A novel therapy for resistant hypertension

Therapeutic intravascular ultrasound is a promising alternative for renal denervation

Sharad V Shetty MBBS MD DM FRACP

Fiona Stanley Hospital , Royal Perth Hospital and Perth Cardiovascular Institute

Ali M Safaa MBChB FRACP

The Royal Perth Hospital, Perth, Western Australia

Systemic hypertension represents a major economic and public health challenge worldwide, considering its high prevalence and the fact that it is one of the most important modifiable risk factors for cardiovascular, cerebrovascular and renal disease.1

However, it is estimated that almost 20% of hypertensive patients have resistant hypertension (RHTN), defined as failure to achieve target blood pressure (BP) despite adherence to optimal doses of at least three antihypertensive agents, including a diuretic.2

Over the last two decades, there has been increasing evidence suggesting that RHTN may, at least in part, be mediated by chronic activation of the renal sympathetic nervous system (SNS).3 Consequently, the renal SNS has emerged as a promising potential target to improve the treatment of RHTN patients, since both the efferent and afferent fibres lie primarily within the adventitia of the renal artery to each kidney; an ideal approach to modulate the renal SNS should aim to achieve selective renal artery denervation with no damage to adjacent structures.

Several different modalities that are currently being tested in both preclinical and clinical settings vary in their potential benefits and pitfalls. These include the radiofrequency ablation (RFA), ultrasound neural ablation, chemical ablation and cryoablation technologies.

Radiofrequency ablation-based renal denervation

RFA is one of the first technologies used in this area, utilising different types of catheters to deliver alternating electrical current to contact points, resulting in tissue damage by both direct resistive heating of the tissue in direct contact with the catheter tip and by thermal conduction to deeper tissue. The catheter tip energy delivery heats up tissue to a target temperature of 50–70C°, where an abrupt rise of impedance suggests overheating and tissue charring at catheter tip. A number of factors can influence tissue destruction, including catheter electrode number and size, tissue apposition and duration and the level of power applied from the RF generator to the targeted tissue. Many catheter designs have been used in preclinical and clinical settings, with varying characteristics in terms of delivery system, number and configuration of electrodes, duration of ablation and cooling mechanisms. 

The most widely tested one is the SymplicityTM Renal Denervation System (Medtronic Inc. Minneapolis, US), using a single unipolar electrode, typically four to six ablations per artery (two minutes duration each). Despite its promising results earlier (Symplicity HTN-1 and Symplicity HTN-2), the double blind, sham-controlled study (Symplicity HTN-3, n=530) failed at its primary efficacy endpoint of office reading systolic blood pressure at six months.4

The EnligHTNTM Multi Electrode Renal Denervation System (St. Jude Medical) has emerged as a more user-friendly RDN technology, utilising a basket mounted four-electrode system, available in two sizes, and achieves target tissue ablation by two ablations/artery (90 seconds sequential ablation per electrode). EnligHTN I trial was a prospective, multicentre clinical study of 46 patients that reported promising results in terms of safety and efficacy.

This was followed by the EnligHTN II trial (started in January 2013), an observational study to further evaluate the mean reduction in systolic blood pressure at six months across all patients post-procedure and within subgroups with varying degrees of kidney functionality. EnligHTN III, announced in May 2013, is another, non-randomised study to be conducted in Austaralia and New Zealand, with view of enrolling up to 50 patients with RHTN, to assess the safety and performance of the next generation EnligHTN RDN System (the ability to deliver simultaneous ablations, potentially reducing the total ablation time from 24 minutes to four minutes). 

There are other RFA devices specifically developed for RDN purposes that are still in their preclinical or early clinical use.

Ultrasound energy-based renal denervation

Applying the same principle, with the use of high intensity ultrasound (HI-US) waves energy can induce the required level of thermal injury to achieve proper neural ablation. The major advantages of US technology are the lack of need for direct tissue contact and the ability to directly target the adventitial layer of the renal artery, where the neural bundle of interest usually lies. However, this deeper denervation property may be potentially harmful to adjacent structures, like the psoas muscle and the bowel.

