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Catheter-based Radiofrequency Renal-nerve Ablation in Patients with Resistant Hypertension
European Journal of Vascular and Endovascular Surgery 43 (2012) 293e299
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Review
Catheter-based Radiofrequency Renal-nerve Ablation in Patients with Resistant Hypertension M. Azizi a, b, c, *, O. Steichen d, e, M. Frank c, G. Bobrie b, P.-F. Plouin a, b, M. Sapoval a, f a
Université Paris-Descartes, Faculté de Médecine, F-75006 Paris, France Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Unité d’Hypertension Artérielle, F-75015 Paris, France c INSERM, CIC 9201, Paris, France d Université Pierre et Marie Curie e Paris 6, Faculté de Médecine, F-75006 Paris, France e Assistance Publique Hôpitaux de Paris, Hôpital Tenon, Service de Médecine Interne, F-75020 Paris, France f Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Radiologie Cardiovasculaire, Paris, France b
WHAT THIS PAPER ADDS Despite the availability of multiple classes of orally active antihypertensive treatments, resistant hypertension remains an important public health issue in 2012. The failure of purely pharmacological approaches to treat resistant hypertension has stimulated interest in invasive device-based treatments. A new catheter system using radiofrequency energy has been developed, allowing an endovascular approach to renal denervation and providing patients with resistant hypertension with a new therapeutic option. To date, this technique has been evaluated only in open-label trials including small numbers of highly selected patients with suitable renal artery anatomy. The benefit/risk ratio of this technique remains to be evaluated.
a r t i c l e i n f o
a b s t r a c t
Article history: Received 7 November 2011 Accepted 28 November 2011 Available online 9 January 2012
This review aims to describe the role and the results of catheter-based renal nerve ablation for the treatment of resistant hypertension. Despite the availability of multiple classes of orally active antihypertensive treatments, resistant hypertension remains an important public health issue in 2012 due to its prevalence and association with target-organ damage and poor prognosis. The failure of purely pharmacological approaches to treat resistant hypertension has stimulated interest in invasive device-based treatments based on old concepts. In the absence of orally active antihypertensive agents, patients with severe and complicated hypertension were widely treated by surgical denervation of the kidney until the 1960s, but this approach was associated with a high incidence of severe adverse events and a high mortality rate. A new catheter system using radiofrequency energy has been developed, allowing an endovascular approach to renal denervation and providing patients with resistant hypertension with a new therapeutic option that is less invasive than surgery and can be performed rapidly under local anaesthesia. To date, this technique has been evaluated only in open-label trials including small numbers of highly selected resistant hypertensive patients with suitable renal artery anatomy. The available evidence suggests a favourable blood pressure-lowering effect in the short term (6 months) and a low incidence of immediate local and endovascular complications. This follow-up period is, however, too short for the detection of rare or late-onset adverse events. For the time being, the benefit/risk ratio of this technique remains to be evaluated, precluding its uncontrolled and widespread use in routine practice. Ó 2011 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.
Keywords: Sympathectomy Antihypertensive agents/therapeutic use Blood pressure Humans Hypertension/drug therapy Hypertension/surgery Kidney/innervation
* Corresponding author. M. Azizi, Unité d’Hypertension Artérielle et Centre d’investigations cliniques, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75908 Paris Cedex 15, France. Tel.: þ33 1 56 09 29 45. E-mail address: [email protected] (M. Azizi).
The involvement of the autonomic nervous system, including the renal sympathetic system, in particular, in the pathophysiology of arterial hypertension was recently highlighted by the publication of preliminary results for the use of catheter-based radiofrequency
1078-5884/$ e see front matter Ó 2011 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejvs.2011.11.022
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renal-nerve ablation to treat resistant hypertension.1,2 The renal autonomic nervous system comprises sympathetic efferent pathways, which run from the hypothalamic autonomic centres to the kidney via the sympathetic ganglia at D12 to L1, and afferent pathways, which originate from the kidneys and run to the autonomic centres.3,4 Both the efferent and afferent nerve fibres follow the renal artery to the kidney and lie primarily within the adventitia. The efferent renal sympathetic system plays a major role in the regulation of blood pressure (BP) by stimulating sodium reabsorption by epithelial tubular cells throughout the nephron, renin release from the juxtaglomerular cells and renal vascular smooth muscle cell contraction, decreasing renal blood flow.3 The afferent autonomic nerve fibres originating from the kidney act as mechanoreceptors or chemoreceptors sensitive to renal injury (stretching and ischaemia), but they also regulate BP by modulating posterior hypothalamic activity, thereby affecting the overall sympathetic outflow to the kidneys, heart and peripheral blood vessels. Sympathetic nervous system overdrive may cause hypertension, not only through its renal effects, but also by increasing cardiac output and peripheral arterial resistance.3 Hypertensive patients have an increased central sympathetic drive, as shown by assessments of muscle sympathetic nerve activity (MSNA).5 The norepinephrine spillover method has also been used to demonstrate the activation of sympathetic nerve outflow to the kidneys and heart. Renal norepinephrine spillover levels are also high in both normalweight patients with essential hypertension and in patients with obesity-related hypertension.3 The degree of sympathetic activation is correlated with hypertension severity and is more marked in patients with diabetes, obesity or metabolic syndrome. It has also been associated with hypertension-related target-organ damage, heart failure, chronic kidney disease and end-stage renal disease. In various rodent or dog models of hypertension, surgical denervation of the renal sympathetic nerve system has been shown to delay or to prevent the occurrence of hypertension in most cases.3 History of Surgical Renal Denervation in the Treatment of Severe and Complicated Hypertension Surgical renal denervation came to prominence as a treatment for severe and complicated hypertension at the end of the 1930s, when no orally active antihypertensive treatments were available.6 The intervention consisted of splanchnicectomy, either alone or combined with total thoracic and partial to total lumbar sympathectomy and celiac ganglionectomy.7 The procedure was particularly invasive, sometimes performed in two steps, 2 weeks apart, and perioperative mortality was high, at about 5%.8,9 Adverse events were frequent, disabling and long lasting, and included severe orthostatic hypotension, sphincter incontinence, sexual dysfunction and paradoxical excessive sweating.10 Furthermore, BP reduction was inconsistent and observed in only z50% of cases.8,9 However, in the absence of orally active antihypertensive treatments, some benefits were observed, in terms of end-organ protection and lower levels of mortality, over a period of more than 10 years.8,9 These effects were partly independent of BP reduction.9 This surgical procedure was abandoned in the 1960s, when effective and much better-tolerated orally active antihypertensive drugs became available.11 Reasons for Renewed Interest in Device-based Treatments: Resistant Hypertension Despite the development of multiple classes of antihypertensive drugs over the last 40 years, improvements in their efficacy and tolerance and the use of combination therapies, target BP is not achieved in a significant proportion of hypertensive patients. BP
control rates of 30e50% have been reported in the hypertensive population from the United States and Europe.12,13 This poor control of hypertension remains a major public health issue, because it directly influences prognosis, target-organ damage and cardio- and cerebrovascular morbidity and mortality.14 However, uncontrolled hypertension rates overestimate the prevalence of resistant hypertension. Indeed, international guidelines define resistant hypertension as a failure to reach BP goal (140 and/or 90 mmHg or 130 and/or 80 mmHg in cases of diabetes or renal insufficiency) in patients treated with an appropriate three-drug regimen, including a diuretic, with all drugs administered at optimal doses.1517 In tertiary care specialised centres, the prevalence of resistant hypertension ranges from 5% to 25% of the hypertensive patients referred.1719 The prevalence of resistant hypertension in the general population is less well known. In the NHANES study, the prevalence of resistant hypertension was z13% in treated hypertensive patients.20 However, the prevalence of resistant hypertension, as defined by office BP measurement, is probably also overestimated. Only 63% of the 8295 patients included in a Spanish registry who had resistant hypertension defined on the basis of office BP measurements had genuine resistant hypertension confirmed by 24 h-ambulatory BP monitoring (ABPM). The overall prevalence of truly resistant hypertension in this registry was thus 7%.21 The use of ABPM or home BP measurements is therefore strongly recommended, to confirm resistant hypertension and to exclude pseudo-resistance.17,18 BP control may be poor for several reasons, including a lack of adherence with treatment and clinical inertia, inadequate control of lifestyle factors, the use of other substances with potential effects on BP and the presence of undetected causes of secondary hypertension.17 Once action has been taken to detect and correct these factors, most international guidelines recommend reducing sodium intake and increasing the intensity of diuretic therapy in patients with resistant hypertension with simplification and intensification of the treatment and of follow-up in a specialist centre.1518 This strengthening of BP management is deemed necessary because resistant hypertension is associated with target-organ damage22 and poor prognosis,14 even in the short term.23 However, despite ‘optimal’ management at specialist centres, many patients continue to display resistant hypertension, even on combinations of several antihypertensive treatments. In this situation of pharmacological failure, invasive device-based treatment approaches have emerged as a new option for treatment. Recent technological progress has allowed the development of invasive approaches, such as renal denervation1,2 and the stimulation of carotid baroreceptors.24 We focus here on renal denervation. Catheter-based Renal Nerve Ablation A new catheter system has been developed, making the endovascular approach to renal denervation an attractive therapeutic option in patients with resistant hypertension. Unlike surgical approaches to renal denervation, the endovascular approach is selective. It is also less invasive and can be performed rapidly under local anaesthesia, with a limited periprocedural risk. The Symplicity Catheter SystemÒ (Medtronic-Ardian) is the only system currently available. It can be used for the selective and sequential denervation of both kidneys, through the focal delivery of four to six low-power radiofrequency energy ablations (5e8 W) along the length of both renal arteries. It consists of an automated low-power radiofrequency generator coupled to a disposable radiofrequency catheter. Prior to the procedure, appropriate systemic anticoagulation should be provided to the patient. Percutaneous femoral access under local anaesthesia is used to introduce the catheter. Selective renal artery catheterisation is
