Chapter 15: Modern and interventional treatments

Device-based treatment of hypertension

Renal denervation (RDN)

Increased activity of the central sympathetic nervous system is an important part of the pathophysiology of hypertension, particularly in obesity, obstructive sleep apnoea and chronic kidney disease. Efferent sympathetic nerves to the kidneys increase renin release by stimulating beta-1 adrenergic receptors on juxtaglomerular cells, reduce renal perfusion and GFR, increase tubular sodium reabsorption and shift the blood-pressure–natriuresis relationship to the right. Conversely, increased afferent signalling from the kidneys to the central nervous system, in response to renal ischaemia, injury, inflammation, fibrosis or other renal changes, can activate a sympathetic reflex, with peripheral vasoconstriction, higher blood pressure and worsening HMOD. The rationale for RDN is to modify excessive signalling between the kidneys and the central nervous system, which may contribute at least partly to the sympathetic overactivity of resistant hypertension.

Intravascular catheter-based RDN devices have made it possible to perform denervation with a less invasive procedure. In humans, RDN has been shown to reduce whole-body and renal sympathetic activity, although this has not been consistent in every study. A recent meta-analysis of the available studies found only a limited relationship between the reduction in sympathetic activity measured by microneurography and the reduction in blood pressure. This is compatible with the possibility that the treatment effect of RDN depends on more than one neural mechanism.

Clinical evidence for the blood-pressure effect of RDN

Early proof-of-concept human studies using radiofrequency energy, unfocused high-frequency ultrasound energy and periarterial alcohol injection reported substantial blood-pressure reductions in people with uncontrolled or resistant hypertension. However, when the sham-controlled SYMPLICITY HTN-3 trial failed in 2014 to show a significant blood-pressure reduction after RDN compared with the sham procedure, clinical investigation of RDN almost stopped.

The absence of a significant reduction in SYMPLICITY HTN-3 was later attributed to energy delivery in the proximal rather than the more distal, innervated parts of the renal artery, incomplete circumferential denervation, high rates of medication changes during the run-in and treatment phases, and inadequate adherence to medication.

Subsequent European and US conferences therefore recommended: (i) improved techniques with complete circumferential ablation of the renal nerves; (ii) strict inclusion criteria and a well-controlled run-in phase; and (iii) objective, individual assessment of medication adherence.

To grade the scientific quality of published randomised controlled trials, the following criteria were applied: a multicentre sham-controlled design; adequate blinding of patients and outcome assessors; ambulatory blood-pressure change as a primary outcome; completion of the study as planned; and use of advanced RDN systems. Of 18 randomised controlled trials already published or in progress, nine met all of these criteria.

The REQUIRE trial, which enrolled people with uncontrolled resistant hypertension, did not meet all quality criteria because treatment physicians and coordinators were not fully blinded and medication adherence was not assessed objectively.

Two randomised controlled trials of periarterial alcohol injection have not yet been published. At present, RDN should therefore rely on procedures applying radiofrequency energy to the main, accessory and distal renal arteries, or unfocused high-frequency ultrasound energy to the main and accessory arteries.

RDN studies without antihypertensive medication

Four of the nine higher-quality randomised trials examined people with uncontrolled office and 24-hour ambulatory blood pressure in the absence of antihypertensive medication, suitable renal-artery anatomy and an eGFR of approximately 40–45 mL/min/1.73 m². In the SPYRAL study, 24-hour systolic blood pressure, the primary endpoint, decreased by 5.0 mmHg compared with the sham procedure (P=0.041).

In SPYRAL HTN-OFF MED, which included 331 people who had stopped all antihypertensive medication, the reduction in 24-hour systolic pressure favoured radiofrequency RDN, with a between-group difference of 3.9 mmHg (P<0.001). In RADIANCE HTN-SOLO, ultrasound RDN reduced daytime systolic pressure by 6.3 mmHg compared with sham treatment (P=0.001). In the pivotal RADIANCE-II trial, 224 people with uncontrolled hypertension were randomised without antihypertensive medication; the reduction in daytime systolic pressure, the primary endpoint, was greater with ultrasound RDN, with a between-group difference of 6.3 mmHg (P<0.001).

There is therefore evidence from several trials that radiofrequency and ultrasound RDN produce a statistically significant reduction in blood pressure in people with hypertension who are not taking antihypertensive medication.

Studies with antihypertensive medication

SPYRAL HTN-ON MED included 80 people with uncontrolled hypertension and elevated 24-hour ambulatory pressure while taking one to three antihypertensive drugs. At six months, radiofrequency RDN was associated with a greater reduction in blood pressure than the sham procedure, with a between-group difference of 7.0 mmHg (P=0.0059), while antihypertensive treatment was unchanged.

In RADIANCE HTN-TRIO, 136 people with uncontrolled resistant hypertension despite more than three drugs were switched during a four-week run-in phase to a single-pill, fixed-dose triple combination before RDN.

