REVIEW URRENT C OPINION

Interventional management in hypertension: where do we stand? Raymond R. Townsend

Purpose of review Device-based interventions to lower drug-resistant hypertension have made the management of this disorder more complicated. In this review, we will focus on developments in this approach to blood pressure care which have appeared over the last year in a published or abstract form. Recent findings Much of the recent literature in this area is characterized by very large office systolic blood pressure reductions, on the order of 25 mmHg at 6 months after intervention. However, the largest and the most rigorously conducted trial of renal denervation failed to meet its efficacy endpoint. We will review some speculations on why that may have occurred. Summary There is little guidance for the management of drug-resistant hypertension in existing guidelines due largely to an absence of clinical trials with hard cardiovascular outcomes; thus, most of the literature relies on short-term (generally less than 1 year) studies that are oriented toward efficacy (i.e., blood pressure reduction per se). With the failure of the Symplicity HTN3 trial to meet its efficacy endpoint, the entire field of renal denervation is under careful scrutiny. From this reviewer’s perspective, this finding seems to be more of a speed-bump than a ‘road closed’ sign for renal denervation, a prompt to reconsider the adequacy of denervation techniques and an encouragement to continue the search for robust predictors of clinical response. Keywords baroreceptor stimulation, drug-resistant hypertension, radiofrequency energy, renal ablation, renal denervation

INTRODUCTION The field of device-based interventions for blood pressure treatment, as well as a variety of other comorbidities (Table 1), is an area of great enthusiasm and rapid flux. Although anticipation of the pivotal Symplicity HTN3 trial (HTN3) was expected to be positive, the announcement by Medtronic (Minneapolis, Minnesota, USA) on 9 January 2014 [http://newsroom.medtronic.com/phoenix.zhtml? c=251324&p=irol-newsArticle&ID=1889335&high light=; accessed 5 April 2014] forced many of us involved in this area of research back to the drawing board. Why was the failure of renal denervation to achieve its top line efficacy endpoint in HTN3 so unexpected? Why did baroreceptor stimulation also fail to achieve the desired degree of efficacy in the Rheos Pivotal trial as well? Examining these issues will help in this opinion piece to both consider where we have been over the last few years, where we are now, and conclude with some www.co-nephrolhypertens.com

speculation on what is next in this intriguing area of investigation.

WHERE WE HAVE BEEN? Both renal denervation (by whatever means) and baroreceptor stimulation have precedents that go back for decades. Denervation in humans was undertaken as a treatment for hypertension in the 1940s and early 1950s when therapies for hypertension were limited to bed rest and draconian sodium reduction achieved with a rice, fruit and distilled Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, Philadelphia, USA Correspondence to Raymond R. Townsend, MD, Nephrology Division, University of Pennsylvania Health System, 3400 Spruce Street, 122 Founders Building, Philadelphia, PA 19104, USA. Tel: +1 215 662 4630; fax: +1 215 662 3459; e-mail: [email protected] Curr Opin Nephrol Hypertens 2014, 23:444–448 DOI:10.1097/MNH.0000000000000046 Volume 23  Number 5  September 2014

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Interventional management in hypertension Townsend

KEY POINTS Key points learned from the Global Symplicity registry have several important things to teach us [15 ]. &&

 The first is the lack of fall, or even an increase, in office systolic pressure when renal denervation is undertaken for nonhypertension-related indications.  Second, the finding that nearly half of the registry enrollees have had ABPM is testimony to the important information that out-of-office monitoring contributes to the care of these patients.  There is no ‘control’ arm in the registry; thus, it will not be able to compare denervation with nondenervation. However, it should be useful to help gauge how long the blood pressure stays reduced (currently there are no studies revealing that) and what is the long-term safety, particularly with respect to kidney function, and perhaps incident renal artery stenosis (which has been virtually nonexistent to date).

