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Device-based Therapies for Resistant Hypertension:Current Status
  JOHTN
THERAPEUTIC
Device-based Therapies for Resistant Hypertension:
Current Status
1Mohsin Wali, 2C Venkata S Ram
1Senior Physician and Consultant, 2Director
2Department of Medicine and Hypertension, University of TexasSouthwestern Medical Center, Dallas, USA and Apollo HospitalsHyderabad, India
Correspondence Author: C Venkata S Ram, Director, Departmentof Medicine and Hypertension, University of Texas SouthwesternMedical Center, Dallas, USA and Apollo Hospitals, HyderabadIndia
e-mail: drram_v@apollohospitals.com
 
ABSTRACT
Resistant hypertension is a serious consequence of uncontrolledhypertension. This condition can lead to significanttarget organ damage. Individuals with resistant hypertensionare highly vulnerable to excessive morbidity and prematuremortality. Hence, it is important to recognise resistant hypertensionas a distinct clinical entity. Whereas aggressive medicaltherapy is indicated to control resistant hypertension, there is agrowing interest and considerable ongoing research on the roleof mechanical device based approaches to control hypertension.Although the results of device based therapy of resistanthypertension are inconsistent, this alternative approach shouldbe pursued further by newer research protocols and novelmethodology.
Keywords: Baroreceptor activation therapy, Resistant hypertension,Renal denervation therapy, Uncontrolled hypertension.
How to cite this article: Wali M, Ram CVS. Device-basedTherapies for Resistant Hypertension: Current Status. HypertensJ 2017;3(1):44-49.
Source of support: Nil
Conflict of interest: None
 
 

INTRODUCTION

Systemic hypertension is a pervasive public healthproblem and is the chief contributor for excessive morbidityand premature mortality worldwide. Despite theprofessional and public educational efforts in the lastthree decades, hypertension vastly is poor controlled,untreated, undertreated, and undiagnosed in the community.Even under optimal conditions of proper diagnosisand treatment of hypertension, the goal blood pressurelevels are generally not achieved in clinical practice.The reasons for poor rates for blood pressure control arecomplex and no unifying explanation is possible. One factor (and not the only one) for poor control of hypertensionis patients' nonadherence to therapy. Effectivetherapy exists for hypertension - lifestyle changes andantihypertensive drugs - but patient compliance remainsa challenging issue. To provide alternate therapies forhypertension and to circumvent the problem of nonadherence,some device-based therapeutic approaches havebeen developed. Various device-based therapies are indifferent phases of clinical development, and no conclusivepractical recommendations can be made out. Thisreview provides an encapsulated update on device-basedtherapy for (resistant) hypertension. It should be clearthat the development of device-based therapy has beenrestricted to "resistant" hypertension, although there issome experience with the technique in patients with otherforms of hypertension, metabolic syndrome, congestiveheart failure (CHF), and obstructive sleep apnea (OSA).The views expressed in this review are mainly pertinentto "resistant" hypertension.
 
BACKGROUND RATIONALE FOR DEVICEBASED
THERAPY FOR HYPERTENSION


There is ample and well-accepted clinical and experimentalevidence to correlate the pathophysiology ofhypertension to the activity of sympathetic nervoussystem (SNS). The level of blood pressure is dictatedpartially by the level of SNS activity. Systemic hypertensionis of multifactorial etiology, but the supremacy ofSNS is unquestionable; inappropriate and heightenedSNS activity elevates the blood pressure directly andindirectly. This concept has led to the development ofantihypertensive drugs aimed at blocking the SNS activityat the cellular receptor level. Further, understandingof this pathophysiology has allowed for the explorationof (physical) sympathectomy to treat human hypertensionin the middle of last century. Nonselective crudesurgical lumbar sympathectomy provided significantrelief from severe hypertension but unfortunately(as expected) caused a number of bothersome side effects,such as symptomatic postural hypertension. Hence, theprocedure did not find a place in the therapy of hypertensionand was abandoned. Moreover, when effectiveantisympathetic blood pressure-lowering medicinesbecame available in the 1950s, surgical sympathectomyvanished from clinical utility. Nevertheless, the surgical sympathectomy results revealed the importance of SNSoveractivity as a major factor in the pathogenesis ofhypertension.
 
