Renal Denervation: An Answer to Resistant Hypertension

Introduction

Several device-based interventions have been developed for addressing hypertension. Among these, catheter-based renal denervation (RDN) boasts the most extensive body of evidence. RDN achieves its antihypertensive effect by modulating the sympathetic nervous system, primarily by interrupting both afferent and efferent sympathetic renal nerves located in the adventitia and perivascular fat surrounding the renal arteries.^1,2 Initial enthusiasm for RDN emerged over a decade ago, driven by significant reductions in blood pressure (BP) observed in patients with severe, seemingly treatment-resistant hypertension in early open-label registries and randomized controlled trials. However, this enthusiasm waned abruptly following the first sham-controlled trial, Symplicity HTN-3, which, while confirming the safety of the procedure, failed to demonstrate its superiority in BP reduction compared to a sham procedure (involving selective renal angiography only) using a monoelectrode radiofrequency (RF) catheter. Reflecting on these first-generation sham-controlled trials, which have been extensively reviewed previously, they have yielded valuable insights into trial design, execution, and conduct. The thorough methodological examination of these trials, along with new understandings of renal nerve distribution, advancements in catheter systems, and the emergence of new procedural techniques, laid the groundwork for the second generation of sham-controlled trials.

RDN is a much-needed therapy in India perspective also as hypertension is a leading cause of morbidity and mortality. Poor drug compliance and multiple medications is a limiting factor for adequate hypertension control in India. Resistant hypertension is also becoming prevalent in the sub-continent and a novel and long-lasting treatment for hypertension is the need of the hour.

Case discussion

A 76-year-old female, presented with history of hypertension for the past 20 years. Over 20 years, despite multiple medication changes her office BP was 204/105 mmHg at presentation. She was on Telmesartan 40mg OD, Prazosin 5mg OD, Dytor 10mg OD, Eptus 25mg ½ OD, Clonidine 200mg TDS, Labetalol 200mg BD and Nifidepine 30mg BD. Even after taking 7 different classes of anti-hypertensive medications, her ambulatory BP was over 170/110 mmHg with nocturnal hypertension as well.

Her left ventricular function, coronary as well as renal angiogram was normal. She had a serum creatinine of 0.7mg/dl, and estimated glomerular filtration rate (eGFR) of 84ml/min/1.73m2. She underwent RDN in April 2024 at Max Super-speciality Hospital, Saket, New Delhi.

We used Symplicity Spyral (Medtronic) Multielectrode (4 monopolar gold electrodes), helical design, rapid exchange monorail catheter, 60 seconds per ablation cycle, 6Fr compatible for doing RDN in this patient. Right femoral arterial 6Fr access was taken. Symplicity Spyral RDN catheter was advanced over the workhorse percutaneous transluminal coronary angioplasty (PTCA) wire in all the distal and proximal renal arteries of size 3-8mm one by one for doing effective RDN. At the start of the procedure, the patient had a BP of 210/135 mmHg. By the end of the procedure her BP on table was 178/100.

After 24 hours of the procedure, her BP was recorded as 142/90 mmHg. On discharge, 48 hours after the procedure, Nifedipine was discontinued and she was sent home without it. At one month follow-up, her current office BP is 140/90 mmHg on 4 anti-hypertensive medications. She hasn’t had any episode of hypertensive urgency since the procedure. Images 1,2 [Image 1(a), Image 1(b), Image 2(a) and Image 2(b)] show the renal vasculature of our patient and subsequent RDN with Symplicity spiral catheter in the vessels.

Image 1: Symplicity Spyral catheters in right renal vasculature

Image 2: Symplicity Spyral catheter in left renal vasculature

Our experience with RDN has been remarkable and the procedure had quite effective results in our patient.

Rationale

The autonomic nervous system plays a crucial role in regulating cardiac output and BP to ensure adequate organ perfusion. Heightened activity of the sympathetic nervous system raises BP through various mechanisms, including peripheral vasoconstriction, decreased venous capacitance, and diminished renal sodium and water excretion. Sympathetic activation, emanating from the nucleus tractus solitarius and rostral ventrolateral medulla, exerts its influence on all peripheral organs. Among these, the kidneys hold a pivotal position in BP control.³ Sympathetic nerve fibres, originating from the abdominal ganglia, travel alongside the renal arteries, converging on the arteries' adventitia from proximal to distal regions. Activation of efferent sympathetic renal nerve fibres prompts renin release via beta-1 adrenergic receptor stimulation at the juxtaglomerular cells, enhances renal tubular sodium reabsorption through alpha-adrenoceptors, and decreases renal blood flow. Additionally, renal afferent sympathetic nerves respond to renal injury via parenchymal nociceptive receptors and changes in pelvic pressure via pressure-sensitive receptors.⁴

In the first half of the 20th century, surgical sympathectomy emerged as a treatment for severe hypertension, serving as an alternative to antihypertensive medications, which were then limited in availability and poorly tolerated. Surgical sympathectomy effectively lowered BP and was linked to improved survival in individuals with severe hypertension.^5,6 However, this approach came with significant drawbacks, including severe side effects such as postural and postprandial hypotension, syncope, incontinence, and sexual dysfunction, as well as high perioperative morbidity and mortality rates ranging from 0.7% to 10.9%.⁷ Nevertheless, surgical sympathectomy underscored the critical role of the sympathetic nervous system in BP regulation.^8-10

Methods of renal denervation

Most RDN systems use RF energy applied via mono or multi electrode catheters to thermally ablate renal sympathetic nerves (Table 1). Of these systems, the most data are available for the multielectrode Symplicity Spyral catheter (Medtronic).