water diet. The surgical approach to sympathetic denervation [6], commonly known as the Smithwick procedure, involved severing sympathetic ganglia in the thoracic and lumbar segments. It did result in a survival benefit when compared with patients who refused the procedure, but it involved difficulty standing, bowel and urinary complaints and erectile dysfunction after the operation, as well as some operative mortality. The concept of ‘pacing’ the baroreceptor by directly applied electrical stimulation on the carotid body also witnessed blood pressure reduction [7,8], but had its own operation-related adverse effects, as well as fasciculation in the tongue and awareness of the electrical activity in the neck in some patients. Thus, both operative interventions, splanchnicectomy and carotid sinus pacing, demonstrated tempting efficacy in seemingly hopeless cases of hypertension, but were balanced by sobering morbidity. In 2009, the results of the first human trial using radiofrequency ablation to selectively denervate the kidney in drug-resistant hypertension were the ‘shock heard round the world’ when originally presented, and then published in the Lancet [1].

Background on ablative techniques Radiofrequency ablation uses radio wave energy, in the neighborhood of about 8 W of energy, to heat up an area in the region of a unipolar electrode to roughly 708C for about 2 min. In the Symplicity catheter trials, using this technology, it was important to have conducive anatomy in the kidney artery.

This was defined as at least 20 mm of working length of the kidney artery before its division into anterior and posterior segments, and at least 4 mm of lumen diameter. People with prior kidney artery interventions (stents especially) were usually excluded from trials, as were people whose kidneys were not supplied (at least 80% supplied) by a single kidney artery and those with atherosclerotic lesions encroaching on more than 50% of the lumen. Typically, circumferential energy applications were applied by beginning distally, carrying out a 2 min treatment [with a continuous monitoring of impedance (to ensure catheter tip contact with the wall) and temperature (to control heating; in part this depends on good blood flow, thus the requirement for a 4-mm lumen diameter)] and then withdrawing about 4–5 mm and turning the catheter about 908 and repeating. Usually, four to seven energy applications are given to each kidney artery. The envelope of the heated area includes the nerves lying tangled at various distances from the lumen embedded in the adventitia of the kidney artery; these are the treatment targets of ablation. Safety of the procedure is discussed in the section ‘Where we stand now?’ below. Ultrasonic ablation uses high-frequency sound waves that are used to lesion the nerves in the kidney arteries. Several ultrasonic devices are undergoing development (see Table 1). Cryoablation has been used as a second-line denervation treatment when radiofrequency ablation has failed to lower blood pressure [9]. The lesion is produced by cooling the artery to 758C. Unlike radiofrequency ablation, pain is much less and limited to the period of initial cooling. Usage of cryoablation clinically has been scant with only three reported instances; however, one patient with end-stage renal disease (a usual contraindication to radiofrequency ablation) has been treated [9]. Drug-delivery techniques have also been used to lesion nerves, often in patients with kidney artery diameters (< 4 mm, see above) considered too small for energy-based ablation techniques. The drugs are delivered locally by accessing the kidney arterial system through a catheter, or percutaneously, and then injecting either ethanol [10], vincristine [10] or guanethidine [11] into the periadventitial space through a tiny needle. Developments in baroreceptor stimulation as a clinical treatment for drug-resistant hypertension have largely been limited to the Rheos device (CVRx, Minneapolis, Minnesota, USA) [12]. This approach places electrodes on the surface of the carotid bifurcation connected by wires to a pacing generator implanted surgically in the chest. When turned on, the signal generator ‘paces’ the carotid baroreceptor that communicates with the brainstem

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Pharmacology and therapeutics Table 1. Update on device approaches to drug resistant hypertension management

Sponsor

Trial name (reference)

Number treated (randomization scheme Active : Control) Outcome summary

Method (catheter type)

Ardian 2009

Symplicity HTN1 [1]

45

Significant reductions in office SBP at 6 (22 mmHg) and 12 (27 mmHg) months

RFA (Arch)

Ardian 2010

Symplicity HTN2 [2]

106 (1 : 1a)

Significant reductions in office SBP of 32 mmHg at 6 months in those treated with RDN

RFA (Arch)

Medtronic 2014

Symplicity HTN3 [3 ] 535 (2 : 1b)

Significant reductions in office SBP of 14 mmHg at 6 months within those treated with RDN and 12 mmHg within those treated with sham. Differences between groups were not significant.