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carried out and the tip of the radiofrequency probe is then applied to the arterial wall, in a zone close to the renal hilum, under radiographic and impedance control (Fig. 1). Each renal nerve ablation sequence lasts for 2 min. At the end of each sequence, the probe is moved to a new position a few millimetres (approximately 5 mm) further back along the artery, with circumferential rotation used to ensure that the position of the probe with respect to the artery circumference is also changed between ablations. A series of four to six ablations per renal artery results in stepwise renal denervation, allowing treatment of the entire circumference of the renal artery along a helical pathway. The energy delivered by the radiofrequency impulses dissipates in the form of heat in the arterial wall, particularly in the adventitia, which houses the autonomic nerves, with blood flow cooling the intima and minimising endothelial injury. The radiofrequency impulses are automatically adjusted by the generator, which monitors the impedance, the energy delivered and the temperature. The energy released during the sequential ablations may cause visceral pain, justifying sedation/analgesia with opiates and narcotics. The intervention is technically easier than renal artery stenting. However, the interventionalist should always keep in mind that those apparently healthy renal arteries may be fragile because they have been exposed to high BP levels for a long time before denervation. There is therefore an increased risk of renal artery dissection (see below). The catheter available today is not an over-the-wire device and, therefore, should be manipulated with caution despite its relatively soft extremity. The use of a guiding catheter or a long sheath can be advocated but more caution is also deemed necessary because its extremity can be very aggressive especially when control angiograms are performed through the side port of the sheath. Permanent flushing of the side port of the sheath/ guiding catheter with heparinised saline is recommended as well as bolus injection of a nitroglycerine into each renal artery in order to reduce spasm prior to the procedure. Before renal denervation is carried out, the suitability of the patient’s renal artery anatomy should be checked, preferably by computed tomography (CT)- or magnetic resonance (MR)-angiography. The ideal anatomical conditions are as follows: presence of a single renal artery on each side, of sufficient length (20 mm) and diameter (4 mm), without stenosis, that has not previously been subjected to angioplasty or stenting and is accessible by percutaneous femoral access. Renal denervation should not be performed in the presence of a solitary functioning kidney. Ideally, the infrarenal abdominal aorta should also be free of major lesions, such as unstable atherosclerotic plaques, aneurism or dissection.
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At the end of the procedure, a global angiogram of the aorta and the renal arteries should be obtained, to check the integrity of the renal arteries (dissection) and the renal parenchyma (infarcts). Some irregularities of the renal artery wall can be observed after renal denervation which do not have pathological significance (Fig. 2). The procedure takes 30e50 min in total, depending on the anatomy of the renal arteries and the skills of the interventionalist (radiologist/cardiologist/surgeon) carrying out the intervention. The patient is then usually monitored for 24 h at the hospital. Despite its apparent simplicity, this procedure should be carried out exclusively at specialist centres. The interventionalist carrying out the intervention should have sufficient experience in the selective catheterisation and angioplasty of the renal arteries, and the necessary technical resources for the management of any immediate complication, such as renal artery dissection in particular (see below), for which stents of larger calibre than those used for coronary arteries may be required. Optimal imaging capacities are also required, as denervation requires accurate catheterisation techniques, often in obese patients. Digital radiographic images of the renal artery before and after denervation and of the kidney should be stored, to allow retrospective analysis in cases of mid- and long-term complications. The images should comprise the renal arteries and parenchyma of both sides after completion of the denervation. Clinical Studies of Radiofrequency-based Renal-nerve Ablation Two principal studies have been published on radiofrequency renal-nerve ablation in patients with resistant hypertension. The first-in-man study, the Simplicity HTN1 study, evaluated the feasibility and safety of the procedure in 50 patients and reported encouraging BP reductions, with no major complications due to the technique.2 This initial cohort was subsequently expanded to 153 patients.25 The second study, the Simplicity HTN2 study, was a multicentre, open, randomised, controlled trial comparing the antihypertensive efficacy of this procedure plus drug treatment with that of drug treatment alone, in 106 patients aged 18e85 years with a systolic BP 160 mmHg (150 mmHg in patients with type 2 diabetes) despite combination therapy with at least three antihypertensive drugs, a creatinine clearance 45 ml min1 and a renal artery anatomy suitable for this procedure (presence of two functioning kidneys with single renal artery on each side, of sufficient length (20 mm) and diameter (4 mm), without stenosis, not previously subjected to angioplasty or stenting).1 The study
Figure 1. A: The tip of the catheter is applied to the arterial wall, close to the hilum, for the first radiofrequency ablation in the right renal artery. The catheter then is pulled back by 5 mm and rotated before delivering the second radiofrequency ablation; 4e6 ablations in each individual renal artery are required for “optimal” renal denervation. B: Renal angiogram of the right renal arteries showing the tip of the catheter applied to the arterial wall.
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Figure 2. Selective angiogram of the right renal artery (left panel, after the 1st RF ablation) and final global angiogram (right panel) showing some irregularities of the renal artery wall (white arrows) after renal denervation.
included middle-aged (mean age: 58 years), overweight (mean body mass index (BMI): 31 kg m2) patients (42% women, 98% Caucasian, 34% type 2 diabetes), mostly with resistant systolic hypertension (mean systolic BP: 178/98 mmHg), 62% of whom were treated with at least five antihypertensive drugs. It should be noted that the definition of resistant hypertension in this trial was not in strict accordance with international guidelines in terms of target BP (>160 mmHg despite triple therapy vs. >140 and/or 90 mmHg despite triple therapy including diuretics) and treatment (z10% of the patients were not given diuretics and less than 20% of patients were treated with an aldosterone antagonist, which is now recommended for the treatment of resistant hypertension17,18). Moreover, ABPM was not required for the confirmation of resistant hypertension and no preliminary investigations to exclude secondary hypertension were requested. Tolerability and Safety of Radiofrequency Renal-nerve Ablation Both studies reported a low incidence of immediate periprocedural complications and short- and medium-term renal and vascular complications (at 6e12 months). Four of the 153 patients of the expanded cohort had immediate complications: one case of renal-artery dissection and three pseudo-aneurysms at the femoral artery site.25 Two patients from this cohort died during follow-up, one from myocardial infarction and the other from sudden death syndrome. An independent data monitoring and safety committee decided that these deaths could not be attributed to the denervation procedure. The significant adverse events reported in the Simplicity HTN2 study (52 procedures) were one pseudo-aneurysm at the femoral artery site and a case of post-procedural hypotension reversed by decreasing the intensity of antihypertensive treatment.1 No orthostatic hypotension was reported and the cardiopulmonary response to exercise was maintained after renal denervation.26 A non-fatal cardio/cerebrovascular event occurred in four of the patients undergoing renal denervation and three patients in the control group. Finally, no significant change in mean
glomerular filtration rate was observed at months, consistent with stable renal function. The overall incidence of early adverse events related to the procedure was 3.5%, based on the combined safety data for the two studies (205 patients, 18 of whom had a maximal follow-up period of 24 months). Radiofrequency ablation is also associated with a theoretical long-term risk of fibrotic scarring that may favour the development of focal renal artery stenoses or aneurysm. Preclinical safety studies in pigs have shown treatment-related renal nerve injury and focal medial and adventitial fibrosis of the renal arteries, associated with minimal intimal thickening and disruption of the internal elastic lamina, and complete re-endothelialisation, with no inflammatory cells, renal artery stenosis or thrombosis, 6 months after renal denervation.27 In 18 patients from the Simplicity HTN1 study, a renal angiogram performed 14e30 days after renal denervation revealed a total absence of renal artery lesions. Imaging of the renal arteries 6 months after the intervention, mostly by renal artery duplex scanning, was available in 43 of 52 patients in the Simplicity HTN2 study and 81 of 153 patients of the extended cohort study; it showed an absence of renal artery lesions.1,25 The progression of underlying atherosclerotic stenosis was observed in one patient after denervation, but did not require treatment.1 In summary, these safety data are reassuring, but they were generated from a small number of procedures performed by expert interventionalists on highly selected patients at specialist reference centres. They do not exclude the possibility of rare (incidence <5%) but serious adverse events, particularly in routine practice. The risk associated with the procedure depends largely on the careful selection of patients eligible for renal denervation and the experience of the interventionalist carrying out the intervention, as already reported for carotid stenting.28 Effect of Radiofrequency Nerve Ablation on Office BP In the Simplicity HTN2 trial, a progressive decrease in office systolic/diastolic BP of 32/12 mmHg was observed at 6 months in 49 of the 52 patients who underwent renal denervation, whereas BP did
Table 1 Blood pressure decrease at 6 months in the two groups of the randomized controlled Symplicity HTN2 trial.1 Results are reported in mmHg, as the mean standard deviation.
