An Update on the Role of Renal Artery Denervation in the Treatment of Hypertension

Abstract

Purpose of review:

This review provides a practical, evidence-based summary of the physiology, major trial data and clinical role of renal denervation in the treatment of hypertension

Recent findings:

The cornerstone of hypertension therapy remains anti-hypertensive medications although this strategy has significant limitations with poor rates of blood pressure control for most patients. Renal denervation was designed to bypass concerns about medication adherence and provide an “always-on” treatment. Recent trial data and meta-analyses are presented demonstrating a modest, although heterogeneous, response to renal denervation which led to the treatment’s recent FDA approval. Improvements in catheter design and renal artery treatment strategy may underlie the improved clinical response to denervation in more recent trials.

Summary:

Hypertension centers involving multi-disciplinary care teams are equipped to provide patients with advanced diagnostic testing for secondary hypertension, comprehensive non-invasive management strategies and invasive renal denervation to address hypertension. Early referral for patients with uncontrolled hypertension can provide patients with nuanced conservative and interventional options which have the potential to improve hypertension related morbidity and mortality. Future studies are needed to identify which patients are most likely to respond to renal denervation.

OPINION STATEMENT

At our institution, the hypertension center involves a multi-disciplinary care team with experience in evaluating and treating advanced hypertension, including cardiologists, interventional radiologists, endocrinologists, nephrologists and general internists as well as registered nurses and clinical pharmacists. Our approach to hypertension care is similar to that recommended by the most recent American Heart Association/American College of Cardiology (AHA/ACC) hypertension guidelines and subsequent societal consensus statements. Patients are treated with a multi-pronged approach including lifestyle modification, identification of secondary causes of hypertension, initiation of best-in-class, first-line anti-hypertensive medications and consideration of invasive renal denervation. All patients referred for renal denervation are first evaluated by hypertension specialists to ensure accurate blood pressure values and thoroughly evaluate secondary causes and other contributors to hypertension. This evaluation includes appropriate diagnostic testing that can inform targeted treatment strategies. We use goal-based shared-decision making to discuss the risks and benefits of renal denervation and the uncertainty about any particular individual’s response to therapy. This discussion includes each patient’s global cardiovascular risk and their preferences regarding treatment modalities. If patients elect to proceed with renal denervation, they are referred to interventional cardiologists with expertise in renal interventions and with specific training in renal denervation procedures. Although rare, centers performing these procedures should have the skill and resources to manage complications. After the procedure, our hypertension center continues to follow patients for medication titration as most patients who have received renal denervation will need ongoing anti-hypertensive medication to maintain blood pressure control. Renal denervation has a role in the treatment of hypertension although future research is needed to identify which patients are most likely to benefit from this adjunctive therapy.

INTRODUCTION

Hypertension is the leading modifiable risk factor associated with world-wide death, accounting for nearly 20% of global deaths as of 2019. (1,2) It remains extremely common, affecting nearly 45% of US adults. (3)The absolute number of people affected has nearly doubled in the last thirty years, increasing from 648 million in 1990 to 1.28 billion in 2019. (4) For more than a century, an association between hypertension and cardiovascular disease has been recognized. (5)The Framingham Heart Study, launched in 1948, provided the first clear evidence of a graded association between hypertension and an increased risk of ischemic heart disease, heart failure, stroke and noncardiac vascular disease. (6)The subsequent Veteran’s Administration (now Veteran’s Affairs) cooperative study established for the first time that treating hypertension improved morbidity and mortality. (7)

Many classes of medications are readily available, are inexpensive and have excellent benefit/harm ratios with favorable side effect profiles. Moreover, even modest reductions in blood pressure can yield substantial clinical benefits – a 5 mm Hg reduction in systolic blood pressure reduces the risk of major adverse cardiac events by 10%. (8)

