Consensus and inconsistency between different consensus documents on renal denervation worldwide: the way forward : Chinese Medical Journal

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Consensus and inconsistency between different consensus documents on renal denervation worldwide: the way forward

Wang, Tzung-Dau

Editor(s): Wang, Ningning

Author Information
Chinese Medical Journal: September 8, 2022 - Volume - Issue - 10.1097/CM9.0000000000002109
doi: 10.1097/CM9.0000000000002109
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Abstract

Hypertension is the most prevalent modifiable cause of cardiovascular diseases and all-cause death worldwide.[1] Numerous pharmacological intervention trials have demonstrated that reducing office or home blood pressure (BP) to <130/80 mmHg can significantly lower the risk of cardiovascular events.[2-6] Although many effective and well-tolerated lifestyle interventions and pharmacological agents can reduce BP, the overall control rates among hypertensive patients remain <25% globally.[1,7] Of the various causes of suboptimal hypertension control, non-adherence to either lifestyle modifications or BP-lowering drugs is the most crucial, and it also negatively impacts the control rates of all non-communicable chronic diseases.[1-8] A study based on the Reimbursement Claims Database in Taiwan (China) from 2001 to 2007 reported that the rate of medication adherence, defined as having medications refilled for ≥80% of days in the year after initiating BP-lowering drugs, was only 18.6%.[9] This finding demonstrates that there is a fundamental flaw in the current management of hypertension, in that relying on self-disciplined daily medication-taking behavior in the long run is not practical. Accordingly, a safe and effective device-based treatment strategy that can attain clinically meaningful, around-the-clock, long-term BP reduction is urgently needed. In this regard, catheter-based renal denervation (RDN) therapy has been widely studied to ascertain whether it can serve as an alternative or complementary BP-lowering strategy.[10] In this narrative review, we provide a rationale and evidence for RDN, then compare the representative consensus documents on RDN worldwide regarding patient selection, pre- and post-RDN assessment recommendations, technical requirements for RDN, clinical practice integration, and knowledge gaps which should be solved to improve the application of this technology. Relevant literature was obtained by searching the PubMed database for research articles published up to October 2021 using the keywords “renal denervation,” “consensus,” “position paper,” and combinations of these terms. Consensus documents and position papers on RDN were chosen if they fulfilled the following selection criteria: endorsed by at least two professional societies or one professional society which encompasses multiple countries/regions, covering at least two of the above-mentioned four sectors (patient selection, pre- and post-RDN assessments, technical requirements, and clinical practice integration), and the most updated version. The references of all selected consensus statements were reviewed and supplemented by personal communications with leading experts on this topic.

Rationale and Clinical Evidence for RDN

Pathophysiology and anatomy for RDN

Hypertension is a multifactorial disease. Sympathetic overactivity, sodium/volume overload, and activation of the renin-angiotensin system are the three major and interrelated mechanisms of hypertension.[11] Acute sympathetic activation causes a transient elevation in BP by stimulating hemodynamic activity.[12,13] Chronic sympathetic overactivity drives sustained hypertension via its effects on the kidneys.[11] The central nervous system and the kidneys communicate reciprocally via renal afferent and efferent nerves. Renal efferent sympathetic nerve activity regulates renal hemodynamics and excretory function in a dose-dependent manner. Low levels of renal sympathetic nerve activity increase the release of renin by stimulating β1-adrenoreceptors on juxtaglomerular cells.[14,15] At slightly higher levels of stimulation, the increase in renin secretion is accompanied by increased renal tubular sodium reabsorption and decreased urinary sodium excretion via α1B-adrenoceptors.[16] Higher levels of renal sympathetic nerve activity decrease renal blood flow and glomerular filtration rate via stimulation of α1A-adrenoceptors.[17] The release of renin also promotes activation of the renin-angiotensin-aldosterone system. This in turn increases the activity of the sympathetic nervous system through the release of angiotensin II, increases sodium and water resorption and renal vasoconstriction, and further enhances the elevation of BP.

