSDN for BP reduction in humans (see Table 1 for a summary).
Symplicity HTN-1 The first proof-of-concept nonrandomized open-label study was the Symplicity HTN-1 study (38). It included 45 patients with resistant essential hypertension without significant renal impairment [estimated glomerular filtration rate (GFR) of ≥45 mL/min/1.73 m2 ]. Resistant
hypertension was defined as office systolic BP of ≥160 mm Hg, despite being treated with at least three antihypertensive drugs (including one diuretic), or as confirmed intolerance to medications. They were analyzed for outcomes up to one year post RSDN. Their baseline mean office BP was 177/101 mm Hg (20/15). Office BPs after the procedure were reduced by −14/−10, −21/−10, −22/−11, −24/−11, and −27/−17 mm Hg at 1, 3, 6, 9, and 12 months, respectively. In the five nontreated patients, the mean rise in office BP was +3/−2, +2/+3, +14/+9, and +26/+17 mm Hg at 1, 3, 6, and 9 months, respectively. The responder rate (defined as systolic BP reduction ≥10 mm Hg) at 6 months was 87%. This was associated with reduction of renal sympathetic activity as evidenced from renal norepinephrine spillover measurements, diminished renin release with a parallel increase in renal plasma flow, and progressive and sustained reductions of central sympathetic outflow from microneurography measurements (39).
Symplicity HTN-2 This was the first randomized controlled clinical trial for percutaneous RSDN (40). Inclusion criteria included patients with office systolic BP of ≥160 mm Hg or ≥150 mm Hg in those with type 2 diabetes. Other inclusion criteria were similar to those in Symplicity HTN-1. The Symplicity HTN-2 study enrolled 106 patients. Patients were randomly assigned to undergo RSDN treatment (N = 52) or to continue with conventional drug treatment (the control group, N = 54). They were analyzed for outcomes up to six months post enrollment. The two groups had similar baseline characteristics and antihypertensive regimens. A similar follow-up protocol was used for both arms to counter the Hawthorne effect (41). At 6 months follow-up, three patients in each group were lost to follow-up. The remaining patients were analyzed. The office BP in the RSDN group (N = 49) was reduced by 32/12 (23/11) from 178/97 (18/16) at baseline (p < 0.0001 for systolic and diastolic www.annualreviews.org • Treatment of Refractory Hypertension
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Table 1 Summary of the Symplicity hypertension (HTN)-1 and -2 trials Symplicity HTN-1 study (38) and extended follow-up (47)
Symplicity HTN-2 study (40)
Design of study
First-in-man, proof-of-concept, international, multicenter, nonrandomized, open-label, efficacy, and safety study 12 months follow up for Symplicity HTN-1 24 months follow-up for extended follow-up study
Prospective, international, multicenter, randomized, open-label, efficacy, and safety study 6 month follow-up
Inclusion criteria
Office systolic BP ≥160 mm Hg on ≥3 anti-HTN drugs, including a diuretic, or confirmed intolerance to medications
Office systolic BP ≥160 mm Hg or ≥150 mm Hg in type 2 diabetes, on ≥3 anti-HTN drugs
Main exclusion criteria
Secondary hypertension, significant heart valve disease, existing permanent pacemaker or implantable cardiac defibrillator, eGFR ≤45 mL/min/1.73 m2 , type 1 diabetes, unsuitable renal artery anatomy
Sample size
45
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Study details
153 (extended follow-up cohort)
52 RSDN group
54 Control
Age, years, mean (SD)
58 (9)
57 (11)
58 (12)
58 (12)
Number of antihypertension medications (mean SD)
4.7 (1.5)
5.1 (1.4)
5.2 (1.5)
5.3 (1.8)
Baseline BP, mm Hg, mean (SD)
177/101 (20/15)
176/98 (17/15)
178/97 (18/16)
178/98 (16/17)
Outcomes Change in office BP, mm Hg, mean
Office systolic and diastolic BP readings were significantly lower after RSDN compared to before RSDN (p ≤ 0.03 for all)
1 month 6 months 12 months 24 months
−14/−10 −22/−11 −27/−11 NA As follow up is only 12 months
Responder rate (systolic BP reduction ≥10 mm Hg) at 6 months