Despite these advantages, there are many challenges associated with controlling hypertension. Most hypertensive individuals are asymptomatic, with more than half of patients with hypertension unaware of their elevated blood pressure. (9) The lack of awareness and symptoms may diminish motivation to seek and follow treatment. Several factors that influence high blood pressure require sustained behavior change including avoiding high sodium foods, curtailing excess alcohol use, increasing exercise and maintaining an optimal weight. Sustained adherence to health behavior changes such as these is challenging. (10) Blood pressure values are frequently inaccurate, making medication titration difficult. (11) Furthermore, “clinical inertia”, or the failure to intensify therapy when guidelines indicate doing so, is a common cause of uncontrolled blood pressure. (12)

Imperfect adherence to prescribed medication is also common. Numerous studies evaluating patients with resistant hypertension have shown nonadherence rates of 30% or higher. (13) Several factors contribute to this poor adherence including medication cost, insurance coverage and medication side effects. Regimen complexity is also a factor. For example, among US Medicare beneficiaries with cardiovascular illness, hypertension is by far the most common comorbid condition; the majority of these patients with high blood pressure are prescribed medication to treat comorbid illness. (14) Medication regimens are typically sustained for years, as most patients will require lifelong antihypertensive drug therapy to achieve blood pressure control. Even with perfect adherence, 10–20% of patients will have persistently elevated blood pressures despite maximally tolerated anti-hypertensive therapy.(15)

Due to these difficulties, rates of BP control are dismal in low-, middle-, and high-income countries. More than three-quarters of US adults with hypertension have BPs above guideline recommendations and the prevalence of controlled BP has decreased since 2013. (16,17) Racial/ethnic disparities also exist: non-Hispanic Black individuals, Hispanic individuals and Asian American individuals have lower blood pressure control rates as compared to White individuals. (17)These data are so alarming that the US Surgeon General published a call to action making hypertension a national priority. (18)

Given the scope of the problem and significant missed opportunity to prevent morbidity and mortality, new approaches and therapies are needed. Renal denervation (RDN) has recently been approved by the FDA to add to the armamentarium of blood pressure control. RDN has been demonstrated to be safe and well tolerated. In addition, as an “always on” therapy, it is not subject to issues of patient adherence. This article will explore the physiologic basis of RDN, the trial data that led to its FDA approval and strategies for its clinical application.

PHYSIOLOGY OF RDN

Blood pressure regulation is achieved by a complex interplay of the central nervous system, cardiovascular system, kidney and adrenal glands. Together, these systems govern cardiac output, peripheral vascular resistance and fluid volume – the key components of blood pressure. More than 50 years ago, Guyton and Coleman postulated that blood pressure homeostasis is achieved by coupling pressure with salt and water excretion by the kidney. (19) As blood pressure rises, the perfusion pressure in the renal artery rises resulting in a rapid increase in sodium and water elimination – the “pressure-natriuresis” mechanism. (20)

This coupling is achieved in part through complex interactions between the renin-angiotensin-aldosterone (RAAS) system and the renal sympathetic nervous system. (21)Specifically, when efferent renal sympathetic fibers running in the adventitia of the renal arteries are stimulated, they promote sodium and water reuptake in the renal tubules and renin secretion from the juxtaglomerular apparatus. (22,23)Interestingly, the renal response appears to be dependent on the intensity of sympathetic stimulation. Low stimulation levels result in renin release, moderate stimulation increases sodium reabsorption and high stimulation increases renal vascular resistance. (24) Efferent renal sympathetic fibers appear to be particularly influential in patients with the metabolic syndrome.(25)

Afferent renal sympathetic fibers likely also contribute to the pathologic development of hypertension. The bulk of afferent renal sympathetic nerves lie in the renal pelvis where they respond to changes in hydrostatic pressure and the chemical environment of the renal interstitium. (26,27)These signals are transmitted through the posterior gray column of the ipsilateral spinal cord to autonomic centers in the central nervous system and to the contralateral kidney – influencing systemic sympathetic tone. (28)Importantly, there is substantial variation in regional sympathetic activity within a patient. (29)For example, patients with advanced heart failure frequently have elevated renal and cardiac sympathetic activation with normal systemic sympathetic activity. (30)

Clinically, manipulating the sympathetic nervous system to ameliorate elevated blood pressures has long been a goal. Nearly a century ago, when oral medications were unavailable for routine treatment of elevated blood pressures, several surgical approaches were developed to treat resistant hypertension. These surgical techniques included radical surgical sympathectomy (severing both the splanchnic nerves and thoracic dorsal sympathetic chain thus interrupting sympathetic outflow) and bilateral adrenalectomy; although widespread adoption was stymied by surgical morbidity and intolerable long-term side effects (ie development of Addison’s disease). (31,32)Notably, side effects did not include dysfunction of renal control of electrolytes and volume. Indeed, as extensive human renal transplant experience shows, the denervated kidney can perform these homeostatic functions normally.