RFA (Flex)

St. Jude 2013

EnligHTN [4]

46

Significant reductions in office SBP of 26 mmHg RFA at 6 months in those treated with RDN

Johnson & Johnson RENABLATE 2012

No human trial data

Enrolling (target n ¼ 35) NCT01756300c

RFA

Boston Scientific 2013

139

Significant reductions in office SBP at 6 (24.6 mmHg) and 12 (29.6 mmHg) months (abstract only)

RFA

Verve

&&

Reduce HTN-1

No human trial data

Uses a transurethral approach

RFA

Recor 2012

Gen-2 Paradise [5]



11

Significant reductions in office SBP of 36 mmHg at 3 months in those treated with RDN

Ultrasound

Kona

WAVE - 1

24

Significant reduction in office SBP at 24 weeks of 29 mmHg

Ultrasound

Peregrine



No human trial data



Alcohol Ablation

Ablative Solutions



No human trial data



Alcohol Ablation

Bullfrog



No human trial data



Guanethidine Ablation

RDN, renal denervation; RFA, radiofrequency ablation; SBP, systolic blood pressure. a Control group ¼ no renal denervation (open label). b Sham control group (blinded). c NCT is a www.clinicaltrials.gov study number designation. A reasonably current overview of kidney denervation technologies and baroreceptor activation is available at: http://www.renaldenervationworld.org/techniquesproducts/pipeline/.

through the ninth cranial nerve. This provides negative stimuli to sympathetic outflow and results in a decline in detectable sympathetic nerve traffic (e.g., by muscle sympathetic nerve activity [13]).

WHERE WE ARE NOW? As of 2014, several devices are available which use the ablation techniques covered above (Table 1), although none are currently approved for use outside research studies in the United States. The occurrence of significant back pain is common during renal denervation and conscious sedation is employed in these patients. The first system to see clinical use was Medtronic’s Symplicity system (Symplicity Catheter, Medtronic, Minneapolis, MN), developed initially by Ardian, which was subsequently bought by Medtronic. As covered in Table 1, preliminary experience with the ablation 446

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technologies was extremely encouraging until the announcement by Medtronic, on 9 January 2014 [http://newsroom.medtronic.com/phoenix.zhtml? c=251324&p=irol-newsArticle&ID=1889335&high light=; accessed 5 April 2014], of the failure to meet the efficacy endpoint in the Symplicity HTN3 trial. This occurred at a time when the Symplicity system was approved for use in 88 countries in the world as of February 2014. The trial results for HTN3 were published concurrent with the late-breaking clinical trial presentation at the American College of Cardiology annual meeting in Washington D.C. [3 ]. Briefly, this pivotal trial enrolled 535 patients with drug-resistant hypertension taking at least three antihypertensive drugs in maximum tolerated dosages. A total of 1441 patients were enrolled in the study and about 60% failed to meet all inclusion criteria as outlined in the design paper [14 ]. The key &&

&

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Interventional management in hypertension Townsend