Office blood pressure measurements Self blood pressure measurements 24 h ABPMa a
AMBP: ambulatory blood pressure measurements.
With denervation (n ¼ 52)
Without denervation (n ¼ 54)
p
32 23/12 11 (n ¼ 49) 20 17/12 11 (n ¼ 32) 11 15/7 11 (n ¼ 20)
þ1 21/0 10 (n ¼ 51) 2 13/0 7 (n ¼ 40) 3 19/1 12 (n ¼ 25)
<0.0001/<0.0001 <0.0001/<0.0001 <0.006/<0.014
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One out of four antihypertensive drugs was stopped because of hypotension
Teletransmitted home BP (mmHg)
Renal denervation 200
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effective, they also indicate that the procedure only partially reduces total sympathetic activity.
180
Critical Appraisal of Published Studies
160
Published studies are subject to several limitations inherent to their open-label design, potentially jeopardising their internal validity and decreasing the degree of BP reduction we can expect to be achieved.32 Indeed, an open-label design is subject to expectation, performance and evaluation biases, particularly in trials evaluating the efficacy of an invasive procedure, such as renal denervation. Furthermore, the evaluation of the BP effect of renal denervation was based on office BP measurement, a primary outcome that may be subject to observer bias. Such biases cannot be ruled out even for the Simplicity HTN2 randomised controlled trial, because the antihypertensive treatment regimen was not standardised, compliance with treatment was not checked during the study and the primary outcome (office BP measurement) was not evaluated blind to treatment allocation. Therefore, active cointerventions (either intentional or non-intentional) and outpatient visits may have been more frequent, and compliance with treatment, dietary and a healthy lifestyle may have been more strongly encouraged by study staff, family members or selfmotivation in patients undergoing renal denervation than in the patients of the control group. Conversely, patients randomised to the control group may have been disappointed with the continuing lack of improvement in BP control and with not being offered ‘the new intervention’. As these patients were aware that they could potentially undergo renal denervation if their BP remained high at 6 months, they may have been reluctant to comply strictly with their antihypertensive treatment regimen and with lifestyle measures, to ensure that they received ‘the new treatment’. Moreover, observer bias may also have influenced office BP measurements in opposite directions in the two randomised groups. An investigator expecting renal denervation to be effective may have been inclined to measure BP differently in the two groups: for example, the resting period before office BP measurements and the number of BP measurements taken may not have been the same in the two groups. Finally, those involved in data analysis were not blind to treatment assignment. All these factors may partly account for the large difference in office BP between the two groups in the Simplicity HTN2 trial, the absence of a decrease in office BP in the control group at 6 months and the large discrepancy between the ambulatory and office BP results. As expected, the BPlowering effects of renal denervation, as assessed by ABPM or selfmeasurement at home, were smaller than those evaluated by office BP measurement. The mean decrease in ambulatory systolic BP in the 20 of the 52 patients with valid 24-h ABPM measurements before and 6 months after renal denervation was only 11 mmHg, much smaller than the 32 mmHg decrease in office systolic BP (Table 1). Furthermore, the difference in 24-h ambulatory BP between the two groups was only 8 mmHg, an effect similar to that expected for the addition of a single antihypertensive agent. ABPM is devoid of the white coat effect, observer bias, digit preference and placebo effect, and provides more reproducible measurements than office BP measurements. It is now the cornerstone of determinations of the antihypertensive efficacy of new drugs, as recommended by international health authorities (United States Food and Drug Administration and European Medicines Agency). Unfortunately, this method was not available to all patients of the Simplicity HTN2 trial. The mean decrease in BP reported in the Simplicity HNT2 study conceals considerable heterogeneity in individual BP responses to renal-nerve ablation, as shown by the large standard deviations of 23 and 15 mmHg associated with the decreases in office and 24-h
140 120 100 80 60 -20
-10
0
10
20
30
40
50
60
70
80
90
Days Figure 3. Teletransmitted home blood pressure (BP) monitoring in a patient treated by renal denervation. The patient had severe hypertension before renal artery denervation, despite being treated with four antihypertensive drugs. The immediate decrease in BP on day 2 after renal denervation (day 0) is of multifactorial origin (36-h bed rest in hospital, contrast injection, sedation, etc.) and is probably not due to the procedure itself. When the patient returned at home, the BP decrease after renal denervation was progressive over 60 days. Symptomatic hypotension occurred around day 65 which imposed to stop one among four antihypertensive treatments. After 3 months, BP level was stabilized at around 130/85 mmHg with a triple antihypertensive therapy. The dotted line shows the BP threshold for uncontrolled hypertension using home BP monitoring (systolic BP > 135 mmHg and/or diastolic BP > 85 mmHg).