In the last two decades there has been an explosion of minimally invasive catheter-based techniques designed to provide the benefit of sympathectomy with reduced surgical morbidity and deleterious side effects. RDN has been evaluated in extensive and diverse animal models of hypertension, initially to elucidate the role of the renal sympathetic nervous system in hypertension and subsequently as models of therapeutic denervation. (33)For example, salt-sensitive swine, genetically hypertensive rats, 2-kidney 1-clip Goldblatt rats, 1-kidney renal hypertension rats and obese dogs have all been evaluated with RDN (albeit with differing techniques for denervation). (34–38) Based on promising blood pressure reductions in these animal models and historical benefit among patients undergoing more extensive sympathectomy, a first-in-human minimally invasive RDN was performed by Schlaich and colleagues in 2009. (39)

RDN DEVICES

Since the first report of RDN in humans, there has been an explosion of minimally invasive techniques designed to provide the benefit of sympathectomy with reduced surgical morbidity and deleterious side effects. Three primary modalities have been developed to provide targeted injury to renal sympathetic nerves without damaging surrounding structures. These modalities include radiofrequency thermal energy, ultrasound-delivered thermal energy and injection of neurolytic agents into the perivascular tissue. Only radiofrequency (ie Symplicity Spyral System by Medtronic) and ultrasound (ie Paradise Ultrasound (US) System by ReCor Medical) devices are currently available for clinical use.

The Symplicity Spyral Renal Denervation System by Medtronic consists of two main components: a single-use catheter (Symplicity Spyral multi-electrode renal denervation catheter (also referred to as “Symplicity Spyral Catheter”) and a reusable radiofrequency generator (also referred to as “Symplicity G3 Renal Denervation RF generator” or “Symplicity G3 RF generator”). (40) Once the renal artery is engaged with a non-jacketed 014 wire, the Symplicity catheter is advanced over the wire to the target vessel and the generator is activated to deliver low-level radiofrequency energy (typically in 8W bursts) through 4 gold electrodes distributed across the helical design. The same catheter can treat vessels 3 to 8mm in diameter. Treatment is initiated in the distal renal artery branches >3mm outside the renal parenchyma where sympathetic innervation is greatest. Denervation is then continued proximally without overlap. 60 seconds of thermal energy is considered a successful treatment. The procedure is repeated for ipsilateral accessory artery branches and the contralateral renal artery. The Symplicity generator uses an algorithm to monitor and control temperature, impedance, and power output to assure delivery of energy to each site.

The Paradise Ultrasound Renal Denervation System (Paradise uRDN System) by ReCor Medical includes the Paradise Catheter with ultrasound transducer, Paradise Generator, Paradise Cartridge, and the Paradise Connection Cable. (41) Following invasive angiography to confirm amenable anatomy, the catheter is positioned in the proximal renal artery and sterile water is circulated through the distal balloon at a pressure of 1.8 atmospheres to serve as a coolant and prevent arterial wall injury from excess heat. The pressurized balloon stabilizes the ultrasound transducer within the main renal artery while high frequency energy (8.7 – 9.3 MHz) is delivered. The system is designed to ablate peri-arterial tissue from 1–6mm from the arterial lumen.