features of this trial that differentiated it from all prior renal denervation trials were two-fold. The first was the need to have patients qualify on the basis of an office systolic blood pressure of 160 mmHg or higher on two office visits, in addition to a 24-h ambulatory blood pressure monitor (ABPM) systolic blood pressure of more than 135 mmHg. The second was the presence of a sham control arm. The sham control arm is, and continues to be, a source of active discussion. When a patient was brought to the catheterization suite for the required prerandomization angiogram (anatomy requirements were covered above), they were given headphones for listening to music, a blindfold, and all were given conscious sedation. Exit interviews with the patients revealed that the majority (about 80%) could not tell whether or not they received the denervation procedure, or just the angiogram without the denervation. Whereas prior Symplicity catheter trials demonstrated an office systolic blood pressure reduction of about 25 mmHg at 6 months, in HTN3 the reduction was 14 mmHg in the denervation arm, and 12 mmHg in the sham control arm. The systolic ABPM responses were 7 mmHg in the denervation arm and 5 mmHg in the sham control arm [3 ]. As a consequence of this, Medtronic released their top line efficacy data on 9 January 2014. Two other aspects deserve a mention. The first is that they more than met the safety endpoints, showing a significant adverse event rate of 1.4% in the denervation group, well below the ‘bar’ of 9.8% set by the protocol designers. Second, the efficacy data were confirmed by an independent statistical review. Somewhat similar findings occurred with the announcement of the Rheos Pivotal trial [12]. This investigation randomized 265 patients with drugresistant hypertension to a different kind of ‘sham’ control. All patients received the device implantation with electrodes placed on both carotid bifurcations. Two-thirds (n ¼ 181) had the device turned ‘on’ at 1 month after procedure and one-third (n ¼ 84) did not have the device activated (‘off’) until 7 months after placement. Efficacy was determined at the 7 months after surgery, or said another way, after 6 months of being either ‘on’ or ‘off’, following a 1-month recovery period. There were five primary endpoints in the trial; two were based on efficacy [acute (6 months) versus sustained (1 year)] and three were based on safety (the operative intervention, the safety of baroreceptor activation therapy and the safety of the device itself). The ‘off’ group had a greater than expected reduction in office blood pressure compared with the ‘on’ group at 6 months. Fifty-four percentage of those in the &&

‘on’ compared with 46% of those in the ‘off’ responded to the procedure [12]. In addition, the goal was to have 82% of patients free of adverse events at 30-day time point, whereas the actual figure was 75%. Thus, one efficacy endpoint and one safety endpoint were not met.

WHERE ARE WE GOING? At this time, the technology leaders in renal denervation seem committed to exploring further the efficacy of the technology in renal denervation. Medtronic, St. Jude and Boston Scientific have indicated that they are continuing with plans to study renal denervation using radiofrequency energy in human hypertension. The use of renal denervation in a number of comorbidities other than hypertension is also continuing at this time (see Table 1 or visit www.clinicaltrials.gov and enter the search term ‘renal denervation’). Ultrasound approaches to renal denervation are also continuing. Medtronic remains committed to the field in its support of the Global Symplicity registry which will track longterm outcomes in 5000 people who have undergone renal denervation [15 ]. The use of renal denervation for patients with less severe degrees of blood pressure elevation (for instance, office values of 140–159 mmHg though taking multiple antihypertensive medications) was discontinued on the basis of the results presented at the American College of Cardiology 2014 Conference for HTN3, and also on the basis of the Global Symplicity registry, in which office systolic reductions in this population were found to be small. Consistent with this, Medtronic announced in March 2014 that they were discontinuing further enrollment into the Symplicity HTN4 trial which had as its entrance systolic blood pressure a value of 140–159 mmHg in the office. &&

CONCLUSION It is often said of clinical trials that once they are over you really figure out how they should be done, and the recent pivotal trials in renal denervation and baroreceptor stimulation are no exceptions to this rule. Updated findings from the registry were presented at the American College of Cardiology 2014 meeting and are summarized in a recent webinar [www.tctmd.com/RDN/ accessed 5 April 2014]. At the present time Medtronic has publicly declared its continued commitment to support renal denervation and will likely move more toward developing the Spyral catheter in this regard, which may better ensure circumferential energy delivery

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Pharmacology and therapeutics

and could also reduce total time in the catheterization laboratory. In addition, they will continue to supply the Symplicity catheter systems to the many countries where the catheter is approved for clinical usage after discussions with the geographic health authorities that oversee these devices. St. Jude, Boston Scientific and Cordis (Johnson & Johnson subsidiary) also appear to remain committed to the technology and have not suspended their programs for their device development. Covidien withdrew from the field of denervation citing costs as the reason. Other technologic approaches appear to be continuing research and development. In this investigator’s opinion, the results of HTN3 represent more of a speed-bump than a ‘Road Closed’ in the field of device-based management of drug-resistant hypertension at this time. Future study design, building on the existing experience so far, will likely focus on assuring adherence, continued use of the sham control, continued reliance on ABPMs to assure out-of-office drug resistance, and a research focus on finding ways, or markers, that assure delivery of adequate denervation energy and that assess the efficacy of the denervation procedure itself. Speculation on what lay behind the findings of HTN3 is beyond the scope of this review, but the webinar cited immediately summarized the HTN3 results, the registry, and the status of the field of renal denervation [www.tctmd.com/ RDN/ accessed 5 April 2014]. Acknowledgements Author (RRT) received consultant income from Medtronic as a member of the United States Advisory Board for the Symplicity HTN3 trial. Conflicts of interest Dr. Townsend has provided consultant services to Medtronic and served on their United States Advisory Board for the Symplicity HTN-3 trial.