not change in 51 of the 54 patients of the control group (1/0 mmHg, Table 1).1 Fig. 3 shows an example of the progressive BP decrease achieved after renal denervation in one patient. The goal systolic BP (<140 mmHg) was reached at 6 months in 39% of the patients in the renal denervation group and 6% of the patients in the control group (p < 0.001). Moreover, 84% of the patients undergoing renal denervation displayed a decrease in systolic BP of at least 10 mm Hg, whereas such a decrease was observed in only 35% of the controls (p < 0.001). Antihypertensive medication was increased during follow-up in four (8%) of the patients undergoing renal denervation and six (12%) of the control patients (p ¼ 0.74). Conversely, antihypertensive medication was decreased in 10 (20%) of the patients undergoing renal denervation and three (6%) of the control patients (p ¼ 0.04). Overall, the percentage of favourable responses attributable to radiofrequency renal nerve ablation was 50%, a figure close to the percentage of responders to surgical sympathetic denervation. Finally, it should be noted that no BP-lowering effects of renal denervation were observed in 10% of patients and antihypertensive medication was never completely stopped in any of the patients. The mechanism of BP reduction by renal denervation has been investigated by muscle sympathetic nerve activity (MSNA) or norepinephrine spillover measurements. In one patient, postganglionic nerve trafficking, as measured by peroneal nerve microneurography, was found to have decreased 1 month after renal denervation and normalised after 1 year, with an improvement in baroreflex sensitivity.29 An improvement of baroreflex sensitivity was also reported in our case series based on a different methodology.30 Renal norepinephrine spillover had decreased by 50%, 15e30 days after renal denervation, in 10 patients in the pilot study. This decrease was associated with a 30% decrease in total body norepinephrine spillover, one-third of which was attributable to a decrease in renal sympathetic activity.31 This effect can probably be accounted for by the ablation of afferent nerve fibres from the kidney, preventing the stimulation of autonomic centres. However, although these data confirm that renal denervation is
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ambulatory systolic BP. This variability is also highlighted by goal office systolic BP being reached in only 39% of the patients and the complete absence of a BP response in 10% of patients. This lack of response may be due to (1) a primary failure of renal denervation, as no imaging or functional marker of the success of this intervention is currently available and/or (2) the multifactorial and complex origin of hypertension and resistance to treatment. Indeed, total and renal sympathetic overactivity may not be the predominant pathogenic factor underlying hypertension and accounting for treatment resistance in an unknown number of patients. Thus, catheter-based renal denervation is not beneficial but is nonetheless associated with potential risks in at least 10% of patients. Unfortunately, no specific factor predictive of the BP response to renal denervation has been identified from the variables considered: age, sex, previous coronary events, diabetes, dyslipidemia, BP or resting heart rate, number of classes of antihypertensive drugs taken, glomerular filtration rate and number of radiofrequency ablations. In the extended cohort study, multivariate analysis showed that a higher basal BP (as expected) and the use of centrally acting antihypertensive agents were significantly associated with better office BP responses.25 Another issue concerns the unknown long-term antihypertensive efficacy of renal denervation. Past experience with surgical renal denervation shows that BP reduction may be maintained over time,8,9 but it is difficult to extrapolate this finding to radiofrequency renal-nerve ablation. Indeed, radiofrequency renalnerve ablation is more selective and, therefore, by definition, less complete. The conservation of anatomical connections makes sympathetic reinnervation possible, a phenomenon that has been documented following renal transplantation.33 However, although the regeneration of efferent renal-nerve fibres with reinnervation of the kidney is well recognised, there is little evidence for the regeneration of afferent nerve fibres in the kidney. This may account for the sustained, long-term BP reduction reported in a small subgroup of patients (23/11 mmHg for office systolic/ diastolic BP at 12 months in 64 patients and 32/14 mmHg at 24 months for 18 patients of the expanded cohort25). These data, which do not take the number of antihypertensive drug used into account, are subject to the same biases as mentioned above. Finally, the external validity of the studies may also be limited because they included a small sample of highly selected patients. In the Simplicity HTN2 study, z45% of the patients who agreed to participate were excluded before randomisation because of white coat resistance and unsuitable renal artery anatomy precluding renal denervation in almost 20% of patients. In addition, the characteristics of the patients e obese, Caucasian patients with resistant hypertension despite treatment with z5 antihypertensive drugs, a glomerular filtration rate >45 ml min1 and a suitable renal artery anatomy e make it difficult to extrapolate the results to the general population of patients with resistant hypertension. For example, obese patients may be more responsive to renal denervation than lean patients, because the pathophysiology of obesity-associated hypertension involves hyperactivity of the sympathetic nervous system, particularly in patients with obstructive sleep apnea syndrome.34,35 Research Perspectives and Clinical Applications Radiofrequency renal-nerve ablation opens up several new possibilities for treatment.32 Various studies are already underway for indications other than resistant hypertension, including metabolic syndrome, heart failure, sleep apnea syndrome, renal insufficiency and diabetic nephropathy. For example, preliminary results have suggested that renal denervation may have a beneficial effect on insulin resistance and sleep apnea syndrome.36,37 Furthermore, new catheter systems will emerge for the renal denervation by
different methodologies, and these systems will have to go through the same evaluation process. Systematic evaluation of the benefit/ risk ratio of the procedure is considered necessary for each category of patients, including those with resistant hypertension. Radiofrequency renal-nerve ablation should therefore still be considered to be in the evaluation process.38 In this context, there are strong arguments against the widespread and uncontrolled use of this procedure in routine practice: an unknown benefit/risk ratio for the treatment of resistant hypertension, inconsistency and unpredictability of the BP response, absence of medical economic evaluation, higher risk when renal denervation is performed by interventionalists less skilled at patient selection and performance of the procedure. Finally, prolonged follow-up of these patients, including non-invasive imaging (preferably MR-angiograms to avoid excess irradiation due to repeated CT-scanners), is essential to assess the long-term adverse effects of renal denervation by radiofrequency energy ablation in healthy renal arteries. To emphasise this point, the release of a new antihypertensive drug onto the market requires testing on several thousands of patients over several months, followed by continuous and indefinite post-release surveillance. The best way to ensure the rigorous follow-up of patients after renal denervation would therefore be to include them in clinical trials or international registries. Funding and Conflict of Interest The authors were involved in the Simplicity HTN2 trial sponsored by ARDIAN Inc. References 1 Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Bohm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 2010;376:1903e9. 2 Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 2009;373:1275e81. 3 DiBona GF, Esler M. Translational medicine: the antihypertensive effect of renal denervation. Am J Physiol Regul Integr Comp Physiol 2010;298:R245e53. 4 Schlaich MP, Sobotka PA, Krum H, Whitbourn R, Walton A, Esler MD. Renal denervation as a therapeutic approach for hypertension: novel implications for an old concept. Hypertension 2009;54:1195e201. 5 Smith PA, Graham LN, Mackintosh AF, Stoker JB, Mary DA. Relationship between central sympathetic activity and stages of human hypertension. Am J Hypertens 2004;17:217e22. 6 Page IH, Heuer GJ. A surgical treatment of essential hypertension. J Clin Invest 1935;14:22e6. 7 Grimson KS, Orgain ES, Anderson B, D’Angelo GJ. Total thoracic and partial to total lumbar sympathectomy, splanchnicectomy and celiac ganglionectomy for hypertension. Ann Surg 1953;138:532e47. 8 Peet MM. Hypertension and its surgical treatment by bilateral supradiaphragmatic splanchnicectomy. Am J Surg 1948;75:48e68. 9 Smithwick RH, Thompson JE. Splanchnicectomy for essential hypertension; results in 1266 cases. J Am Med Assoc 1953;152:1501e4. 10 Doumas M, Faselis C, Papademetriou V. Renal sympathetic denervation and systemic hypertension. Am J Cardiol 2010;105:570e6. 11 VA Trial. Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mmHg. J Am Med Assoc 1967;202:1028e34. 12 Egan BM, Zhao Y, Axon RN. US trends in prevalence, awareness, treatment, and control of hypertension, 1988e2008. J Am Med Assoc 2010;303:2043e50. 13 Prugger C, Keil U, Wellmann J, de Bacquer D, de Backer G, Ambrosio GB, et al. Blood pressure control and knowledge of target blood pressure in coronary patients across Europe: results from the EUROASPIRE III survey. J Hypertens 2011;29:1641e8. 14 Boutitie F, Gueyffier F, Pocock S, Fagard R, Boissel JP. J-shaped relationship between blood pressure and mortality in hypertensive patients: new insights from a meta-analysis of individual-patient data. Ann Intern Med 2002;136:438e48. 15 Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo Jr JL, et al. Seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 2003;42:1206e52. 16 Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, et al. 2007 ESH-ESC practice guidelines for the management of arterial hypertension:
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ESH-ESC task force on the management of arterial hypertension. J Hypertens 2007;25:1751e62. Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, et al. Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American heart association professional education committee of the council for high blood pressure research. Hypertension 2008;51:1403e19. Sarafidis PA, Bakris GL. Resistant hypertension: an overview of evaluation and treatment. J Am Coll Cardiol 2008;52:1749e57. Frank M, Bobrie G, Azizi M, Peyrard S, Plouin PF. Clinical profile of patients referred to a tertiary hypertension unit in a city area. J Hypertens 2010:28. e264. Persell SD. Prevalence of resistant hypertension in the United States, 2003e2008. Hypertension 2011;57:1076e80. de la Sierra A, Segura J, Banegas JR, Gorostidi M, de la Cruz JJ, Armario P, et al. Clinical features of 8295 patients with resistant hypertension classified on the basis of ambulatory blood pressure monitoring. Hypertension 2011;57:898e902. Cuspidi C, Macca G, Sampieri L, Michev I, Salerno M, Fusi V, et al. High prevalence of cardiac and extracardiac target organ damage in refractory hypertension. J Hypertens 2001;19:2063e70. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004;363:2022e31. Scheffers IJ, Kroon AA, Schmidli J, Jordan J, Tordoir JJ, Mohaupt MG, et al. Novel baroreflex activation therapy in resistant hypertension: results of a European multi-center feasibility study. J Am Coll Cardiol 2010;56:1254e8. Symplicity HTN-1 Investigators. Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months. Hypertension 2011;57:911e7. Ukena C, Mahfoud F, Kindermann I, Barth C, Lenski M, Kindermann M, et al. Cardiorespiratory response to exercise after renal sympathetic denervation in patients with resistant hypertension. J Am Coll Cardiol 2011;58:1176e82. Rippy MK, Zarins D, Barman NC, Wu A, Duncan KL, Zarins CK. Catheter-based renal sympathetic denervation: chronic preclinical evidence for renal artery safety. Clin Res Cardiol 2011;100:1095e101.