REVIEW OF CLINICAL TRIALS

Promising cohort studies and case reports exploring endovascular RDN provided the initial proof-of-concept foundation and enthusiasm for subsequent clinical trial investigations. (42) The first randomized, blinded, sham-control trial exploring RDN was SYMPLICITY-HTN-3. (43) The study included patients with severe resistant hypertension on 3 or more antihypertensives and randomized them to receive a sham procedure or RDN with the Symplicity Flex system, a single electrode radiofrequency device. At 6 months, although there was a notable blood pressure reduction in the intervention arm, patients in the sham control arm were also observed to have a similar blood pressure reduction and thus the study failed to achieve its primary outcome. Potential explanations for this include permissive use of breakthrough blood pressure agents in the sham control arm and concerns about performance of the Symplicity Flex system, where catheter ablations were focused only in the proximal vessel and were erratic based on the end-catheter design (44) Unsurprisingly, several similar trials, including RSD-Leipzig and ReSET, which studied the Symplicity Flex system, similarly failed to achieve their primary endpoints. (45)

Limitations of prior studies and the advancement of novel devices gave rise to a new generation of sham-control RDN trials implementing both radiofrequency and ultrasound mediated techniques. The first of which came from the SPYRAL HTN Global Clinical Program which implemented the Symplicity Spyral system, a multiple electrode radiofrequency device. The SPYRAL HTN-OFF MED Pilot (2017) randomized patients not on antihypertensive agents to RDN vs sham procedure groups. At 3 months post-procedure, the mean difference in 24-hr ambulatory SBPs from baseline between RDN and sham-control groups was −5.0 mmHg. (46) This study was followed by SPYRAL HTN-ON MED (2018), which implemented the sham-control study design with patients on one to three antihypertensive agents. At 6 months post-procedure, there was no significant difference in mean difference in 24-hr ambulatory SBPs from baseline between RDN and sham-control. However, the mean difference in office SBP from baseline between RDN and sham-control groups was significant and found to be −4.9 mmHg. (47) The HTN-ON Med trial had important challenges in implementation, including breakthrough medication usage in the sham arm and completion of follow-up during the COVID19 pandemic. Long-term data from HTN-ON MED ultimately found a significant difference in the mean 24-hr ambulatory SBPs at 36 months from baseline between RDN and sham-control groups to be −10.0 mmHg. (47)

Alongside SPYRAL HTN-ON-MED, the sham-control RADIANCE trials began exploring the ultrasound-mediated Paradise system. In RADIANCE-HTN-SOLO (2018), patients with hypertension who were not on antihypertensive agents were randomized to receive RDN vs sham procedure. At 2 months post-procedure, the mean difference in daytime ambulatory blood pressure from baseline between the RDN group and the sham-control group was −6.3 mmHg. (48) Additionally, there was durable treatment effect seen at 36 months post-procedure with the mean difference in office systolic blood pressure from baseline between the RDN group and the sham-control group found to be −8.4 mmHg. (49)

Following RADIANCE-HTN-SOLO came the SPYRAL HTN-OFF MED Pivotal Trial (2020). Expanding on and incorporating data from its Pilot predecessor, patients not on antihypertensive agents were randomized to RDN vs sham procedure groups. At 3 months post-procedure, the mean difference in 24-hr ambulatory SBPs from baseline between RDN and sham-control groups was −3.9 mmHg, providing further support for radiofrequency mediated denervation. (50) In 2021, RADIANCE HTN-TRIO, studying patients with uncontrolled blood pressure on 3 antihypertensive agents with the same sham-control design, provided further insights for ultrasound-mediated denervation in combination with antihypertensives. At 2 months post-procedure, the median difference in daytime ambulatory blood pressure from baseline between RDN group and sham-control group was −4.5 mmHg. (51) Again, there was durable treatment effect seen at 24 months post-procedure with the mean difference in office systolic blood pressure from baseline between the RDN group and the sham-control group found to be −14.6 mmHg. (52) RADIANCE II (2023), implementing the sham-control design with patients who had hypertension on up to two antihypertensive medications, yielded further support for denervation. At 2 months post-procedure, the mean difference in daytime ambulatory blood pressure from baseline between the RDN group and the sham-control group was −6.3 mmHg. (53)