The Therapeutic Intra Vascular Ultra Sound (TIVUSTM) System

This is an ultrasound-based RDN system, developed by Cardiosonic Ltd. (Tel Aviv, Israel), that utilises the HI-US property to achieve safe and therapeutic thermal renal artery denervation.

TIVUSTM mechanism of action

The TIVUSTM system has two main components: a control console that generates non-focused HI-US waves that are directly delivered into the tissue of interest via a catheter-mounted US transducer. This catheter tip transducer is positioned inside the renal artery at a safe distance from the artery wall, hence delivering the non focused HI-US at the desired tissue depth, at which point the high frequency mechanical oscillations transform into heat with a temperature range of 50–80°, a temperature high enough to produces irreversible axonal degeneration and permanent neural cell damage,5 resulting in adventitial RDN. 

One advantage associated with the use of this technology compared to the conventional RFA technology is the avoidance of renal artery wall mechanical damage, since the US transducer is positioned in the middle of the vessel lumen, thereby avoiding any direct contact with arterial intima. This can also be of particular use in patients with previous renal artery stenting, in which the RFA technology is ineffective given the mechanical barrier presented by the stent in the artery wall. Another advantage of using the TIVUSTM system is the uninterrupted renal blood flow during HI-US delivery, allowing cooling of the US transducer as well as the intimal layer of the renal artery.

TIVUSTM technical and procedural aspects

The TIVUSTM (Cardiosonic Ltd. Tel Aviv, Israel) first generation catheter was a unidirectional, as was the second generation catheter, but the latter was steerable, while the third (and the most advanced) generation, is the Multidirectional TIVUS™ catheter (Figure 1). 

This catheter is introduced through a common femoral arterial access, using a 6Fr compatible catheter, with an overall usable length of 645mm. It has a radiopaque tip that helps positioning it in the renal artery over a 0.014” guiding wire, using fluoroscopic guidance. There is a lever at the catheter handle that can open and close a petal-shaped distancing device, through which the ultrasonic element position can be maintained in the centre of the renal artery.

One of the safety enhanced features this technology possesses is the transducer’s indication of distance from the artery wall, as well as the presence of thermistors that provide screen displayable live feedback of temperature of blood flowing over each of the ultrasonic elements during the procedure. These two features enable to apply therapy when deemed to be safe, or alternatively, automatically turn the energy off when required.

The circumferential nerve ablation is achieved through three well-spaced and self-contained locations (30 seconds/ablation) along the renal artery. The procedure is then repeated for the contralateral renal artery.

TIVUSTM preclinical and clinical data

Preclinical

The TIVUS™ preclinical animal work included over 250 swine samples, assessing safety and performance in comparison to existing RFA-based technology. These studies showed neither statistically significant kidney function alteration nor luminal narrowing on angiography, yet the therapy was shown to be effective as evidenced by an average of 50% reduction (42–93%) in norepinephrine concentration compared to independent non-treated animals.

Clinical

The TIVUS™ clinical trials were prospective, multicentre, non-randomised, single-arm, and open-label clinical studies, using both unidirectional and multidirectional catheters.

TIVUS™ I

This was the TIVUS™ first in man (FIM) study carried out in six centres across Europe, Australia and Israel. Inclusion criteria were severe resistant hypertension with systolic office blood pressure >160mmHg, ambulatory systolic BP >135mmHg whilst on three or more antihypertensive medications (including a diuretic). The procedure was performed using unidirectional catheter (including a steerable catheter) and a modular console. The study completed successful enrolment of 15 patient plus an additional three patients under compassionate use due to impaired renal function and prior stent. All patients were successfully treated with no device related complications. Patients were followed up for six months for efficacy end point and up to 12 months for safety end points. The reduction in BP achieved was consistent with the coexisting RFA RDN trials. Other advantages identified were positive user feedback, less painful procedure compared with RF technology (evidenced by substantially less analgesics and site feedback), and less contrast use given the inherent characteristics of US.