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28 Nallamothu BK, Gurm HS, Ting HH, Goodney PP, Rogers MA, Curtis JP, et al. Operator experience and carotid stenting outcomes in Medicare beneficiaries. Jama 2011;306:1338e43. 29 Schlaich MP, Sobotka PA, Krum H, Lambert E, Esler MD. Renal sympatheticnerve ablation for uncontrolled hypertension. N Engl J Med 2009;361:932e4. 30 Baudrie V, Frank M, Steichen O, Elghozi J-L, Sapoval M, Bobrie G, et al. Influence of renal artery denervation on blood pressure variability and baroreflex sensitivity: a prospective consecutive case-series. J Hypertens 2011:29. e50. 31 Esler M, Schlaich M, Sobotka P, Whitbourn R, Sadowski J, Bartus K, et al. Catheter-based renal denervation reduces total body and renal noradrenaline spillover and blood pressure in resistant hypertension. J Hypertens 2009;27. S167. 32 Doumas M, Douma S. Renal sympathetic denervation: the jury is still out. Lancet 2010;376:1878e80. 33 DiBona GF. Renal innervation and denervation: lessons from renal transplantation reconsidered. Artif Organs 1987;11:457e62. 34 Kotchen TA. Obesity-related hypertension: epidemiology, pathophysiology, and clinical management. Am J Hypertens 2011;23:1170e8. 35 Somers VK, White DP, Amin R, Abraham WT, Costa F, Culebras A, et al. Sleep apnea and cardiovascular disease: an American heart Association/ American College of Cardiology Foundation scientific statement from the American heart association Council for high blood pressure Research Professional Education committee, Council on clinical Cardiology, Stroke Council, and Council on cardiovascular Nursing. J Am Coll Cardiol 2008;52:686e717. 36 Mahfoud F, Schlaich M, Kindermann I, Ukena C, Cremers B, Brandt MC, et al. Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertension: a pilot study. Circulation 2011;123:1940e6. 37 Witkowski A, Prejbisz A, Florczak E, Kadziela J, Sliwinski P, Bielen P, et al. Effects of renal sympathetic denervation on blood pressure, sleep apnea course, and glycemic control in patients with resistant hypertension and sleep apnea. Hypertension 2011;58:559e65. 38 Barkun JS, Aronson JK, Feldman LS, Maddern GJ, Strasberg SM, Altman DG, et al. Evaluation and stages of surgical innovations. Lancet 2009;374:1089e96.
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Review
Catheter-based Radiofrequency Renal-nerve Ablation in Patients with Resistant Hypertension M. Azizi a, b, c, *, O. Steichen d, e, M. Frank c, G. Bobrie b, P.-F. Plouin a, b, M. Sapoval a, f a
Université Paris-Descartes, Faculté de Médecine, F-75006 Paris, France Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Unité d’Hypertension Artérielle, F-75015 Paris, France c INSERM, CIC 9201, Paris, France d Université Pierre et Marie Curie e Paris 6, Faculté de Médecine, F-75006 Paris, France e Assistance Publique Hôpitaux de Paris, Hôpital Tenon, Service de Médecine Interne, F-75020 Paris, France f Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Radiologie Cardiovasculaire, Paris, France b
WHAT THIS PAPER ADDS Despite the availability of multiple classes of orally active antihypertensive treatments, resistant hypertension remains an important public health issue in 2012. The failure of purely pharmacological approaches to treat resistant hypertension has stimulated interest in invasive device-based treatments. A new catheter system using radiofrequency energy has been developed, allowing an endovascular approach to renal denervation and providing patients with resistant hypertension with a new therapeutic option. To date, this technique has been evaluated only in open-label trials including small numbers of highly selected patients with suitable renal artery anatomy. The benefit/risk ratio of this technique remains to be evaluated.
a r t i c l e i n f o
a b s t r a c t
Article history: Received 7 November 2011 Accepted 28 November 2011 Available online 9 January 2012
This review aims to describe the role and the results of catheter-based renal nerve ablation for the treatment of resistant hypertension. Despite the availability of multiple classes of orally active antihypertensive treatments, resistant hypertension remains an important public health issue in 2012 due to its prevalence and association with target-organ damage and poor prognosis. The failure of purely pharmacological approaches to treat resistant hypertension has stimulated interest in invasive device-based treatments based on old concepts. In the absence of orally active antihypertensive agents, patients with severe and complicated hypertension were widely treated by surgical denervation of the kidney until the 1960s, but this approach was associated with a high incidence of severe adverse events and a high mortality rate. A new catheter system using radiofrequency energy has been developed, allowing an endovascular approach to renal denervation and providing patients with resistant hypertension with a new therapeutic option that is less invasive than surgery and can be performed rapidly under local anaesthesia. To date, this technique has been evaluated only in open-label trials including small numbers of highly selected resistant hypertensive patients with suitable renal artery anatomy. The available evidence suggests a favourable blood pressure-lowering effect in the short term (6 months) and a low incidence of immediate local and endovascular complications. This follow-up period is, however, too short for the detection of rare or late-onset adverse events. For the time being, the benefit/risk ratio of this technique remains to be evaluated, precluding its uncontrolled and widespread use in routine practice. Ó 2011 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.
Keywords: Sympathectomy Antihypertensive agents/therapeutic use Blood pressure Humans Hypertension/drug therapy Hypertension/surgery Kidney/innervation
* Corresponding author. M. Azizi, Unité d’Hypertension Artérielle et Centre d’investigations cliniques, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75908 Paris Cedex 15, France. Tel.: þ33 1 56 09 29 45. E-mail address: [email protected] (M. Azizi).
The involvement of the autonomic nervous system, including the renal sympathetic system, in particular, in the pathophysiology of arterial hypertension was recently highlighted by the publication of preliminary results for the use of catheter-based radiofrequency
1078-5884/$ e see front matter Ó 2011 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejvs.2011.11.022
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renal-nerve ablation to treat resistant hypertension.1,2 The renal autonomic nervous system comprises sympathetic efferent pathways, which run from the hypothalamic autonomic centres to the kidney via the sympathetic ganglia at D12 to L1, and afferent pathways, which originate from the kidneys and run to the autonomic centres.3,4 Both the efferent and afferent nerve fibres follow the renal artery to the kidney and lie primarily within the adventitia. The efferent renal sympathetic system plays a major role in the regulation of blood pressure (BP) by stimulating sodium reabsorption by epithelial tubular cells throughout the nephron, renin release from the juxtaglomerular cells and renal vascular smooth muscle cell contraction, decreasing renal blood flow.3 The afferent autonomic nerve fibres originating from the kidney act as mechanoreceptors or chemoreceptors sensitive to renal injury (stretching and ischaemia), but they also regulate BP by modulating posterior hypothalamic activity, thereby affecting the overall sympathetic outflow to the kidneys, heart and peripheral blood vessels. Sympathetic nervous system overdrive may cause hypertension, not only through its renal effects, but also by increasing cardiac output and peripheral arterial resistance.3 Hypertensive patients have an increased central sympathetic drive, as shown by assessments of muscle sympathetic nerve activity (MSNA).5 The norepinephrine spillover method has also been used to demonstrate the activation of sympathetic nerve outflow to the kidneys and heart. Renal norepinephrine spillover levels are also high in both normalweight patients with essential hypertension and in patients with obesity-related hypertension.3 The degree of sympathetic activation is correlated with hypertension severity and is more marked in patients with diabetes, obesity or metabolic syndrome. It has also been associated with hypertension-related target-organ damage, heart failure, chronic kidney disease and end-stage renal disease. In various rodent or dog models of hypertension, surgical denervation of the renal sympathetic nerve system has been shown to delay or to prevent the occurrence of hypertension in most cases.3 History of Surgical Renal Denervation in the Treatment of Severe and Complicated Hypertension Surgical renal denervation came to prominence as a treatment for severe and complicated hypertension at the end of the 1930s, when no orally active antihypertensive treatments were available.6 The intervention consisted of splanchnicectomy, either alone or combined with total thoracic and partial to total lumbar sympathectomy and celiac ganglionectomy.7 The procedure was particularly invasive, sometimes performed in two steps, 2 weeks apart, and perioperative mortality was high, at about 5%.8,9 Adverse events were frequent, disabling and long lasting, and included severe orthostatic hypotension, sphincter incontinence, sexual dysfunction and paradoxical excessive sweating.10 Furthermore, BP reduction was inconsistent and observed in only z50% of cases.8,9 However, in the absence of orally active antihypertensive treatments, some benefits were observed, in terms of end-organ protection and lower levels of mortality, over a period of more than 10 years.8,9 These effects were partly independent of BP reduction.9 This surgical procedure was abandoned in the 1960s, when effective and much better-tolerated orally active antihypertensive drugs became available.11 Reasons for Renewed Interest in Device-based Treatments: Resistant Hypertension Despite the development of multiple classes of antihypertensive drugs over the last 40 years, improvements in their efficacy and tolerance and the use of combination therapies, target BP is not achieved in a significant proportion of hypertensive patients. BP