In addition to the abundance of sham-control trial data, the Global Symplicity Registry (2019), which followed patients treated with Symplicity Flex, provided important longitudinal data. Three years after treatment with RDN, there was a durable decrease in office and 24-hr ambulatory SBP of −16.5 mmHg and −8.0 mmHg. (54) In 2021, the SPYRAL AFFIRM trial, a single-arm, open-label trial studying patients who were treated with RDN, was initiated. This ongoing study is similarly expected to add valuable long-term safety and efficacy data information to the current evidence in support of RDN. (55)

While the SPYRAL and RADIANCE trials provided the foundation for FDA approval of renal denervation, it is pertinent to discuss the trials exploring a third mechanism of denervation, the alcohol-mediated technique. Alcohol-mediated ablation, which is not currently approved by the FDA, occurs via a catheter-based device, such as the Peregrine system, which delivers dehydrated ethanol via microneedles. TARGET BP OFF-MED (2023) was a sham-control trial studying this device in patients with uncontrolled hypertension not on antihypertensives. TARGET BP I was also a sham-control trial studying the Peregrine system in patients with hypertension on two to five antihypertensives. Neither trial found a significant difference in mean ambulatory SBP at their respective eight-week and three-month primary endpoints. (56,57) However, the TARGET BP OFF-MED trial did show a trend of reduced medication burden at 12-month follow-up in those treated with RDN, suggesting a possible positive treatment effect.

In addition to assessment of efficacy, the previously discussed trials also provided key safety data. A recent meta-analysis analyzing 15 RCTS including the above trials, found that there were no immediate procedural complications associated with RDN and that there were few short- and long-term adverse events. Access site complications and acute kidney injury occurred in 2.3% and 0.64% of all RDN and sham cases respectively. Renal artery stenosis occurred in 0.4% of denervation cases compared to none in sham group. No patients progressed to end-stage renal disease in either group. The meta-analysis found that at a mean follow-up of five months, there were three deaths, nine cerebral vascular accidents, and eight myocardial infarctions reported in denervation groups, compared to two, seven, and six in sham groups respectively. (58) Taken collectively, the renal denervation sham-control trials demonstrate adequate short- and long-term safety profiles with infrequent adverse advents.

In summary, the SPYRAL and RADIANCE trials implementing the Symplicity Spyral and Paradise systems provided valuable efficacy and safety data in support of RDN as a viable treatment for patients with uncontrolled hypertension, both synergistically with and independently from pharmacologic antihypertensives. The ongoing SPYRAL AFFIRM trial will provide additional long-term safety and efficacy data. While the TARGET trials failed to show statistically significant difference in blood pressure outcomes using the Peregrine system, TARGET BP OFF-MED demonstrated a trend towards lower medication burden at 12-months, suggesting that more data may be needed to understand the effects of alcohol-mediated denervation. Core characteristics and outcomes of these key trials are summarized in Table 1.

Table 1.

Core characteristics and outcomes of key renal denervation trials

Denervation System (Method)	Trial	Sham Control?	On Antihypertensive Agents?	Number of Participants	Outcomes
					Change in 24-hr ambulatory SBP from baseline (mmHg)	Δ RDN and Sham Groups	Change in office systolic blood pressure (mmHg)	Δ RDN and Sham Groups
Symplicity Flex (Radiofrequency)	SYMPLICITY-HTN-3	Yes	Yes	535	RDN: −6.8 Sham: −4.8	−2.0	RDN: −14.1 Sham: −11.7	−2.4
	RSD-Leipzig	Yes	Yes	71	RDN:−7.0 Sham: −3.5	−3.5	Not Assessed	-
	ReSET	Yes	Yes	69	RDN:−3.7 Sham: −2.6	−1.3	Not Assessed	-
Symplicity Spyral (Radiofrequency)	SPYRAL HTN-OFF MED Pilot	Yes	No	80	RDN:−5.5 Sham: −0.5	−5.0	RDN: −10.0 Sham: −2.3	−7.3
	SPYRAL HTN-OFF MED Pivotal	Yes	Yes	331	RDN: −4.7 Sham: −0.6	−4.1	RDN: −9.2 Sham: −2.5	−6.7
	SPYRAL HTN-ON MED	Yes	Yes	337	RDN:−6.5 Sham: −4.5	−2.0	RDN: −9.9 Sham: −5.1	−4.8
	SPYRAL AFFIRM	No	Yes	-	-	-	-	-
Paradise (Ultrasound)	RADIANCE HTN-SOLO	Yes	No	146	RDN:−7.0 Sham: −3.1	−3.9	RDN: −10.8 Sham: −3.9	−6.9
	RADIANCE HTN-TRIO	Yes	Yes	136	RDN:−8.5 Sham: −2.9	−5.6	RDN: −9.0 Sham: −4.0	−6.0
	RADIANCE II	Yes	No	224	RDN:−7.7 Sham: −1.7	−6.0	RDN: −11.0 Sham: −5.5	−5.5
Peregrine (Alcohol-Mediated)	TARGET BP OFF-MED	Yes	No	100	RDN:−2.9 Sham: −1.4	−1.5	RDN: −4.0 Sham: −0.6	−3.4
	TARGET BP 1	Yes	Yes	301	RDN: −10.0 Sham: −6.8	−3.2	RDN: −12.7 Sham: −9.7	−3.0