Table 1: Characteristics of the most important RDN catheter systems

Abbreviations: RDN-Renal denervation

Symplicity Spyral radiofrequency catheter system

We used this system in our patient. The SPYRAL HTN clinical trial program began with two international, multicenter pilot trials utilizing a sham-controlled design, albeit not powered for efficacy outcomes.11 These trials investigated the Symplicity Spyral catheter system and comprised 80 patients each with mild-to-moderate hypertension. One trial involved concomitant antihypertensive medication (SPYRAL HTN-ON MED) while the other did not (SPYRAL HTN-OFF MED). Both trials demonstrated notable reductions in BP following RDN, with minimal BP changes observed in the sham treatment group.^12,13

Following this, two international randomized, sham-controlled trials were conducted, specifically powered to detect changes in 24-hour systolic BP among patients with mild-to-moderate hypertension, either receiving antihypertensive medications (SPYRAL HTN-ON MED Expansion) or not (SPYRAL HTN-OFF MED Pivotal). These trials employed an adaptive Bayesian design, incorporating 80 patients from the pilot trials as informative priors and conducting interim analyses to permit early cessation based on efficacy or futility. The SPYRAL HTN-OFF MED Pivotal trial demonstrated the superiority of RF-RDN over sham in reducing BP, particularly in the absence of concomitant antihypertensive medications. Both primary and secondary effectiveness outcomes were achieved, showing reductions in 24-hour and office systolic BP after 3 months by 3.9 mmHg (95% Bayesian credible interval [BCI]: 1.6 to 6.2) and 6.5 mmHg (95% BCI: 3.5 to 9.6), respectively, with a posterior probability of superiority exceeding 0.999 for both outcomes.^14,15

In contrast to other trials within the SPYRAL HTN program, the SPYRAL HTN-ON MED Expansion trial did not exhibit a significant treatment difference in 24-hour systolic BP between the RDN and sham control groups at the 6-month mark. The primary efficacy outcome showed a marginal difference of -0.03 mmHg (95% BCI: -2.82 to 2.77), with a posterior probability of superiority of 0.51. Notably, while 24-hour BP reductions in the RDN groups remained consistent across trials, there was an unexpectedly large reduction in BP observed in the sham group. Prespecified analyses revealed an imbalanced intensification of medication in the sham group, particularly among patients treated in the USA, extending up to 6 months. Additionally, substantial differences in 24-hour BP patterns were noted between patients enrolled before and during the COVID-19 pandemic.16 Consequently, due to these significant disparities between the pilot and expansion groups, nearly all pilot data for both the sham and treatment groups were disregarded as informative priors for the primary analysis. However, several secondary efficacy outcomes were achieved, including greater reductions in office systolic (adjusted treatment difference: -4.9 mmHg, 95% CI: -7.91 to -1.89; p=0.002) and diastolic BP (-2.0 mmHg, 95% CI: -3.9 to -0.1; p=0.04) in the RDN group compared to the sham group. Analysis of hourly changes in ambulatory systolic and diastolic BP revealed larger reductions during the night in the RDN group compared to the sham group, while daytime BP reductions were similar. These nighttime BP reductions are particularly significant as they are closely linked to adverse cardiovascular events and damage associated with hypertension.¹⁷

Long-term follow-up findings from the Global SYMPLICITY Registry, primarily utilizing the monoelectrode Symplicity Flex catheter system (Medtronic), indicate sustained BP reduction effects for a period of up to three years. Similarly, the SPYRAL HTN-ON MED trial showcased a comparable BP-lowering impact over a three-year follow-up period, while various single-centre, open-label studies reported maintained BP reductions for up to ten years.

Both initial and subsequent studies on radiofrequency renal denervation (RF-RDN) have consistently demonstrated the safety of the procedure, dispelling concerns regarding deteriorating kidney function and the incidence of renal artery stenosis post RDN. Available studies have not reported instances of acute kidney injury or significant declines in kidney function over time. Patients participating in sham-controlled RF RDN trials typically had either normal kidney function or mild-to-moderate impairment at baseline, characterized by an eGFR exceeding 45 ml/min/1.73 m².¹⁸