control rates of 30e50% have been reported in the hypertensive population from the United States and Europe.12,13 This poor control of hypertension remains a major public health issue, because it directly influences prognosis, target-organ damage and cardio- and cerebrovascular morbidity and mortality.14 However, uncontrolled hypertension rates overestimate the prevalence of resistant hypertension. Indeed, international guidelines define resistant hypertension as a failure to reach BP goal (140 and/or 90 mmHg or 130 and/or 80 mmHg in cases of diabetes or renal insufficiency) in patients treated with an appropriate three-drug regimen, including a diuretic, with all drugs administered at optimal doses.1517 In tertiary care specialised centres, the prevalence of resistant hypertension ranges from 5% to 25% of the hypertensive patients referred.1719 The prevalence of resistant hypertension in the general population is less well known. In the NHANES study, the prevalence of resistant hypertension was z13% in treated hypertensive patients.20 However, the prevalence of resistant hypertension, as defined by office BP measurement, is probably also overestimated. Only 63% of the 8295 patients included in a Spanish registry who had resistant hypertension defined on the basis of office BP measurements had genuine resistant hypertension confirmed by 24 h-ambulatory BP monitoring (ABPM). The overall prevalence of truly resistant hypertension in this registry was thus 7%.21 The use of ABPM or home BP measurements is therefore strongly recommended, to confirm resistant hypertension and to exclude pseudo-resistance.17,18 BP control may be poor for several reasons, including a lack of adherence with treatment and clinical inertia, inadequate control of lifestyle factors, the use of other substances with potential effects on BP and the presence of undetected causes of secondary hypertension.17 Once action has been taken to detect and correct these factors, most international guidelines recommend reducing sodium intake and increasing the intensity of diuretic therapy in patients with resistant hypertension with simplification and intensification of the treatment and of follow-up in a specialist centre.1518 This strengthening of BP management is deemed necessary because resistant hypertension is associated with target-organ damage22 and poor prognosis,14 even in the short term.23 However, despite ‘optimal’ management at specialist centres, many patients continue to display resistant hypertension, even on combinations of several antihypertensive treatments. In this situation of pharmacological failure, invasive device-based treatment approaches have emerged as a new option for treatment. Recent technological progress has allowed the development of invasive approaches, such as renal denervation1,2 and the stimulation of carotid baroreceptors.24 We focus here on renal denervation. Catheter-based Renal Nerve Ablation A new catheter system has been developed, making the endovascular approach to renal denervation an attractive therapeutic option in patients with resistant hypertension. Unlike surgical approaches to renal denervation, the endovascular approach is selective. It is also less invasive and can be performed rapidly under local anaesthesia, with a limited periprocedural risk. The Symplicity Catheter SystemÒ (Medtronic-Ardian) is the only system currently available. It can be used for the selective and sequential denervation of both kidneys, through the focal delivery of four to six low-power radiofrequency energy ablations (5e8 W) along the length of both renal arteries. It consists of an automated low-power radiofrequency generator coupled to a disposable radiofrequency catheter. Prior to the procedure, appropriate systemic anticoagulation should be provided to the patient. Percutaneous femoral access under local anaesthesia is used to introduce the catheter. Selective renal artery catheterisation is
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carried out and the tip of the radiofrequency probe is then applied to the arterial wall, in a zone close to the renal hilum, under radiographic and impedance control (Fig. 1). Each renal nerve ablation sequence lasts for 2 min. At the end of each sequence, the probe is moved to a new position a few millimetres (approximately 5 mm) further back along the artery, with circumferential rotation used to ensure that the position of the probe with respect to the artery circumference is also changed between ablations. A series of four to six ablations per renal artery results in stepwise renal denervation, allowing treatment of the entire circumference of the renal artery along a helical pathway. The energy delivered by the radiofrequency impulses dissipates in the form of heat in the arterial wall, particularly in the adventitia, which houses the autonomic nerves, with blood flow cooling the intima and minimising endothelial injury. The radiofrequency impulses are automatically adjusted by the generator, which monitors the impedance, the energy delivered and the temperature. The energy released during the sequential ablations may cause visceral pain, justifying sedation/analgesia with opiates and narcotics. The intervention is technically easier than renal artery stenting. However, the interventionalist should always keep in mind that those apparently healthy renal arteries may be fragile because they have been exposed to high BP levels for a long time before denervation. There is therefore an increased risk of renal artery dissection (see below). The catheter available today is not an over-the-wire device and, therefore, should be manipulated with caution despite its relatively soft extremity. The use of a guiding catheter or a long sheath can be advocated but more caution is also deemed necessary because its extremity can be very aggressive especially when control angiograms are performed through the side port of the sheath. Permanent flushing of the side port of the sheath/ guiding catheter with heparinised saline is recommended as well as bolus injection of a nitroglycerine into each renal artery in order to reduce spasm prior to the procedure. Before renal denervation is carried out, the suitability of the patient’s renal artery anatomy should be checked, preferably by computed tomography (CT)- or magnetic resonance (MR)-angiography. The ideal anatomical conditions are as follows: presence of a single renal artery on each side, of sufficient length (20 mm) and diameter (4 mm), without stenosis, that has not previously been subjected to angioplasty or stenting and is accessible by percutaneous femoral access. Renal denervation should not be performed in the presence of a solitary functioning kidney. Ideally, the infrarenal abdominal aorta should also be free of major lesions, such as unstable atherosclerotic plaques, aneurism or dissection.
295
At the end of the procedure, a global angiogram of the aorta and the renal arteries should be obtained, to check the integrity of the renal arteries (dissection) and the renal parenchyma (infarcts). Some irregularities of the renal artery wall can be observed after renal denervation which do not have pathological significance (Fig. 2). The procedure takes 30e50 min in total, depending on the anatomy of the renal arteries and the skills of the interventionalist (radiologist/cardiologist/surgeon) carrying out the intervention. The patient is then usually monitored for 24 h at the hospital. Despite its apparent simplicity, this procedure should be carried out exclusively at specialist centres. The interventionalist carrying out the intervention should have sufficient experience in the selective catheterisation and angioplasty of the renal arteries, and the necessary technical resources for the management of any immediate complication, such as renal artery dissection in particular (see below), for which stents of larger calibre than those used for coronary arteries may be required. Optimal imaging capacities are also required, as denervation requires accurate catheterisation techniques, often in obese patients. Digital radiographic images of the renal artery before and after denervation and of the kidney should be stored, to allow retrospective analysis in cases of mid- and long-term complications. The images should comprise the renal arteries and parenchyma of both sides after completion of the denervation. Clinical Studies of Radiofrequency-based Renal-nerve Ablation Two principal studies have been published on radiofrequency renal-nerve ablation in patients with resistant hypertension. The first-in-man study, the Simplicity HTN1 study, evaluated the feasibility and safety of the procedure in 50 patients and reported encouraging BP reductions, with no major complications due to the technique.2 This initial cohort was subsequently expanded to 153 patients.25 The second study, the Simplicity HTN2 study, was a multicentre, open, randomised, controlled trial comparing the antihypertensive efficacy of this procedure plus drug treatment with that of drug treatment alone, in 106 patients aged 18e85 years with a systolic BP 160 mmHg (150 mmHg in patients with type 2 diabetes) despite combination therapy with at least three antihypertensive drugs, a creatinine clearance 45 ml min1 and a renal artery anatomy suitable for this procedure (presence of two functioning kidneys with single renal artery on each side, of sufficient length (20 mm) and diameter (4 mm), without stenosis, not previously subjected to angioplasty or stenting).1 The study
Figure 1. A: The tip of the catheter is applied to the arterial wall, close to the hilum, for the first radiofrequency ablation in the right renal artery. The catheter then is pulled back by 5 mm and rotated before delivering the second radiofrequency ablation; 4e6 ablations in each individual renal artery are required for “optimal” renal denervation. B: Renal angiogram of the right renal arteries showing the tip of the catheter applied to the arterial wall.