During the two-month assessment, ultrasound RDN reduced daytime systolic pressure more than the sham procedure, with a between-group difference of 4.5 mmHg (P=0.022). Triple therapy remained unchanged and adherence remained stable at approximately 80% in both groups.

Published meta-analyses that included randomised trials of high, moderate and low methodological quality have produced variable results. Nevertheless, randomised-trial data consistently show a reduction in 24-hour blood pressure after RDN, ranging from 3.9 to 7.0 mmHg for systolic pressure and from −3.7 to −6.9 mmHg for diastolic pressure. Important gaps remain in defining the expected magnitude or distribution of the reduction after RDN. An individual-patient-data meta-analysis could address this more effectively, although pooled analyses of ultrasound-RDN trials have shown a consistent blood-pressure-lowering effect.

Head-to-head comparisons with properly conducted intensive drug-treatment studies are also needed. The Prague-15 study, which reported similar effects for RDN and optimised drug therapy mainly through the addition of spironolactone, was inconclusive: after six months, 25% of the RDN group had also been prescribed spironolactone, while only 61% of the drug-treatment group were still taking it.

No strong predictor of the future blood-pressure response to RDN has been identified apart from pretreatment blood pressure. This finding is not specific to RDN and has been observed in nearly all trials of antihypertensive drugs. However, the absence of a diagnostic measure that predicts response to a device-based treatment such as RDN remains an important limitation.

Safety

The main safety concerns with RDN are possible injury to the arterial endothelium, intima and media from the applied energy; renal-artery dissection; contrast-associated kidney injury in the short term; and de novo renal-artery stenosis or loss of GFR in the longer term.

No safety signal was identified in the sham-controlled randomised trials, where rates of major adverse events were similar in the RDN and control groups. This conclusion applies to the studied population, generally with an eGFR above 40 mL/min/1.73 m². A meta-analysis of 50 studies including 10,249 patients estimated the incidence of renal-artery stenting after RDN at 0.20 per year, similar to the reported natural occurrence of renal-artery stenosis in hypertension.

Randomised trials using non-invasive renal-artery imaging one year after the procedure have systematically supported the vascular safety of RDN. Similarly, a meta-analysis of 48 studies involving 2,381 patients found no meaningful change in GFR after a mean follow-up of 9.1 months. No acute kidney injury or time-dependent decline in kidney function was reported. In the Global SYMPLICITY registry, the observed fall in eGFR was within the expected age-related decline, although follow-up so far has been limited to three years.

Because currently available RDN devices require femoral-artery access, access-site vascular complications may occur, including haematoma, pseudoaneurysm, fistula and bleeding.

Durability

Long-term data from randomised trials are available, although patients and physicians were generally unblinded after six and twelve months, respectively, and antihypertensive medication was added, changed or stopped by primary-care physicians. Based on an analysis of patients enrolled in the Global SYMPLICITY registry (n=2,652), the documented blood-pressure reduction after RDN appeared to be maintained for up to 36 months.

Similarly, RDN-associated blood-pressure reduction was found during three years of follow-up in RADIANCE HTN-SOLO. However, because of the high rate of crossover to RDN, no formal comparison with the sham group was provided. Comparable limitations affect the three-year durability data reported by SPYRAL HTN-ON MED and the reported long-term increase in the blood-pressure-lowering effect in SYMPLICITY HTN-3, because the size of the long-term pressure difference depends on whether patients who crossed over to RDN are included in the comparison group.

The persistence of the blood-pressure reduction associated with RDN appears inconsistent with functional renal reinnervation reported in hypertensive patients after RDN, although nerve regrowth has been reported in experimental animal models. The function of regrown nerves in these models is uncertain, and long-term human data still require further study. Notably, clinically meaningful reinnervation has not been observed in long-term studies after kidney transplantation.

Clinical application

Intravascular RDN using radiofrequency or unfocused high-frequency ultrasound is a treatment option, either as an adjunct to or an alternative to intensifying medication, in selected patients with uncontrolled resistant hypertension confirmed by ambulatory monitoring after secondary causes have been excluded.

Patients who repeatedly do not adhere to medication, when this reflects an unwillingness to take treatment, or who cannot tolerate several antihypertensive drugs may be considered for RDN after receiving clear information about the possible limited effect and uncertain benefits, as well as procedure-related risks.

Such patients may be taking fewer than three drugs when RDN is considered. To date, there has been no prospective, multicentre, blinded, randomised trial of RDN specifically in this setting. Unfortunately, the same is true of all drug-treatment strategies for truly resistant hypertension. It is therefore unknown whether the blood-pressure reduction in resistant hypertension translates into cardiovascular protection. The value of blood-pressure reduction as a surrogate marker is necessarily extrapolated from the large body of randomised evidence in people with non-resistant hypertension.