Afferent renal nerve fibers are predominantly located in the renal pelvis, and to a lesser degree in the renal cortex. Renal afferent nerve activity is modulated by two types of receptors: (1) mechanoreceptors, which are activated by changes in hydrostatic pressure and renal vasculature pressure, and (2) chemoreceptors, which are activated by ischemia and changes in the chemical environment of the renal interstitial.[18] Afferent nerve fibers project to the autonomic central nuclei and can increase central sympathetic output, which in turn activates sympathetic activity in various targets including the vasculature, heart, and other organs.[19] Afferent nerve fibers also project to the contralateral kidney and allow cross-talk between the two kidneys to regulate renal hemodynamics.[20] It is still not certain whether afferent and efferent renal sympathetic nerve fibers are distributed differently. Therefore, selective denervation of either efferent or afferent renal sympathetic nerves is not feasible for RDN using radiofrequency or ultrasound energy. In animal studies, the application of capsaicin at a high dose (33 mol/L) has been shown to induce selective denervation of renal afferent nerves which express capsaicin receptors.[21]

Renal sympathetic nerve fibers have been assumed to follow the main renal artery to the kidneys. However, a recent study demonstrated that a significant proportion of renal nerves, called late-arriving nerves, bypass the main renal artery to reach the kidneys (in 73% of the right kidney and 53% of the left kidney).[22] Late arriving nerves have frequently been associated with polar and accessory renal arteries. Correspondingly, a greater reduction in BP has been reported in patients with denervated accessory arteries compared to those with incompletely denervated accessory arteries.[23] In approximately 30% of individuals, the kidneys are supplied by extra-renal arteries in addition to bilateral single renal arteries.[24] These extra-renal arteries include accessory arteries that enter the kidneys from the hilum with the main renal artery, and polar arteries which enter the renal parenchyma directly from the renal cortex away from the hilum.[25]

Renal sympathetic nerve fibers which follow the renal arteries to the kidneys are located primarily in the tunica adventitia and outer media of the renal arteries.[26,27] All previous studies have shown that sympathetic nerves in the branches and distal segment of the main renal artery are closer to the vascular lumen compared to those in the proximal and middle segments of the main renal artery. Several studies have reported that approximately 50% and 90% of nerves are located within 2.5 mm and 6.5 mm from the luminal surface, respectively.[27-29] These findings are consistent with animal studies which demonstrated that combined ablations of the main renal artery plus branches resulted in the greatest reductions in renal norepinephrine content and cortical axon density compared with conventional treatment of the main renal artery alone.[30] Taken together, this evidence gave rise to the current ablation strategy which focuses on the distal segment of the main renal artery, renal artery branches, and accessory renal arteries. However, this strategy can only be done by using an intra-arterial radiofrequency catheter at present.

Surgical splanchnicectomy

Before the advent of BP-lowering medications, the neurosurgeon A. W. Adson at the Mayo Clinic was the first to treat malignant hypertension with bilateral surgical RDN in 1925.[10] Because surgical RDN done via renal decapsulation or resection of tissue along the renal arteries results in only a modest and short-lived effect, the more radical surgical sympathectomy, thoracolumbar splanch-nicectomy to remove dorsal ganglia from T8/T9 to L1/2 was introduced in the 1930s. In 1953, Smithwick and Thompson[31] reported the outcomes of 1266 cases treated with thoracolumbar splanchnicectomy for severe hypertension who were followed for 5 to 14 years. The mortality rate at 5 years was 19% in the sympathectomy group and 54% for those treated medically, but at a cost of significant adverse events, including postural hypotension, syncope, incontinence, and impotence. Approximately 45% of the surviving operated patients had significant reductions in BP throughout the 5-year follow-up period, while the other 55% had no change or an increase in BP.