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Device-based Therapies for Resistant Hypertension: Current Status

In the last decade, technological and safety advanceshave led to the refined techniques to selectively ablaterenal sympathetic activity, so-called renal denervation(RDN) therapy (Table 1).1,2 The field of RDN as a clinicaland research tool expanded at a rapid pace, culminatingin a number of clinical trials in human hypertension.Similarly, baroreceptor activation therapy (BAT) hasalso been developed simultaneously as a method ofsympathetic deactivation to treat hypertension. LikeRDN therapy, clinical trials with BAT for resistanthypertension have yielded excellent initial results. Inspite of the enthusiasm for device-based therapy to treat(resistant) hypertension, its role for clinical applicationremains to be clarified. This article provides a statusupdate on the evolving role of device-based therapiesfor hypertension.

RENAL DENERVATION THERAPY IN PATIENTS
WITH (RESISTANT) HYPERTENSION


While experimental RDN therapy has been tried for anumber of years, it is only in the last decade that we haveapplied this technique in clinical hypertension. Withadvances in our knowledge about renal sympatheticfibers and their correlative integration with SNS, andadvent of transcatheter techniques, several devices havebeen developed to cause selective RDN in patients withhypertension. The RDN catheters inserted in the renalarteries deliver enough thermal injury through the renalartery to disrupt the local afferent and efferent nervefibers. Radiofrequency ablation is the preferred modeof energy to achieve RDN. Minimum number of ablationsites in both renal arteries is required for effectivedenervation with the interruption of afferent and efferentrenal nerve traffic. The SNS activity falls and so does theblood pressure level.

Symplicity HTN-1 was the first clinical study to evaluatethe safety and efficacy of RDN therapy in 50 patientswith resistant hypertension (Graph 1).3 The RDN therapyresulted in phenomenal blood pressure reduction in the office at 1 month (-14/-10 mm Hg) and at 6 months(-27/-17 mm Hg). Ambulatory blood pressure monitoring(ABPM) in a small subset of patients, however, showedonly a modest BP reduction [-11 mm Hg, systolic (SBP)].4The subsequent Symplicity HTN-2 was conducted in alarger group (106 patients) with resistant hypertension.5In 50% of the study population RDN was performed andin the other 50%, medical treatment was continued. In theRDN therapy group blood pressure fell significantly at1 month (-20/-7 mm Hg) and at 6 months (-32/-12 mmHg), while the control group showed no change in theBP level. As in Symplicity HTN-1 trial, in this study also,ABPM showed only a modest fall in BP (-11/-7 mm Hg)in a small subgroup of patients.

Table 1: Why RDN for hypertension?
Device-based Therapies for Resistant Hypertension:Current Status

 
Device-based Therapies for Resistant Hypertension:Current Status
Graph 1: Symplicity HTN-1 trial: 24-month results

Along with these trials, other RDN studies showedimpressive results in the unblinded, single-arm protocols.The office BP reductions were indeed dramatic (↓ SBP20-30 mm Hg). Thus, the earlier unblinded, nonrandomizedRDN therapy trials generated much enthusiasm,offering a possible breakthrough in the management ofresistant hypertension. However, the enthusiasm quicklywaned after the publication of trials with rigorous studydesigns, such as Symplicity HTN-3.

Symplicity HTN-3 was a randomized, sham-controlled,single-blind study to evaluate the safety and efficacy ofRDN in a resistant hypertension. The study utilized arigorous protocol design to measure the true therapeuticeffect as a result of intervention. In contrast to the previousRDN studies, Symplicity HTN-3 was a US-based studyin 90 research sites. It included African-Americans in thestudy as this group is prone to have resistant hypertension.At 6 months, the study met its "safety" objective, which isreassuring. However, the study failed to meet its "efficacy"primary objective (Graph 2).6 Results indicated that therewere no differences in the achieved BP levels betweenthe RDN and Sham (medical) groups. The SBP fell by 14.1 ± 24 mm Hg in the RDN group and by 11.7 ± 26 mmHg in the sham group (p = 0.255). Similarly, the ABPMresults showed a drop of SBP by 6.75 ± 15.11 mm Hg in theRDN group compared with a drop by 4.79 ± 17.25 mm Hgin the control group (p = 0.979). The results of SymplicityHTN-3 as expected caused a serious setback to the role ofRDN to treat resistant hypertension.7,8 The very concept ofRDN to lower the BP has been brought into debate by theSymplicity HTN-3 results (Table 2). However, SymplicityHTN-3 has left many unanswered questions and createda need to develop newer ways to cause "effective" and"complete" RDN in patients with hypertension (Tables 3and 4; Graph 3).
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Mohsin Wali, C Venkata S Ram