Using outcome estimates derived from a large meta-analysis of randomised trials relating blood-pressure reduction to events, the Global SYMPLICITY registry concluded that RDN might reduce relative stroke risk by 43%, while absolute risk of major adverse cardiovascular events might fall from 11.7% in the control group to 8.6% after RDN. Similarly, in 3,077 registry patients, it was estimated that a 10% increase in time within a systolic target of 120–140 mmHg during the first six months after RDN might reduce the risk of major cardiovascular events during months 6–36 by 15%. These conclusions are limited because the blood-pressure–outcome relationship used in the analysis was not derived specifically from patients with resistant hypertension.

RDN should be performed only in experienced specialist centres with a multidisciplinary team and a structured pathway for evaluating people with hypertension. Understanding the patient’s perspective and exploring preferences and expectations are essential before the procedure. The benefits and risks of RDN should be addressed through shared decision-making. In one survey, approximately one third of people with hypertension were inclined to prefer RDN over drug treatment. This was particularly seen in younger people, men, those who had experienced adverse effects and those who acknowledged poor adherence.

Carotid baroreceptor stimulation

Stretch-sensitive baroreceptors in the carotid sinus and aortic arch participate in short- and long-term blood-pressure regulation. External carotid baroreceptor stimulation using a pacemaker-like device, or baroreflex neuromodulation using an endovascular self-expanding nitinol implant in the carotid artery, has been studied for resistant hypertension.

Carotid baroreceptor stimulation has been associated with lower sympathetic nerve activity in studies of people with hypertension. A sympathoinhibitory effect has also been observed when stimulation was applied in hypertensive patients.

The first-generation bilateral electrical stimulation system (Rheos, CVRx) was tested in a pivotal double-blind randomised trial that included 265 people with resistant hypertension. After six months, the reduction in office blood pressure was significantly greater in the treatment group than in the sham group. However, the study failed to meet two of its five co-primary endpoints and safety was not established. Rheos therefore did not receive FDA approval for use in resistant hypertension.

A second-generation unilateral system (Barostim) was developed to reduce procedural complexity, complications and cost. At present, however, randomised controlled trials with this newer system in resistant hypertension are not available. Endovascular baroreflex amplification is achieved by implanting a dedicated stent designed to passively increase wall stretch by increasing the effective vessel radius while preserving pulsatility. In the small, open-label, uncontrolled CALM-FIM first-in-human study, 30 people underwent implantation of the MobiusHD system. At six months, office and ambulatory blood pressure were significantly lower than baseline, and the reduction appeared to persist through 36 months. Several randomised trials are investigating this approach.

Other device-based treatments

Creation of a fixed-diameter iliac arteriovenous anastomosis using a catheter-based device (ROXcoupler, ROX Medical) was studied in resistant hypertension with the intention of lowering peripheral vascular resistance. Creating this shunt produced a significant blood-pressure reduction in the prospective, open-label, randomised ROX CONTROL HTN trial. However, 33% of patients who received the arteriovenous anastomosis developed late ipsilateral venous stenosis requiring treatment. The procedure was discontinued because of the potential high frequency of heart failure after coupler treatment.

The Moderato system (BackBeat cardiac neuromodulation therapy, Orchestra BioMed) is a responsive, dual-chamber implantable pulse generator that variably shortens and lengthens the atrioventricular interval. By shortening atrioventricular coupling, left-ventricular filling and blood pressure may be reduced.

The device intermittently delivers asymmetric sequences of one to three beats with a longer atrioventricular delay, with the aim of preventing compensatory baroreflex-mediated activation of the sympathetic nervous system.

After the initial proof-of-concept MODERATO I study, which included 35 people with uncontrolled hypertension despite two antihypertensive drugs, MODERATO II was conducted as a prospective, multicentre, randomised, double-blind study. In that trial, 68 people with uncontrolled hypertension despite at least one drug and an indication for implantation or replacement of a dual-chamber pacemaker underwent Moderato implantation. In the treatment group, 24-hour systolic blood pressure fell immediately after activation and the blood-pressure-lowering effect was maintained through six months of follow-up.

Although the primary efficacy endpoint, the between-group difference in change in 24-hour systolic pressure, was met and the treatment appeared safe over six months, the long-term consequences of cardiac neuromodulation require investigation in larger trials.

Device-based treatments such as carotid baroreceptor stimulation, arteriovenous anastomosis and cardiac neuromodulation through a dedicated pacemaker are not recommended for routine treatment of hypertension.

Studies mentioned

• SYMPLICITY HTN-3 raised important questions about procedural efficacy and trial design.
• SPYRAL HTN-ON MED and other sham-controlled trials reported modest average reductions in ambulatory and office pressure.
• Global SYMPLICITY analyses suggest possible cardiovascular benefit, but outcome evidence remains less mature than the blood-pressure evidence.
• The ESC/EAPCI consensus statement recommends specialist selection and informed consent.