Contemporary RDN

The contemporary percutaneous RDN procedure was designed to attenuate renal sympathetic activity by ablating peri-arterial adventitial afferent and efferent sympathetic nerves in a less invasive and more focused manner. Various animal models have shown that selective RDN prevents or delays the onset of or ameliorates the severity of hypertension.[10,32] The technologies studied in published single-arm RDN trials include using intra-arterial catheters to deliver either radiofrequency or ultrasound energy through the arterial wall, transurethral catheters to ablate the renal pelvis, external devices to focus the ultrasound energy around the renal artery, or intra-arterial catheters to deliver neurotoxins (ethanol, guanethidine, etc) in the peri-arterial space in patients with resistant hypertension. Nevertheless, only intra-arterial radiofrequency ablation technology has been extensively studied in clinical trials, followed by intra-arterial ultrasound technology.[33] Since 2009, percutaneous RDN via radiofrequency ablation of renal arteries has been shown to be effective in reducing office BP in patients with resistant hypertension in mostly open-label, singlearm studies.[34,35] serious setback occurred in 2014 with the publication of the SYMPLICITY HTN-3 study, which showed that RDN was no more effective than a sham procedure.[36] Despite several shortcomings with the SYMPLICITY HTN-3 study,[37] it triggered the evolution of RDN in almost every aspect, from study design to ablation strategies.

Second-generation RDN trials

From 2017 onward, six carefully designed, randomized sham-controlled, second-generation RDN trials (SPYRAL HTN-OFF MED, SPYRAL HTN-OFF MED Pivotal, SPYRAL HTN-ON MED, RADIANCE-HTN SOLO, RADIANCE-HTN TRIO, and REQUIRE) with ambulatory BP measurements as the endpoint were published, and they serve as reliable models to assess the efficacy and safety of RDN.[38-43] All six trials were of moderate size (80–331 participants), and all but the REQUIRE trial[41] showed comparable and clinically meaningful BP reductions (approximately 10 mmHg in office systolic BP and 6 to 9 mmHg in 24-h ambulatory systolic BP) in patients with either drug-naïve, uncontrolled, or resistant hypertension 2 to 6 months following RDN. The clinical significance of the approximately 10 mmHg reduction in office systolic BP achieved by RDN was corroborated in subsequent studies. In the STEP trial, a difference of 9.2 mmHg in office systolic BP was associated with a 26% relative risk reduction in cardiovascular events among 8511 Chinese hypertensive patients during a median follow-up period of 3.3 years.[4] In addition, among 296 patients who underwent RDN, Fengler et al[44] reported a 25% relative risk reduction in cardiovascular events per 10 mmHg difference in 24-h systolic ambulatory BP at 3 months during a median follow-up period of 48 months. Trials of RDN achieved by radiofrequency energy with dedicated branch artery ablation have shown consistent results, whereas RDN with ultrasound energy was not associated with significant between-group BP differences in the REQUIRE trial, in which all participants were from Japan and South Korea. No serious adverse events were reported in any of the trials. In summary, the six trials confirmed the short-term efficacy and safety of RDN with intra-arterial radiofrequency or ultrasound energy.[33]

SPYRAL HTN-OFF MED is an international, multicenter, single-blind, randomized sham-controlled trial which enrolled 80 patients with an office systolic BP between 150 and 180 mmHg, office diastolic BP ≥90 mmHg, and 24-h ambulatory systolic BP between 140 and 170 mmHg after 3 to 4 weeks of medication washout.[43] Eligible patients were drug-naïve or able to discontinue existing antihyper-tensive medications, with drug testing during the screening. The primary effectiveness endpoint was the change in 24-h ambulatory BP at 3 months between patients who underwent RDN using the multielectrode SPYRAL radio-frequency catheter (Medtronic, Santa Rosa, CA, USA) and a sham control group. The operators were advised to treat the distal segments of the main renal arteries and the branches because of the close proximity of renal nerves in the distal segments. The primary efficacy endpoint of the SPYRAL HTN-OFF MED Pivotal trial was the baseline-adjusted change in 24-h systolic BP at 3 months follow-up.[45] A Bayesian approach was used to combine data from both the SPYRAL HTN-OFF MED (n= 80) and pivotal (n= 251) trials. Compared with the sham group (n = 165), 24-h systolic BP (−3.9 mmHg; Bayesian 95% credible interval: −6.2 to −1.6) and office systolic BP (−6.5 mmHg; 95% credible interval: −9.6 to −3.5) were significantly reduced in the treatment group (n = 166).[40] Analyzes of the 24-h BP patterns demonstrated that RDN provided around-the-clock BP reductions during daytime and nighttime. The “ always-on” effect of RDN differentiates it from antihy-pertensive medications, with which the BP-lowering effects are subject to half-lives, adherence, and dosing.