−20/−10 −25/−11 −23/−11 −32/−14
87% (92% in extended follow-up cohort)
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84%
35% (p < 0.0001)
BP). The responder rate at 6 months was 84%. Adequate BP control (defined as achieving systolic BP < 140 mm Hg) was successful in 39% of patients in the RSDN group and in 3% of patients in the control group (p < 0.0001). Home BP recordings confirmed the observed office BP changes with a reduction in home BP by 20/12 (17/11) mm Hg in the RSDN group (N = 49) and an increase of 2/0 (13/7) mm Hg in the control group (N = 51, p < 0.001). Left ventricular hypertrophy (LVH) is an indicator of cardiac end-organ damage 354
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in arterial hypertension, and its presence is associated with an increased rate of cardiovascular events and death (42) independent of other cardiovascular risk factors and, notably, independent of BP values (43). Fortunately, it has been shown consistently that LVH regression was accompanied by favorable outcomes (44). In a Symplicity HTN-2 substudy, there was demonstration of significantly reduced LV mass and improved diastolic function in patients who had undergone the procedure for resistant hypertension (45). This might have
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important prognostic implications in patients with resistant hypertension and LVH. There was concern that the initial BPlowering effect would be temporary, diminishing after the renal sympathetic efferents regenerate and reinnervate the kidneys (46). However, the BP-lowering effect from percutaneous RSDN has been shown to be sustained for more than two years without significant adverse events. The Symplicity HTN-1 investigators reported longer-term follow-up data on their initial cohort (38) and a larger group of similar patients who were subsequently treated with RSDN in a nonrandomized manner (47). A total of 153 patients were treated with percutaneous RSDN. Baseline values included mean office BP of 176/98 (17/15) mm Hg and a mean of 5.1 (1.4) antihypertension medications. Postprocedure office BPs were reduced by 20/10, 24/11, 25/11, 23/11, 26/14, and 32/14 mm Hg at 1, 3, 6, 12, 18, and 24 months respectively. The procedure was without complication in 97% of patients (149 of 153). The four acute procedural complications included three groin pseudoaneurysms and one renal artery dissection, all managed without further complications. The persistent BP-lowering effect demonstrated (47) may be explained by the removal of renal afferent activity and the subsequent effects on central sympathetic outflow in contrast to efferent nerves; the afferent nerves do not appear to have the capacity to regrow (48).
Symplicity HTN-3 The Symplicity HTN-3 trial is an ongoing prospective randomized masked-procedure single-blind study with expected enrollment of 530 patients in the United States. Its aim is to evaluate the safety and effectiveness of catheter-based bilateral renal denervation for the treatment of uncontrolled hypertension as defined in the previous Symplicity HTN-1 and -2 trials. One criterion for inclusion is that candidates have a 24-h average systolic BP ≥135 mm Hg by ambulatory blood pressure monitoring (ABPM) to exclude patients with
white-coat hypertension. Unique to this trial are the single-blind sham procedures to look at placebo effects. Endpoints to be assessed (up to 6 months) include change in average 24-h systolic BP by ABPM and change in office-based systolic BP (49). In the Symplicity HTN-1 and -2 trials, the systolic and diastolic BP was reduced by 15– 30 mm Hg and 10–15 mm Hg, respectively. In contemporary pharmacology trials, the average systolic and diastolic BP drops were 4– 12 mm Hg and 4–9 mm Hg, respectively (6, 50). A significant proportion of patients discontinued their medications for various reasons (50). However, unlike pharmacological trials, the percutaneous RSDN trials do not have clinical outcome data at present.