Key: SBP = systolic blood pressure, RDN = renal denervation, mmHg = millimeters of mercury

FDA APPROVAL

Both the radiofrequency-mediated Symplicity Spyral and ultrasound-mediated Paradise RDN systems received FDA breakthrough device status in 2021 due to their initial demonstration of efficacy in treatment of uncontrolled hypertension as outlined previously. The FDA review also found similar levels of adverse events to those of other catheter-based procedures, namely access-site complications and vasospasm. Additionally, there was no evidence of renal injury, clinically-significant renal artery stenosis, or renal artery injury requiring intervention following RDN with either system. (40,41)

Given the reassuring safety data combined with the trial evidence of modest reduction in blood pressure, the Symplicity Spyral System and Paradise System each received FDA approval in November 2023. The approvals identify RDN as “adjunctive treatment in hypertension patients in whom lifestyle modifications and antihypertensive medications do not adequately control blood pressure,” while also providing contraindications, including pregnancy, fibromuscular dysplasia, and specific anatomical limitation outlined in final FDA approval documentation.

RDN TECHNIQUE

Although the delivery of neurolytic therapy differs between modality, each technique shares substantial overlap for accessing the renal artery lumen. Full technical details for performing and trouble-shooting the procedure are beyond the scope of this review, however, a brief review of the procedure is useful for framing potential complications and counseling patients. Additional technical procedural details are published elsewhere; as are recommendations for the standards or operator knowledge and procedural skill sets for peripheral interventions and RDN. (59–61)

Prior to the procedure, anatomical imaging (CTA or MRA) is often used to size the renal arteries prior to the procedure and ensure no anatomical exclusion criteria are present. FDA listed contraindications to the Symplicity and Paradise catheters are the same and include renal artery diameter <3mm or >8mm, renal artery fibromuscular dysplasia (FMD), prior renal artery stent, renal artery aneurysm, stenosis <30%, presence of kidney or adrenal tumors, pregnancy or iliac/femoral artery stenoses that preclude insertion of the catheter.

After patients are deemed candidates, they are brought to a procedural suite and are given conscious sedation as is typical of coronary angiography. (62)After the patient is sedated, a femoral arteriotomy is performed, ideally under ultrasound guidance to improve the speed and safety of arterial access. (63)A sheath is then introduced into the femoral arteriotomy site (6 Fr for Symplicity system and 7 Fr for Paradise US system) and the patient is anticoagulated (typically unfractionated heparin or bivalirudin to achieve an activating clotting time of >250). A non-selective aortic angiogram is obtained next to evaluate the position of the main renal artery and any accessory branches that may warrant treatment. Accessory arteries are common, occurring in roughly one-third of people. (64)Most fluoroscopic images can be obtained in a posterior-anterior projection although slight cranial or caudal with ipsilateral oblique angling may help with overlapping vascular branches. Once the renal artery and accessory branches are identified a guide catheter is used to engage the renal artery. A “no touch” technique for engaging the renal arteries may help to reduce the potential for intimal disruption and cholesterol plaque embolization. (65) After the artery is engaged, selective renal angiography is performed to assure candidacy for RDN. The RDN intervention is then performed as recommended by the manufacturer (see below for details). After denervation, angiography of the renal arteries is repeated to assess for renovascular injury. At the conclusion of the procedure, all wires and sheaths are removed via the femoral arteriotomy site and the wound is closed with manual pressure or a hemostatic closure device. Most procedures can be performed in an endovascular suite with conscious sedation and same day discharge.