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Figure 2. Selective angiogram of the right renal artery (left panel, after the 1st RF ablation) and final global angiogram (right panel) showing some irregularities of the renal artery wall (white arrows) after renal denervation.
included middle-aged (mean age: 58 years), overweight (mean body mass index (BMI): 31 kg m2) patients (42% women, 98% Caucasian, 34% type 2 diabetes), mostly with resistant systolic hypertension (mean systolic BP: 178/98 mmHg), 62% of whom were treated with at least five antihypertensive drugs. It should be noted that the definition of resistant hypertension in this trial was not in strict accordance with international guidelines in terms of target BP (>160 mmHg despite triple therapy vs. >140 and/or 90 mmHg despite triple therapy including diuretics) and treatment (z10% of the patients were not given diuretics and less than 20% of patients were treated with an aldosterone antagonist, which is now recommended for the treatment of resistant hypertension17,18). Moreover, ABPM was not required for the confirmation of resistant hypertension and no preliminary investigations to exclude secondary hypertension were requested. Tolerability and Safety of Radiofrequency Renal-nerve Ablation Both studies reported a low incidence of immediate periprocedural complications and short- and medium-term renal and vascular complications (at 6e12 months). Four of the 153 patients of the expanded cohort had immediate complications: one case of renal-artery dissection and three pseudo-aneurysms at the femoral artery site.25 Two patients from this cohort died during follow-up, one from myocardial infarction and the other from sudden death syndrome. An independent data monitoring and safety committee decided that these deaths could not be attributed to the denervation procedure. The significant adverse events reported in the Simplicity HTN2 study (52 procedures) were one pseudo-aneurysm at the femoral artery site and a case of post-procedural hypotension reversed by decreasing the intensity of antihypertensive treatment.1 No orthostatic hypotension was reported and the cardiopulmonary response to exercise was maintained after renal denervation.26 A non-fatal cardio/cerebrovascular event occurred in four of the patients undergoing renal denervation and three patients in the control group. Finally, no significant change in mean
glomerular filtration rate was observed at months, consistent with stable renal function. The overall incidence of early adverse events related to the procedure was 3.5%, based on the combined safety data for the two studies (205 patients, 18 of whom had a maximal follow-up period of 24 months). Radiofrequency ablation is also associated with a theoretical long-term risk of fibrotic scarring that may favour the development of focal renal artery stenoses or aneurysm. Preclinical safety studies in pigs have shown treatment-related renal nerve injury and focal medial and adventitial fibrosis of the renal arteries, associated with minimal intimal thickening and disruption of the internal elastic lamina, and complete re-endothelialisation, with no inflammatory cells, renal artery stenosis or thrombosis, 6 months after renal denervation.27 In 18 patients from the Simplicity HTN1 study, a renal angiogram performed 14e30 days after renal denervation revealed a total absence of renal artery lesions. Imaging of the renal arteries 6 months after the intervention, mostly by renal artery duplex scanning, was available in 43 of 52 patients in the Simplicity HTN2 study and 81 of 153 patients of the extended cohort study; it showed an absence of renal artery lesions.1,25 The progression of underlying atherosclerotic stenosis was observed in one patient after denervation, but did not require treatment.1 In summary, these safety data are reassuring, but they were generated from a small number of procedures performed by expert interventionalists on highly selected patients at specialist reference centres. They do not exclude the possibility of rare (incidence <5%) but serious adverse events, particularly in routine practice. The risk associated with the procedure depends largely on the careful selection of patients eligible for renal denervation and the experience of the interventionalist carrying out the intervention, as already reported for carotid stenting.28 Effect of Radiofrequency Nerve Ablation on Office BP In the Simplicity HTN2 trial, a progressive decrease in office systolic/diastolic BP of 32/12 mmHg was observed at 6 months in 49 of the 52 patients who underwent renal denervation, whereas BP did
Table 1 Blood pressure decrease at 6 months in the two groups of the randomized controlled Symplicity HTN2 trial.1 Results are reported in mmHg, as the mean standard deviation.
Office blood pressure measurements Self blood pressure measurements 24 h ABPMa a
AMBP: ambulatory blood pressure measurements.
With denervation (n ¼ 52)
Without denervation (n ¼ 54)
p
32 23/12 11 (n ¼ 49) 20 17/12 11 (n ¼ 32) 11 15/7 11 (n ¼ 20)
þ1 21/0 10 (n ¼ 51) 2 13/0 7 (n ¼ 40) 3 19/1 12 (n ¼ 25)
<0.0001/<0.0001 <0.0001/<0.0001 <0.006/<0.014
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One out of four antihypertensive drugs was stopped because of hypotension
Teletransmitted home BP (mmHg)
Renal denervation 200
297
effective, they also indicate that the procedure only partially reduces total sympathetic activity.
180
Critical Appraisal of Published Studies
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Published studies are subject to several limitations inherent to their open-label design, potentially jeopardising their internal validity and decreasing the degree of BP reduction we can expect to be achieved.32 Indeed, an open-label design is subject to expectation, performance and evaluation biases, particularly in trials evaluating the efficacy of an invasive procedure, such as renal denervation. Furthermore, the evaluation of the BP effect of renal denervation was based on office BP measurement, a primary outcome that may be subject to observer bias. Such biases cannot be ruled out even for the Simplicity HTN2 randomised controlled trial, because the antihypertensive treatment regimen was not standardised, compliance with treatment was not checked during the study and the primary outcome (office BP measurement) was not evaluated blind to treatment allocation. Therefore, active cointerventions (either intentional or non-intentional) and outpatient visits may have been more frequent, and compliance with treatment, dietary and a healthy lifestyle may have been more strongly encouraged by study staff, family members or selfmotivation in patients undergoing renal denervation than in the patients of the control group. Conversely, patients randomised to the control group may have been disappointed with the continuing lack of improvement in BP control and with not being offered ‘the new intervention’. As these patients were aware that they could potentially undergo renal denervation if their BP remained high at 6 months, they may have been reluctant to comply strictly with their antihypertensive treatment regimen and with lifestyle measures, to ensure that they received ‘the new treatment’. Moreover, observer bias may also have influenced office BP measurements in opposite directions in the two randomised groups. An investigator expecting renal denervation to be effective may have been inclined to measure BP differently in the two groups: for example, the resting period before office BP measurements and the number of BP measurements taken may not have been the same in the two groups. Finally, those involved in data analysis were not blind to treatment assignment. All these factors may partly account for the large difference in office BP between the two groups in the Simplicity HTN2 trial, the absence of a decrease in office BP in the control group at 6 months and the large discrepancy between the ambulatory and office BP results. As expected, the BPlowering effects of renal denervation, as assessed by ABPM or selfmeasurement at home, were smaller than those evaluated by office BP measurement. The mean decrease in ambulatory systolic BP in the 20 of the 52 patients with valid 24-h ABPM measurements before and 6 months after renal denervation was only 11 mmHg, much smaller than the 32 mmHg decrease in office systolic BP (Table 1). Furthermore, the difference in 24-h ambulatory BP between the two groups was only 8 mmHg, an effect similar to that expected for the addition of a single antihypertensive agent. ABPM is devoid of the white coat effect, observer bias, digit preference and placebo effect, and provides more reproducible measurements than office BP measurements. It is now the cornerstone of determinations of the antihypertensive efficacy of new drugs, as recommended by international health authorities (United States Food and Drug Administration and European Medicines Agency). Unfortunately, this method was not available to all patients of the Simplicity HTN2 trial. The mean decrease in BP reported in the Simplicity HNT2 study conceals considerable heterogeneity in individual BP responses to renal-nerve ablation, as shown by the large standard deviations of 23 and 15 mmHg associated with the decreases in office and 24-h
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Days Figure 3. Teletransmitted home blood pressure (BP) monitoring in a patient treated by renal denervation. The patient had severe hypertension before renal artery denervation, despite being treated with four antihypertensive drugs. The immediate decrease in BP on day 2 after renal denervation (day 0) is of multifactorial origin (36-h bed rest in hospital, contrast injection, sedation, etc.) and is probably not due to the procedure itself. When the patient returned at home, the BP decrease after renal denervation was progressive over 60 days. Symptomatic hypotension occurred around day 65 which imposed to stop one among four antihypertensive treatments. After 3 months, BP level was stabilized at around 130/85 mmHg with a triple antihypertensive therapy. The dotted line shows the BP threshold for uncontrolled hypertension using home BP monitoring (systolic BP > 135 mmHg and/or diastolic BP > 85 mmHg).