Safety Profile of Percutaneous Radiofrequency Renal Denervation in the Treatment of Resistant Hypertension In the evaluation of any novel therapy, safety is a major concern. Preclinical animal studies have shown percutaneous RSDN to be safe (51). In the Symplicity HTN-1 trial (38), there was one intraprocedural renal artery dissection. This occurred before RF energy delivery without further sequelae. There were no other renovascular complications. GFR was not significantly affected. This good renal safety profile was also seen in the expanded and extended Symplicity HTN-1 cohort study (47). Up to 24 months, there were no long-term significant renovascular complications and no deterioration of renal function. In the Symplicity HTN-2 trial (40), renal safety was demonstrated again. There were no renal artery complications. Transient intraprocedural bradycardia occurred in seven (13%) patients who had RSDN. They responded to atropine without complications. There were no significant changes in the mean estimated glomerular filtration rate (eGFR) as defined in reference paper 37, serum creatinine, and cystatin C concentrations between the treatment and control groups at 6-month follow-up. www.annualreviews.org • Treatment of Refractory Hypertension
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NEWER RENAL SYMPATHETIC DENERVATION SYSTEMS
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At present, most clinical experience has been with percutaneous RSDN catheters that have a single electrode, mounted on the terminal end of a steerable catheter utilizing RF waves as the ablation modality. Numerous newer RSDN systems are emerging; these are undergoing human safety and efficacy trials (Table 2). All these new devices allow for simultaneous application of ablation energy at multiple different points in the renal artery lumen to denervate the renal sympathetic nerves. This allows for shorter procedure time and, more importantly for the patient, fewer and shorter periods of pain during the application of the ablation energy on the renal sympathetic nerves. There is also a theoretically reduced volume of nephrotoxic contrast used. This allows a greater pool of patients to undergo this procedure safely. The newer multi-electrode radiofrequency renal denervation (RSDN) catheters can allow smaller and shorter renal arteries to be ablated. There is also a race to develop safer ablation energy modalities.
Radiofrequency as a Renal Denervation Modality The new RSDN systems employ multiple RF ablation electrodes mounted on steerable basket-like shaped catheters as in the St. Jude Medical EnligHTNTM system or spiral-shaped catheters as in the Medtronic Multi-Electrode Radiofrequency Renal Denervation System. Preliminary (unpublished) 6-month data on the EnligHTN system (N = 46) have shown efficacious BP reduction, with 76% of patients achieving systolic BP reduction of ≥10 mm Hg at 6 months postprocedure. The mean BP reduction at 6 months was −26/−10 mm Hg, from 176/96 mm Hg at baseline to 150/86 mm Hg. The Covidien OneShotTM system employs a saline-irrigated balloon catheter, with a spiral RF electrode on the balloon. It permits a single RF energy application lasting only 2 min per renal artery. The application of saline irrigation in RF ablation is reported to produce 356
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deeper and wider ablation zones while reducing the amount of char formation and minimizing damage to nontarget tissue. The Vessix V2 Renal Denervation SystemTM is an over-thewire low-pressure balloon catheter with multiple RF electrodes mounted on the exterior of the balloon. It claims to offer treatment times of 30 s. The balloon catheter also accommodates smaller arterial diameters (3.0 mm). The St. Jude Medical EnligHTNTM , Covidien OneShotTM , and Vesix V2 systems have obtained Conformit´e Europ´eenne (CE) approval.
Ultrasound as a Renal Sympathetic Denervation Modality There is another CE-approved percutaneous ablation catheter that uniquely employs ultrasound as the denervation modality. The R RSDN System ReCor Medical PARADISE employs a catheter with a cylindrical transducer within a low-pressure balloon that emits ultrasound energy circumferentially, effecting renal denervation. It is claimed that this allows complete circumferential denervation more consistently and efficiently than the standard RF ablation catheter. In a small study (N = 11), this ultrasound RSDN method appeared to be a safe and effective treatment for resistant hypertension (52).