A notable development in procedural technique is a greater emphasis on treating distal segmental renal artery branches and accessory renal arteries with their segmental branches. The first RDN devices treated only the main renal artery, proximal to segmental artery branches. This strategy was pursued because the main renal artery was easiest to access and because it was believed that the sympathetic renal fibers arborized uniformly throughout the course of the renal artery. After equivocal findings in randomized control trials, however, a more detailed evaluation of human sympathetic neural anatomy was pursued. (58) Recent studies have shown that a substantial portion of sympathetic nerves bypass the main renal artery entirely. These “late-arriving nerves” touch down first in the segmental main and accessory renal arteries and extend distally. (66) Regardless of touchdown location, sympathetic nerves are closer to the arterial lumen in the distal arteries than in proximal segments. (67) This has important potential implications among device techniques, as currently, only radiofrequency ablation can treat these more distal targets. However, there have been no rigorous head-to-head comparisons of different denervation modalities, so it remains uncertain if these anatomic considerations are important for clinical benefit.

There is no consensus yet on appropriate follow-up for patients after RDN. The procedure has been exceptionally safe in clinical trials with few long-term renal artery injuries. For example, a meta-analysis of 14 RDN studies showed only one of 511 patients with new renal artery stenosis (median 11-month follow-up). (68) Therefore, renal artery imaging post-procedure is likely unnecessary without other clinical evidence of renal artery injury. Most patients will still have hypertension after RDN, so continued management of patient’s BP is important.

USING RDN IN CLINICAL PRACTICE

With FDA approval, nearly 93 million US adults with uncontrolled hypertension qualify for RDN based on the broad parameters outlined by the FDA. (69) Immediate delivery of therapy to all these individuals is not feasible so clinicians must select patients appropriate for RDN while awaiting evolving scientific evidence that may provide more specific guidance about those most likely to benefit. Additionally, the US Centers for Medicare and Medicaid Services (CMS) approved a new ICD-10-PCS billing code which allows for an additional maximum of $14,950 reimbursement for RDN in addition to regular Medicare Severity Diagnosis Related Group payments when using these devices for inpatient procedures. (70) Although there are suggestions that this may be cost-effective, if all eligible patients were to receive the therapy, the up-front cost would be substantial. (71)

To help guide patient selection, numerous national, international and societal consensus documents have been created. (61,72–76) These statements generally emphasize the importance of extrapolating safety and efficacy trial data only to patients like those in trials. Particularly relevant subsets of patients that were excluded from trials include those with moderate or greater chronic kidney disease (SPYRAL trials excluded patients with estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m², and the RADIANCE trials excluded patients with eGFR <40 mL/min/1.73 m²) or one of many renal anomalies (for example adult polycystic kidney disease (PCKD), single kidney, renal tumors, renal stents, renal transplantation, or fibromuscular dysplasia among others). The consensus statements universally recommend completion of a secondary hypertension workup and treatment of any underlying condition before considering RDN.

Based on the consensus statements, we propose a synthesized approach to patient selection which fits into our center’s overall model of hypertension management (Figure 1). The critical elements include using high-quality BP data, discussing lifestyle modification, optimizing medical therapy with first line, best-in-class antihypertensives, addressing sources of medication non-adherence and identifying and treating secondary causes and contributors to hypertension. More specific to RDN are the importance of multidisciplinary teams, patient preference and shared decision making. These are important topics that are worth discussing in turn.

Figure 1. A multidisciplinary team approach to the management of hypertension.