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REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-ofprinciple cohort study. Lancet 2009; 373:1275–1281. 2. Esler MD, Krum H, Sobotka PA, et al., SYMPLICITY HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 2010; 376:1903–1909. 3. Bhatt DL, Kandzari DE, O’Neill WW, et al., SYMPLICITY HTN-3 Investigators. && A controlled trial of renal denervation for resistant hypertension. N Engl J Med 2014; 370:1393–1401. Major findings of a rigorously controlled trial of renal denervation. The findings in this study are under active discussion among both investigators and industry leaders in the technology. 4. Worthley SG, Tsioufis CP, Worthley MI, et al. Safety and efficacy of a multielectrode renal sympathetic denervation system in resistant hypertension: the EnligHTN I trial. Eur Heart J 2013; 34:2132–2140. 5. Mabin T, Sapoval M, Cabane V, et al. First experience with endovascular ultrasound renal denervation for the treatment of resistant hypertension. EuroIntervention 2012; 8:57–61. 6. Smithwick RH, Porell WJ, Whitelaw GP. Diagnosis of hypertension of adrenal and renal origin. JAMA 1960; 174:127–132. 7. Mohaupt MG, Schmidli J, Luft FC. Management of uncontrollable hypertension with a carotid sinus stimulation device. Hypertension 2007; 50:825– 828. 8. Drews JA, Stansel HC Jr, Glenn WW. Carotid sinus nerve stimulation: studies on the mechanism of the hypotensive response. Vasc Surg 1968; 2:78–87. 9. Patel HC, Dhillon PS, Mahfoud F, et al. The biophysics of renal sympathetic denervation using radiofrequency energy. Clin Res Cardiol 2014; 103:337– 344. 10. Stefanadis C, Toutouzas K, Vlachopoulos C, et al. Chemical denervation of the renal artery with vincristine for the treatment of resistant arterial hypertension: first-in-man application. Hellenic J Cardiol 2013; 54:318–321. 11. Manning PT, Powers CW, Schmidt RE, Johnson EM Jr. Guanethidine-induced destruction of peripheral sympathetic neurons occurs by an immunemediated mechanism. J Neurosci 1983; 3:714–724. 12. Bisognano JD, Bakris G, Nadim MK, et al. Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: results from the double-blind, randomized, placebo-controlled rheos pivotal trial. J Am Coll Cardiol 2011; 58:765–773. 13. Heusser K, Tank J, Engeli S, et al. Carotid baroreceptor stimulation, sympathetic activity, baroreflex function, and blood pressure in hypertensive patients. Hypertension 2010; 55:619–626. 14. Kandzari DE, Bhatt DL, Sobotka PA, et al. Catheter-based renal denervation & for resistant hypertension: rationale and design of the SYMPLICITY HTN-3 Trial. Clin Cardiol 2012; 35:528–535. Design paper for HTN3; clearly lays out the run-in phase, the need for meeting ambulatory blood pressure monitor criteria to be randomized, and the presence of the sham control arm. 15. Bohm M, Mahfoud F, Ukena C, et al. Rationale and design of a large registry on && renal denervation: the Global SYMPLICITY registry. EuroIntervention 2013; 9:484–492. As of January 2014, there are about 1000 patients in this worldwide registry. It has efficacy and safety data for the renal denervation procedure.

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Interventional management in hypertension: where do we stand?

Device-based interventions to lower drug-resistant hypertension have made the management of this disorder more complicated. In this review, we will fo...
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