TIVUS™ II 

This is multicentre, prospective, non-randomised trial aims to validate safety and performance of the TIVUS™ multidirectional catheter. It started enrolling patients at seven participating centres in Australia, Europe and Israel in August 2013, with an estimated total of 80 patients to be recruited (25 patients being enrolled to date), and an estimated study completion date in December 2016.  The study has three concurrent registries, all with a documented 24 ABPM systolic BP of >135mmHg (Table 1).

Anatomical eligibility, just like other RDN trials, mandated a minimum renal artery diameter >4mm diameter and >20mm length. Renal artery stenosis of <50% and renal artery aneurysms, were allowed to be enrolled at the interventional cardiologists’ discretion. 

An interim report of 18 recruited patients was presented in EuroPCR 2014,6 of those, 14 (78%) were males. Fifteen patients were enrolled according to inclusion criteria and three treated under compassionate use applications (two patients post-renal stent and one with impaired renal function). 

The baseline mean office BP was 174.3/88.4mmHg, with an average of 4.7 antihypertensive medications. Patients underwent TIVUSTM bilateral RDN with median treatment points of eight. All 18 procedures were performed successfully with no device-related complications. At one and three month follow-up, patients’ office BP decreased by 28/10mmHg (n=18), and 25/10mmHg (n=16), respectively. Two patients required anti-HTN medication reduction.

Other invasive ultrasound energy-based RDN technologies

The PARADISETM catheter system (ReCor Medical, Menlo Park, CA, USA) is another ultrasound based RDN catheter. The system uses a six French compatible over the wire catheter, the distal tip of which holds an ultrasound transducer contained within a low-pressure inflatable balloon. This balloon allows cooled fluid to circulate and hence prevents endothelial wall damage, with the main advantage, once inflated, is allowing uniform circumferential distribution of ultrasound energy into the surrounding artery. One of the anticipated benefits of this system over the traditional RFA RDN is a shorter procedure time, largely driven by shorter energy delivery cycle due to its circumferential nature and therefore less treatment sites are required. 

Data from three month follow-up in patients with resistant HTN treated using the PARADISE system showed promising results with an average reduction of office and home BP of –36/–17 and –22/–12mmHg respectively.7 ReCor Medical has reported six month follow-up data in six patients in a company press release demonstrating an average of 33mmHg systolic BP reduction [ReCor Medical, 2012a]. Renal DenervatIon by Ultrasound Transcatheter Emission (REALISE) trial is currently underway [Clinical Trials.gov identifier: NCT01529372] will help further assess this technology.

Non-invasive ultrasound-based technology

The use of external ultrasound is currently being investigated by Kona Medical, Campbell CA. The system is designed to deliver a low-intensity focused ultrasound (LIFU) energy from an external source to the renal nerves. FIM trials involved treating five participants (presented at TCT, 2012) were undertaken in Australia and employed two unilateral ablations performed three weeks apart. There were no major adverse events mong the treated patients, and mean BP reduction was –30.1/–11.4mmHg at three weeks. 

References 

1. Kearney P et al.  Worldwide prevalence of hypertension: a systematic review.  J Hypertension 2004;22:11–19.
2. Kapil V, Jain AK, Lobo MD. Renal sympathetic denervation – A review of applications in current practice. Intervent Cardiol Rev 2014;9(1):54–61.
3. Esler M. The sympathetic nervous system through the ages: from Thomas Willis to resistant hypertension. Exp Physiol 2011;96:611–22.
4. Bhatt D et al. A controlled trial of renal denervation for resistant hypertension (Simplicity HTN-3). N Engl J Med 2014;370:1393–401.
5. Xu D, Pollock M. Experimental nerve thermal injury. Brain 1994;117(2):375–84.
6. Shetty S et al. Renal denervation using the novel therapeutic intra-vascular ultrasound (TIVUS™) catheter system – Preliminary report of first-in-man safety and performance study. www.pcronline.com/eurointervention/AbstractsEuroPCR2014/OP206/#sthash.p2….
7. Mabin M et al. First experience with endovascular ultrasound renal denervation for the treatment of resistant hypertension. EuroIntervention 2012;8:57–61.