Key: BP = blood pressure, RDN = renal denervation

Multidisciplinary hypertension teams should be led by a hypertension specialist who serves a central role in coordinating patient’s hypertension care, often this is a cardiologist, nephrologist, endocrinologist or internal medicine physician with specific training in evaluating and managing patients with complex hypertension. Additional team members may include nurses, advanced practice nurses, physician assistants, clinical pharmacists, nutritionists, social workers, and allied health professionals. For example, nurses are critical for triage, home BP recordings and a variety of patient concerns. Consultants in nephrology (for patients with advanced kidney disease or PCKD), endocrinology (for patients with primary aldosteronism, Cushing syndrome, congenital adrenal hyperplasia, and pheochromocytoma), interventional radiology (adrenal vein sampling), adrenal surgery and interventional cardiology (for renal artery stenting and RDN) ensure that patients receive expert care within a variety of hypertension domains. Hypertension-trained clinical pharmacists have been shown to improve BP control in part by implementing strategies to improve medication adherence and prospectively identifying drug interactions. (77) The multidisciplinary hypertension team is ideally suited to evaluate secondary causes of hypertension and to consider the risks and benefits of RDN.

Patient preference is central to the individualized evaluation of RDN. Patients may choose an invasive or noninvasive strategy for treatment of hypertension for various nuanced reasons. In one survey, control of blood pressure was the most important driver of patient preference although patients may choose RDN to minimize medication burden, side effects or cost. (78) Regardless of motivation, it is important to counsel patients that only a minority of individuals will be able to stop all medications and maintain adequate BP control.

Goal-based shared decision making (SDM) is the ideal process by which patients and the multidisciplinary hypertension team determine a treatment plan. (79) SDM is best understood as a conversation among experts. (80) Patients are expert on their values, goals, preferences and perception of risk. Clinicians are expert on workup and treatment options as well as the available knowledge about the risks and benefits of each. To achieve excellent SDM, language must be stripped of technical jargon. SDM in RDN requires that clinicians are transparent about the uncertainty of an individual patient’s response to RDN and the durability of that response. Although many metrics have been evaluated, pre-procedural BP is the only reliable predictor of BP response after the procedure. (81–86) Moreover, although it has not been observed clinically in RDN, sympathetic reinnervation may occur in the denervated kidney, as described in some patients after kidney transplantation. (87,88)

Patients may benefit from visual aids that serve as a reference outside of appointments to help guide complicated decision making. Indeed, these Patient Decision Aids (PDAs) have shown efficacy in more than 100 randomized control trials and have been used successfully in other cardiovascular domains. (89,90)There are clear guidelines to ensure guide PDA creation and quality. (91) Still, no PDA is yet available for RDN, an unmet need.

Finally, clinicians have a responsibility to triage patients for RDN. For example, it is reasonable to consider earlier intervention for patients with high cardiovascular risk who may derive the greatest clinical benefit. Clinicians must also be cognizant of how a patient’s race, ethnicity, gender and other factors influence what therapies are offered. Women and racial or ethnic minorities are less likely to receive a wide variety of cardiovascular treatments as compared to men and persons who self-identify as White. For example, women and racial and ethnic minorities have a lower likelihood of receiving implantable cardioverter-defibrillators, cardiac resynchronization therapy, and advanced heart failure therapies. (92–95) Of critical relevance, Non-Hispanic Black Americans have a higher prevalence of hypertension and lower rates of BP control, a primary driver of a higher incidence of cardiovascular disease. (96)

CONCLUSIONS

Hypertension is the leading cause of treatable death and disability worldwide and rates of BP control are poor and decreasing despite the availability and proven efficacy of a broad array of medication options and lifestyle modifications. RDN is an attractive treatment strategy for its potential to address many of the challenges posed by antihypertensive medication regimens. Although data has been mixed, the bulk of randomized, sham-controlled data suggests a modest benefit to RDN for most patients although there is significant variability in response. As there is a critical need for alternative treatments for hypertension, we feel that the addition of this novel approach is an important tool in the armamentarium for hypertension therapy. Further studies to identify which patients are most likely to benefit from RDN are critical as is an equitable, need-based launch of this newly approved therapy. Multidisciplinary hypertension teams are optimally positioned to guide patients through the complicated workup and treatment of hypertension including identifying patients who are most likely to benefit from RDN therapy.