Device-based Therapies for Resistant Hypertension:Current Status
Graph 2: Primary efficacy 6-month endpoint: Office SBP

Table 2: Why did Symplicity-3 fail?
Device-based Therapies for Resistant Hypertension:Current Status

Table 3: Renal denervation: Issues
Device-based Therapies for Resistant Hypertension:Current Status

Table 4: Revival of RDN-factors
Device-based Therapies for Resistant Hypertension:Current Status

 
Device-based Therapies for Resistant Hypertension:Current Status
Graph 3: Procedural aspects in Symplicity HTN-3

OFFICE/CLINIC BLOOD PRESSURE
MEASUREMENTS VS ABPM IN RDN
THERAPY TRIALS


Until the Symplicity HTN-3 trial, ABPM was utilized onlyin small subsets in the previous RDN studies. AlthoughABPM was only done in small numbers in the previousstudies, the results indicated a remarkable discrepancybetween the office BP levels and ABP levels. Another RDNstudy - Enlig HTN-1 - also showed a marked discrepancybetween the office BP levels and ABP levels utilizinga different multielectrode catheter.9 Small studies inspecial populations with hypertension, such as chronickidney disease and OSA also exposed the discrepanciesbetween the office BP and ABP levels after RDN therapy.Taken together, these results show an important differencebetween the office BP levels and ABP levels, raisingquestions about the enduring efficacy of RDN in clinicalpractice. The exact reason for the discrepancy is notconclusively known and remains speculative. The RDNtherapy appears to eliminate the white coat effect!

NEWER TECHNIQUES AND DEVICES FOR RDN

The Symplicity HTN trials utilized single-electrode catheterfor renal nerve ablation. Complete RDN may not bepossible with this catheter, which may not create preciseenergy-driven lesions; operators' experience and technicalskills may be a critical factor in achieving adequate RDN.The newly designed next generation of multiple electrodecatheters is aimed to deliver radiofrequency energy to arterialadventia with "precision" and to all the four quadrants,possibly eliminating the operator-dependent factors. Thenewer techniques (and catheters) will allow for targeteddenervation sites circumferentially in both the main renalartery and the branches. Research is also being done toevaluate "chemical" RDN using alcohol or sympatholyticdrugs at the catheter tip. Whether drug-eluded catheters offer a special benefit beyond a mere electromechanicalablation remains to be determined.
 
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Device-based Therapies for Resistant Hypertension: Current Status

Device-based Therapies for Resistant Hypertension:Current Status
Fig. 1: The Baroreflex as a therapeutic target

Device-based Therapies for Resistant Hypertension:Current Status
Graph 4: Sustained reduction in 24-hour ABPM with BAT application

BARORECEPTOR ACTIVATION THERAPY

Modulation (activation) of baroreceptors has been shownto cause a decrease in the SNS activity via central mechanisms(Fig. 1). Afferent reflexes originating from thecarotid body inhibit the cardiovascular efferents fromthe brain, resulting in a sympathetic deactivation whichleads to a fall in the systemic vascular resistance and inthe heart rate. In essence, carotid body stimulations lowerthe peripheral sympathetic tone by inhibiting the SNSpathways in the brain. This neural mechanism has beeninvoked to lower the blood pressure in experimental andclinical hypertension, further confirming the role of SNSin the pathogenesis of hypertension. Long-term observationswith BAT are not yet available, but the short-termresults are encouraging.10,11
 
Device-based Therapies for Resistant Hypertension:Current Status
Graph 5: New 5-year long-term SBP data in resistant HTN

The Rheos BAT system is an implantable device totreat hypertension and possibly CHF. The first humanstudy done with the Rheos system was a proof-of-concept efficacy and safety study; at 3 months BAT device placedpatients showed an office BP reduction of 21/12 mm Hgand ABP was reduced by 6/4 mm Hg. At 2 years followup,the office BP was reduced by 33/22 mm Hg and ABPwas reduced by 24/13 mm Hg (Graph 4).12 These resultswere significant. In general, BAT was well tolerated andsafe except one instance of postoperative stroke and oneinstance requiring repositioning of the device. The Rheospivotal trial13 was a larger, placebo-controlled, and properlyrandomized trial; 265 patients participated in this trial.Although the blood pressure fell significantly when thedevice was turned "on," there was no difference when thedevice was turned "off." Long-term follow-up (48 months)showed sustained BP reduction and safety (Graph 5).