A meta-analysis incorporating studies published until January 2019, encompassing data from 5,769 subjects with 10,249 patient-years of follow-up, indicated a pooled annual incidence rate for stent implantation following RF-RDN of 0.2%, comparable to the reported natural incidence of renal artery stenosis in hypertension. Additionally, the SPYRAL HTN-OFF MED Pivotal and SPYRAL HTN-ON MED Expansion trials, not covered in the meta-analysis, reaffirmed the safety profile of the procedure. The rate of major adverse events at one month among the initial 253 patients treated with RDN in both SPYRAL HTN-OFF and SPYRAL HTN-ON MED trials was 0.4% (1/253). Notably, no adverse device-related events were recorded, except for one patient undergoing femoral pseudoaneurysm repair at the access site during the SPYRAL HTN-ON MED Expansion Study. ¹⁹

Overall, the procedural risk associated with RF-RDN aligns with the anticipated complication rate of other elective transfemoral arterial access procedures (1-2%). The ongoing SPYRAL AFFIRM trial is currently assessing the long-term safety and efficacy of the Symplicity Spyral catheter system in a real-world setting, enrolling up to 1,000 patients with uncontrolled hypertension and powered for subgroups including type 2 diabetes, isolated systolic hypertension, and chronic kidney disease (ClinicalTrials. gov: NCT05198674). Based on available evidence, the U.S. Food and Drug Administration (FDA) has approved the Symplicity Spyral RDN system for hypertension treatment.^20,21 Figure 1 explains the Key components of a safe and effective procedure.

Figure 1: Key components of a safe and effective procedure²⁵

Abbreviations: ACT : activated clotting time, AE: adverse events, Fr: French; IMA: internal mammary artery, JR: Judkins right coronary, MP: multipurpose; PA: posteroanterior, RDC: renal double curve

Consensus statements and guideline recommendations

The 2018 European Society of Cardiology (ESC)/European Society of Hypertension (ESH) hypertension guidelines were informed by the initial generation of sham-controlled RDN trials. They advise against the routine use of device-based therapies for hypertension treatment, unless within the framework of clinical studies and randomized controlled trials, pending further evidence on their safety and efficacy.22 Acknowledging emerging evidence, several national and international societies and expert groups, including the ESC Council on Hypertension and the European Association of Percutaneous Cardiovascular Interventions (EAPCI), have issued consensus statements. Additionally, the ESH recently updated its hypertension guidelines. Both the ESC/EAPCI consensus statement and the ESH regard RDN as a viable treatment option for patients with resistant hypertension or uncontrolled hypertension despite combination antihypertensive therapy, or in cases where drug treatment causes significant side effects and negatively impacts quality of life (Class II recommendation in the ESH guidelines).

Importantly, both the ESC/EAPCI consensus statement and the ESH hypertension guidelines recommend an eGFR ≥40 ml/min/1.73 m2, consistent with inclusion criteria in the sham controlled trials. Evidence supporting treatment in patients with more severely impaired kidney function is derived from pilot studies and registries.23,24 Patient selection should involve shared decision-making, ensuring that patients are well-informed about RDN's benefits, limitations, and potential risks. Patients should understand that: (i) there is substantial interindividual variability in response across all sham-controlled trials, regardless of the device used; (ii) similar to antihypertensive medications, there is no reliable predictor of BP response to RDN for individual patient selection; and (iii) while the primary goal is BP reduction, most patients will likely require additional antihypertensive medications. (Table 2)

In second-generation RDN trials, BP reductions ranged from 9.0 mmHg to 11.0 mmHg for office systolic BP and from 4.7 mmHg to 8.5 mmHg for 24-hour systolic BP in the RDN groups.

Table 2: Key statements on RDN in the 2022 ESC/EAPCI consensus statement and 2023 ESH hypertension guidelines Abbreviations: COR- Class of recommendation, eGFR-estimated glomerular filtration rate, LOE-Level of evidence, RDN-Renal denervation

Points to ponder

Despite the demonstrated safety and efficacy of ultrasound (US)- and RF-RDN in reducing BP, several critical questions remain unanswered. Firstly, there is a lack of specific predictors or markers for BP response or successful outcomes following RDN. Secondly, unlike first-line antihypertensive medications, there is a dearth of cardiovascular outcome trials for RDN. Given the current low residual risk and the likelihood of confounding factors, the prospect of an outcome trial for RDN in the near future seems unlikely, although it is certainly desirable. However, while BP reduction is a well-established surrogate for reducing cardiovascular outcomes, there is uncertainty regarding whether the BP changes associated with RDN offer similar benefits. An analysis of the Global SYMPLICITY Registry indicated that increased time spent within the target BP range following RDN was linked to fewer major cardiovascular events. It is worth noting that several commonly used BP-lowering therapies, including exercise, metabolic surgery, and various drugs, lack support from cardiovascular outcome trials in hypertension. Lastly, there is a notable absence of well-designed cost effectiveness studies for RDN.

Conflicts of interest

None

Funding source

None

Acknowledgments

None

Conclusion

Several high-quality trials have examined RF and US catheter systems, demonstrating their safety and effectiveness in reducing BP through RDN. As ongoing research explores new technologies, RDN has emerged as a well established and guideline-endorsed treatment approach for hypertension. To ensure the best possible outcomes and safety, RDN procedures should be conducted exclusively at specialized centres staffed by multidisciplinary teams specializing in hypertension management. Throughout the decision-making process, the preferences of well-informed patients should be prioritized.