PRESENT INDICATIONS FOR PERCUTANEOUS RENAL SYMPATHETIC DENERVATION TREATMENT OF HYPERTENSION On the basis of current clinical evidence (38, 40), RSDN is indicated for resistant severe essential hypertension with no significant renal impairment (estimated GFR ≥45 mL/min/1.73 m2 ) and suitable renal artery anatomy. Resistant severe hypertension is defined as office systolic BP of ≥160 mm Hg, or ≥150 mm Hg in type 2 diabetes, despite treatment with at least three antihypertensive drugs (including one diuretic) or confirmed intolerance to
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Table 2 New renal sympathetic denervation (RSDN) systems
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RSDN system
Device features
Clinical evidence
St. Jude Medical EnligHTNTM multi-electrode system (CE Mark approval in May 2012)
Steerable catheter, with multiple electrodes at the distal basket-like end RF generator
Safety and efficacy study of Renal Artery Ablation in Resistant Hypertension Patients (EnligHTN I), NCT01438229. Completed enrollment number 47 Papademetriou V. 2012. EnligHTN I: safety and efficacy of a novel multi-electrode renal denervation catheter in patients with resistant hypertension: a first-in-human multicenter study. Presented at Am. Heart Assoc. Congress, Los Angeles, Nov 3–7 International Long-Term Follow-Up Study of Patients With Uncontrolled Hypertension (EnligHTN II), NCT01705080 Expected enrollment number 500 Enrollment period January to December 2013
Medtronic Multi-Electrode Radiofrequency System
Steerable catheter with multiple electrodes at the distal helical coil end RF generator
Multi-Electrode Radiofrequency Renal Denervation System Feasibility Study, NCT01699529 Expected enrollment number 50 Enrollment period September 2012 to September 2013
Covidien OneShotTM system (CE Mark approval in February 2012)
A saline-irrigated balloon catheter with a helical electrode on its surface RF generator
Ormiston J. 2012. OneShot. Feasibility study to evaluate the Maya Renal Hypertension Ablation System for chronic hypertension. RHAS Trial. TCT2012, Miami. The Rapid Renal Sympathetic Denervation for Resistant Hypertension (RAPID I) trial, NCT01520506 Expected enrollment number 40 Enrollment period May 2012 to November 2013
Vessix V2 (CE Mark approval in May 2012)
Low-pressure balloon catheter with multiple electrodes mounted on the exterior of the balloon RF generator
Treatment of resistant hypertension using a RF percutaneous transluminal angioplasty catheter (REDUCE-HTN), NCT01541865 Expected enrollment number 150 Enrollment period February 2012 to March 2013
ReCor Medical PARADISE (CE Mark approval in February 2012)
Catheter with a distal cylindrical transducer, within a low-pressure balloon that emits ultrasound energy circumferentially, effecting renal denervation Ultrasound generator
Bonan R. 2012. PARADISE: first-in-man results of a novel circumferential catheter-based ultrasound technology for renal denervation. Abstr. presented at Annu. Sci. Sess. Eur. Assoc. Percutaneous Cardiovascular Interventions, Paris, May 16 Renal Denervation by Ultrasound Transcatheter Emission (REALIZE), NCT01529372. A single-arm, open-label, prospective, first-in-man study with a 12-month follow-up period Estimated enrollment 20 Enrollment period May 2012 to July 2014 Transcatheter Intravascular Ultrasound Energy Delivery for Renal Denervation (ACHIEVE), NCT01789918. A single-arm, open-label, prospective, postmarket follow-up study to be conducted with a 12-month follow-up period Estimated enrollment 50 Enrollment period February 2013 to February 2015
Abbreviations: CE approval, Conformit´e Europ´eenne approval; HTN, hypertension.
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medications. Diuretics that are useful for treatment of poorly controlled hypertension include long-acting thiazides, long-acting loop diuretics, and mineralocorticoid receptor antagonists (11). Addition of spironolactone to existing multi-antihypertension drug regimens (inclusive of diuretics) has been shown to be efficacious in reducing BP in resistant hypertension. In the nonrandomized post hoc analysis of the Anglo-Scandinavian Cardiac Outcomes TrialBlood Pressure Lowering Arm, the addition of spironolactone to a triple-drug treatment led to a significant decrease of systolic BP of 21.9 mm Hg and diastolic BP of 9.5 mm Hg (53). A subsequent randomized double-blind, placebocontrolled, multicenter trial yielded similar but more modest BP reductions (54). In this study, patients with resistant hypertension while on ≥3 antihypertension medications (inclusive of a long-acting loop diuretic) were given either spironolactone or a placebo. At eight weeks, the ABPM nighttime systolic, 24-h ABPM systolic, and office systolic BP values were significantly decreased by spironolactone (differences of −8.6, −9.8, and −6.5 mm Hg, respectively; p = 0.011, 0.004, and 0.011, respectively), whereas the fall of the respective diastolic BP values was not significant (−3.0, −1.0, and −2.5 mm Hg, respectively; p = 0.079, 0.405, and 0.079, respectively). The adverse events in both groups were comparable. Suitable renal artery anatomy at present means the presence of solitary renal arteries without significant renal stenosis (