not change in 51 of the 54 patients of the control group (1/0 mmHg, Table 1).1 Fig. 3 shows an example of the progressive BP decrease achieved after renal denervation in one patient. The goal systolic BP (<140 mmHg) was reached at 6 months in 39% of the patients in the renal denervation group and 6% of the patients in the control group (p < 0.001). Moreover, 84% of the patients undergoing renal denervation displayed a decrease in systolic BP of at least 10 mm Hg, whereas such a decrease was observed in only 35% of the controls (p < 0.001). Antihypertensive medication was increased during follow-up in four (8%) of the patients undergoing renal denervation and six (12%) of the control patients (p ¼ 0.74). Conversely, antihypertensive medication was decreased in 10 (20%) of the patients undergoing renal denervation and three (6%) of the control patients (p ¼ 0.04). Overall, the percentage of favourable responses attributable to radiofrequency renal nerve ablation was 50%, a figure close to the percentage of responders to surgical sympathetic denervation. Finally, it should be noted that no BP-lowering effects of renal denervation were observed in 10% of patients and antihypertensive medication was never completely stopped in any of the patients. The mechanism of BP reduction by renal denervation has been investigated by muscle sympathetic nerve activity (MSNA) or norepinephrine spillover measurements. In one patient, postganglionic nerve trafficking, as measured by peroneal nerve microneurography, was found to have decreased 1 month after renal denervation and normalised after 1 year, with an improvement in baroreflex sensitivity.29 An improvement of baroreflex sensitivity was also reported in our case series based on a different methodology.30 Renal norepinephrine spillover had decreased by 50%, 15e30 days after renal denervation, in 10 patients in the pilot study. This decrease was associated with a 30% decrease in total body norepinephrine spillover, one-third of which was attributable to a decrease in renal sympathetic activity.31 This effect can probably be accounted for by the ablation of afferent nerve fibres from the kidney, preventing the stimulation of autonomic centres. However, although these data confirm that renal denervation is
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ambulatory systolic BP. This variability is also highlighted by goal office systolic BP being reached in only 39% of the patients and the complete absence of a BP response in 10% of patients. This lack of response may be due to (1) a primary failure of renal denervation, as no imaging or functional marker of the success of this intervention is currently available and/or (2) the multifactorial and complex origin of hypertension and resistance to treatment. Indeed, total and renal sympathetic overactivity may not be the predominant pathogenic factor underlying hypertension and accounting for treatment resistance in an unknown number of patients. Thus, catheter-based renal denervation is not beneficial but is nonetheless associated with potential risks in at least 10% of patients. Unfortunately, no specific factor predictive of the BP response to renal denervation has been identified from the variables considered: age, sex, previous coronary events, diabetes, dyslipidemia, BP or resting heart rate, number of classes of antihypertensive drugs taken, glomerular filtration rate and number of radiofrequency ablations. In the extended cohort study, multivariate analysis showed that a higher basal BP (as expected) and the use of centrally acting antihypertensive agents were significantly associated with better office BP responses.25 Another issue concerns the unknown long-term antihypertensive efficacy of renal denervation. Past experience with surgical renal denervation shows that BP reduction may be maintained over time,8,9 but it is difficult to extrapolate this finding to radiofrequency renal-nerve ablation. Indeed, radiofrequency renalnerve ablation is more selective and, therefore, by definition, less complete. The conservation of anatomical connections makes sympathetic reinnervation possible, a phenomenon that has been documented following renal transplantation.33 However, although the regeneration of efferent renal-nerve fibres with reinnervation of the kidney is well recognised, there is little evidence for the regeneration of afferent nerve fibres in the kidney. This may account for the sustained, long-term BP reduction reported in a small subgroup of patients (23/11 mmHg for office systolic/ diastolic BP at 12 months in 64 patients and 32/14 mmHg at 24 months for 18 patients of the expanded cohort25). These data, which do not take the number of antihypertensive drug used into account, are subject to the same biases as mentioned above. Finally, the external validity of the studies may also be limited because they included a small sample of highly selected patients. In the Simplicity HTN2 study, z45% of the patients who agreed to participate were excluded before randomisation because of white coat resistance and unsuitable renal artery anatomy precluding renal denervation in almost 20% of patients. In addition, the characteristics of the patients e obese, Caucasian patients with resistant hypertension despite treatment with z5 antihypertensive drugs, a glomerular filtration rate >45 ml min1 and a suitable renal artery anatomy e make it difficult to extrapolate the results to the general population of patients with resistant hypertension. For example, obese patients may be more responsive to renal denervation than lean patients, because the pathophysiology of obesity-associated hypertension involves hyperactivity of the sympathetic nervous system, particularly in patients with obstructive sleep apnea syndrome.34,35 Research Perspectives and Clinical Applications Radiofrequency renal-nerve ablation opens up several new possibilities for treatment.32 Various studies are already underway for indications other than resistant hypertension, including metabolic syndrome, heart failure, sleep apnea syndrome, renal insufficiency and diabetic nephropathy. For example, preliminary results have suggested that renal denervation may have a beneficial effect on insulin resistance and sleep apnea syndrome.36,37 Furthermore, new catheter systems will emerge for the renal denervation by
different methodologies, and these systems will have to go through the same evaluation process. Systematic evaluation of the benefit/ risk ratio of the procedure is considered necessary for each category of patients, including those with resistant hypertension. Radiofrequency renal-nerve ablation should therefore still be considered to be in the evaluation process.38 In this context, there are strong arguments against the widespread and uncontrolled use of this procedure in routine practice: an unknown benefit/risk ratio for the treatment of resistant hypertension, inconsistency and unpredictability of the BP response, absence of medical economic evaluation, higher risk when renal denervation is performed by interventionalists less skilled at patient selection and performance of the procedure. Finally, prolonged follow-up of these patients, including non-invasive imaging (preferably MR-angiograms to avoid excess irradiation due to repeated CT-scanners), is essential to assess the long-term adverse effects of renal denervation by radiofrequency energy ablation in healthy renal arteries. To emphasise this point, the release of a new antihypertensive drug onto the market requires testing on several thousands of patients over several months, followed by continuous and indefinite post-release surveillance. The best way to ensure the rigorous follow-up of patients after renal denervation would therefore be to include them in clinical trials or international registries. Funding and Conflict of Interest The authors were involved in the Simplicity HTN2 trial sponsored by ARDIAN Inc. References 1 Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Bohm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 2010;376:1903e9. 2 Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 2009;373:1275e81. 3 DiBona GF, Esler M. Translational medicine: the antihypertensive effect of renal denervation. Am J Physiol Regul Integr Comp Physiol 2010;298:R245e53. 4 Schlaich MP, Sobotka PA, Krum H, Whitbourn R, Walton A, Esler MD. Renal denervation as a therapeutic approach for hypertension: novel implications for an old concept. Hypertension 2009;54:1195e201. 5 Smith PA, Graham LN, Mackintosh AF, Stoker JB, Mary DA. Relationship between central sympathetic activity and stages of human hypertension. Am J Hypertens 2004;17:217e22. 6 Page IH, Heuer GJ. A surgical treatment of essential hypertension. J Clin Invest 1935;14:22e6. 7 Grimson KS, Orgain ES, Anderson B, D’Angelo GJ. Total thoracic and partial to total lumbar sympathectomy, splanchnicectomy and celiac ganglionectomy for hypertension. Ann Surg 1953;138:532e47. 8 Peet MM. Hypertension and its surgical treatment by bilateral supradiaphragmatic splanchnicectomy. Am J Surg 1948;75:48e68. 9 Smithwick RH, Thompson JE. Splanchnicectomy for essential hypertension; results in 1266 cases. J Am Med Assoc 1953;152:1501e4. 10 Doumas M, Faselis C, Papademetriou V. Renal sympathetic denervation and systemic hypertension. Am J Cardiol 2010;105:570e6. 11 VA Trial. Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mmHg. J Am Med Assoc 1967;202:1028e34. 12 Egan BM, Zhao Y, Axon RN. US trends in prevalence, awareness, treatment, and control of hypertension, 1988e2008. J Am Med Assoc 2010;303:2043e50. 13 Prugger C, Keil U, Wellmann J, de Bacquer D, de Backer G, Ambrosio GB, et al. Blood pressure control and knowledge of target blood pressure in coronary patients across Europe: results from the EUROASPIRE III survey. J Hypertens 2011;29:1641e8. 14 Boutitie F, Gueyffier F, Pocock S, Fagard R, Boissel JP. J-shaped relationship between blood pressure and mortality in hypertensive patients: new insights from a meta-analysis of individual-patient data. Ann Intern Med 2002;136:438e48. 15 Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo Jr JL, et al. Seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 2003;42:1206e52. 16 Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, et al. 2007 ESH-ESC practice guidelines for the management of arterial hypertension:
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