SPYRAL HTN-ON MED is a parallel study of the SPYRAL HTN-OFF MED study, which was conducted to clarify the role of RDN in daily practice.[38] Its inclusion criteria were the same as SPYRAL HTN-OFF MED, but also included patients on one to three antihypertensive medications with stable doses for at least 6 weeks. To confirm adherence to the medications, drug testing was applied before and during the study. The results showed that RDN (n = 38) significantly reduced office and 24-h BP in uncontrolled hypertensive patients prescribed up to three antihypertensive medications compared to a sham operation (n = 42) at 6 months (−9.4/−5.2 and −9.0/−6.0 mmHg for office and 24-h ambulatory BP, respectively). No major adverse events were reported. The prospective SPYRAL HTN-ON MED Expansion trial to further confirm the efficacy and safety of RDN in uncontrolled hypertensive patients is still ongoing.[45]

The differences in results between SYMPLICITY HTN-3 and the series of SPYRAL trials have been attributed to the elimination of confounders related to medication use, newer catheter design, distal and branch artery ablation strategy, and a longer run-in period to minimize regression to the mean bias.[46]

The RADIANCE-HTN trials are multicenter, single-blind, randomized, sham-controlled trials conducted to investigate the BP-lowering efficacy of ultrasound-based RDN using the Paradise catheter system (ReCor Medical, Palo Alto, CA, USA) to ablate the main renal artery in patients with hypertension either without (SOLO cohort) or with (TRIO cohort) antihypertensive medications compared to a sham control group. The RADIANCE-HTN SOLO trial was conducted in the United States and Europe.[39] The inclusion criteria differed slightly from the SPYRAL HTN trials and included daytime ambulatory BP between 135/85 and 170/105 mmHg after 4-weeks discontinuation of up to two antihypertensive medications. The reduction in daytime ambulatory systolic BP at 2 months, which was its primary endpoint, was greater with RDN (n = 74) than with a sham procedure (n = 72) (−8.5 and −2.2 mmHg for the RDN and sham groups, respectively). The BP-lowering effect of RDN was maintained at 12 months (decrease in daytime ambulatory systolic BP from baseline: 16.5 ± 12.9 mmHg), and the patients in the RDN group were on fewer antihypertensive drugs than those in the sham group (1.0 vs. 1.4 antihypertensive drugs; P = 0.015). However, the mean between-group difference in daytime ambulatory systolic BP change adjusted for the number of antihyper-tensive medications was no longer significant after 12 months (−2.3 mmHg; 95% CI: −5.9 to 1.3; P = 0.20).[47,48] When interpreting the 12-month results, it should be emphasized that statistical adjustments cannot eradicate the confounding effect of differences in the number and type of medications on between-group BP. In addition, the impact of differences in the number of antihypertensive medications was highly variable. In the STEP trial, a difference of 0.4 in the daily number of antihypertensive drugs between groups was associated with a 9.2 mmHg difference in systolic BP.

The RADIANCE-HTN TRIO trial included patients with drug-resistant hypertension (daytime ambulatory BP ≥135/85 mmHg) in the United States and Europe who were stabilized on a single-pill triple antihypertensive drug combination for 4 weeks before randomization to an RDN or sham procedure group.p[42] The primary endpoint was the change in daytime ambulatory systolic BP at 2 months in the intention-to-treat population. A total of 136 patients were randomly assigned to undergo RDN (n = 69) or a sham procedure (n = 67), and the results showed that RDN reduced daytime ambulatory systolic BP more than the sham procedure (median between-group difference −4.5 mmHg [95% CI −8.5 to −0.31]; adjusted P = 0.02). Full adherence to the medication at 2 months among patients with urine samples was similar in both groups (82%). There were no differences in safety outcomes between the two groups.