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Mohsin Wali, C Venkata S Ram

The second-generation Rheos device is considerablysmaller than its predecessor and the procedure (surgical)is much simpler.14 In the Barostim neo trial using the newand improved BAT device for resistant hypertension, investigatorsshowed a remarkable drop in BP (26/12 mm Hg)at 6 months. The ABPM results also showed significantreductions in the BP. No major procedure- or devicerelatedcomplications were observed. Further validationof BAT results will need a sham-controlled trial likeSymplicity HTN-3. Studies are in progress to furtherelucidate the role of BAT in the long-term management of(resistant) hypertension and to test the concept potentialin the management of CHF

MEDIAN NERVE MODULATION

Median nerve modulation concept has been revived bythe technological development of a small coin whichgently stimulates the median nerve. The Ecoin isimplanted under the forearm skin to activate the mediannerve. The relatively low-powered electrical stimulus,thus generated, communicates with the multiple pathwaysin the brain that control the blood pressure. Theprocedure takes only 20 minutes to perform in the officesetting. The dormant science of median nerve modulationhas been successfully revived by the technologicaldevelopment of Ecoin and median nerve mapping.

A recent multicenter double-blinded, and shamcontrolledstudy in resistant hypertensives showed thatmedian nerve modulation with Ecoin showed a significantimprovement in the office and ABP levels.15 At6 months, patients' office BP and ambulatory BP fell significantly(Graph 6). No major procedure-related adverseeffects were noted. The results of this promising pilotstudy warrant larger controlled trials to determine theapplicability of median nerve modulation in the clinicalmanagement of (resistant) hypertension.

Device-based Therapies for Resistant Hypertension:Current Status
Graph 6: Office SBP at 6 months postactivation of Ecoin

 
CENTRAL ARTERIOVENOUS COUPLER
THERAPY FOR RESISTANT HYPERTENSION


Hypertrophy of the arteries makes the blood vesselsstiff and less compliant, leading to an increase in vascularresistance (and, thus, in the BP). A more advancedtechnique, the Rox coupler creates a small arteriovenousfistula (AVF) between the iliac artery and vein with acontrolled shunt flow creating a low-resistance vascularbed and the system vascular resistance table. In apreliminary Rox coupler AVF study, the office and ABPlevels were lower at 6 months. A larger study (40 activepatients and 40 controls) showed that at 6 months theAVF group showed a significant reduction in the officeBP as well as in the ABP levels.16,17 The novel techniquewas shown to be effective, but a third of AVF patientsdeveloped ipsilateral venous stenosis, which resolvedafter stenting or venoplasty. This unique promising procedureawaits further testing and additional researchstudies.

CONCLUSION

Resistant hypertension is a complex clinical problemwith multiple pathophysiological mechanisms. Resistanthypertension can cause significant target organ damage,premature mortality, and excessive morbidity. At present,chronic management of resistant hypertension is unsatisfactory.Side effects from drug therapy and poor adherenceare the chief reasons why blood pressure control isdifficult in the community setting.

Device-based therapies for hypertension have beendeveloped on the basis of pathophysiological mechanisms,which raise the blood pressure. Interrupting thesemechanisms by mechanical means has been shown tolower the blood pressure in experimental hypertensionand in clinical studies. So far, most experience withdevices to treat hypertension has been gained with RDNand BAT for resistant hypertension. While the initialresults from RDN were "sensational," randomized trialswith strict criteria showed that RDN was not superiorto medical treatment. Hence, the development of RDNtherapy has taken a big setback. Currently, RDN therapyfor hypertension is being reassessed with newer refinedtechniques to achieve "effective" RDN. The methodsof accomplishing RDN more optimally are also beingevaluated; similarly, techniques to improve BAT areunderway. While the enthusiasm for device-based therapiesis somewhat tempered at present, the approach isbeing revived through innovations in device technology,technical modifications, and proper selection of patients.The ongoing research studies will define possible roleof device-based therapy to treat hypertension in selectGraph 6: Office SBP at 6 months postactivation of Ecoin populations.
 
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Device-based Therapies for Resistant Hypertension: Current Status

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