The REQUIRE trial investigated the BP-lowering efficacy of ultrasound RDN in patients with resistant hypertension from Japan and South Korea.[41] Adults with resistant hypertension (seated office BP ≥ 150/90 mmHg and 24-h ambulatory systolic BP ≥140 mmHg) and suitable renal artery anatomy were randomized to undergo ultrasound RDN or a sham procedure. The primary endpoint was the change from baseline in 24-h ambulatory systolic BP at 3 months. A total of 143 patients were included (72 RDN, 71 sham control), and the reduction from baseline in 24-h ambulatory systolic BP at 3 months was comparable between the RDN (−6.6 mmHg) and sham control (−6.5 mmHg) groups (difference: −0.1, 95% CI: −5.5 to 5.3; P = 0.97). No major adverse events were reported in either group. Compared to the other second-generation RDN trials, the sham group in this study had a greater reduction in ambulatory BP. The lack of efficacy in the REQUIRE trial casts doubts on the efficacy of ultrasound RDN, which can only be done in the main renal artery rather than in branches and some accessory renal arteries due to size limitations.

RDN registries

Several ongoing RDN registries provide evidence regarding the longer-term efficacy and safety in a real-world setting.[49-52] The Global Symplicity Registry (GSR) is the largest prospective, open-label, single-arm, multicenter registry of patients undergoing RDN using Medtronic's Symplicity catheters. Enrollment is ongoing, with close to 3000 patients from 196 sites worldwide.[49] Among 2237 patients enrolled and treated with the Symplicity Flex catheter, Mahfoud et al[53] investigated 1742 who were followed for >3 years and reported baseline office and 24-h ambulatory systolic BP values of 166 ± 25 and 154 ± 18 mmHg, respectively. Moreover, the reduction in systolic BP after RDN was sustained over the 3-year follow-up period, including decreases in both office (−16.5 ± 28.6 mmHg, P < 0.001) and 24-h ambulatory systolic BP (−8.0 ± 20.0 mmHg; P < 0.001). This level of sustained reduction in systolic BP at 3 years is at least comparable and even numerically greater than the level achieved in all randomized, sham-controlled second-generation RDN trials. No safety concerns were reported, including renal events, during the 3-year follow-up period.

In addition to providing reassuring longer-term efficacy and safety information, data from the GSR suggest that there may be ethnic differences in BP-lowering responses following radiofrequency RDN. In the GSR Korea substudy,[54,55] after propensity score matching, the reduction in office systolic BP at 6 months was similar between Korean (n = 93) and Caucasian (n = 169) patients (−19.4 ± 17.2 vs. −20.9 ± 21.4 mmHg, respectively) treated with the Symplicity Flex catheter for main renal artery ablation. However, the reduction in office systolic BP at 12 months was greater in the Korean patients compared to the Caucasian patients (−27.2 ± 18.1 vs. −20.1 ± 23.9 mmHg, respectively; P = 0.004).[54] Among the 102 Korean patients followed for up to 36 months, the reductions in office systolic BP at 12 months, 24 months, and 36 months were −26.7 ± 18.5, −30.1 ± 21.6, and −32.5 ± 18.8 mmHg, respectively. The differences in systolic BP reductions between the Korean and Caucasian patients remained after 12 months.[55]

In the GSR Taiwan (China) substudy, a total of 26 patients were enrolled (mean age 59.1 ± 13.8 years, baseline office systolic BP 168.2 ± 19.8 mmHg, 8 treated with the Symplicity Flex catheter, and 18 treated with the Symplicity Spyral catheter).[56] In the Symplicity Flex group, the reductions in office systolic BP at 3 months and 3 years were 14.9 ± 14.7 and 29.7 ± 25.9 mmHg, respectively (both P < 0.05 vs. baseline). In addition, the reductions in office systolic BP at 3 months and 2 years in the Symplicity Spyral group were 21.2 ± 28.7 and 42.4 ± 10.7 mmHg, respectively (both P < 0.05 vs. baseline).

This real-world evidence shows that BP decreased continuously for 12 months in the Asian patients treated with RDN, with an average reduction in office systolic BP at 12 months of approximately 20 to 30 mmHg. In the non-Asian patients, office systolic BP reduced continuously for 6 months following RDN and plateaued thereafter, with an average reduction of 15 to 20 mmHg. The neutral results of the REQUIRE trial in resistant hypertensive patients in Japan and South Korea cast doubts on the “ethnic differences in response to RDN” hypothesis.[41]

Although there are currently no published RDN registries in mainland China, two RDN clinical trials have been conducted. RDN was performed using a saline-irrigated ablation catheter in one of the trials,[57] and by adventitia ablation using a radiofrequency catheter following laparoscopic adrenalectomy in the other trial.[58] Although no sham-controlled groups were included, both randomized trials demonstrated the efficacy of RDN in reducing office and ambulatory BP for up to 12 months.

Consensus Documents on RDN Worldwide

Although it is not yet possible to fully understand the long-term durability and safety of newer-generation RDN, potential interactions with medications, and generalizabil-ity to heterogeneous hypertensive populations, it would not be in the best interest of public health to prevent patient access to these devices over these concerns, given the widespread non-adherence to antihypertensive medications and the unsatisfactory hypertension control rates worldwide. Following the publication of a series of second-generation randomized sham-controlled RDN trials which support the efficacy and safety of RDN, professional societies of hypertension, cardiology, cardiovascular interventions, and nephrology worldwide have issued either consensus statements or position papers by incorporating updated information and opinions from experts to clarify concerns regarding the clinical applicability of RDN and knowledge gaps since 2019.[10,59,61] The contents of these consensus statements have mainly focused on: (1) who are the ideal candidates for RDN, (2) pre- and post-RDN assessments, (3) technical and procedural requirements, (4) clinical practice integration, and (5) knowledge gaps. Consensus and inconsistencies between four representative consensus documents from the Taiwan Hypertension Society and Taiwan Society of Cardiology (THS/TSOC 2019),[10] Asia Renal Denervation Consortium (ARDeC 2020),[59] European Society of Hypertension (ESH 2021),[60] and Society for Cardiovascular Angiography & Intervention and National Kidney Foundation (SCAI/NKF 2021)[61] are summarized in Table 1 and discussed in the following sections. Practical tips for the clinical implementation of RDN based on shared recommendations from these documents are listed in Table 2.

Table 1 - Summary of four representative consensus documents on renal denervation.[10,56-58]
THS/TSOC 2019 ARDeC 2020 ESH 2021 SCAI/NKF 2021
Patient selection Blood pressure profiles • Systolic-diastolic combined hypertension • Resistant, uncontrolled, or masked uncontrolled hypertension • An alternative or additive treatment strategy • Persistent uncontrolled hypertension despite guideline-based therapy
• Based on ambulatory BP monitoring• Regardless of the use of antihypertensive medications • Considered as an initial or complementary treatment strategy • Confirmation of hypertension by out-of-office BP monitoring (ambulatory or home BP)
Patient profile RDNi2 • Salt sensitivity: asleep hypertension, morning hypertension • Patient preference • Patient preference
Resistant hypertension • Sympathetic overactivity: faster 24-h heart rate, obstructive sleep apnea, paroxysmal atrial fibrillation, etc. • Stage of hypertensive disease • Evidence of hypertensive endorgan damage
• Vasculature or organ Damage • Resistant hypertension • Comorbidities • Established cardiovascular disease
Non-adherence to drugs • Established cardiovascular disease
Intolerance to drugs • Intolerance/nonadherence to drugs
• Treatment-resistant secondary (2ndary) hypertension
Pre-RDN assessments RAS CT or MR renal artery angiography Not available Not available
• CT or MR Renal artery angiography
Ambulatory BP monitoring after witnessed drug intake
Secondary hypertension identified and treated
Post-RDN assessments • Ambulatory BP monitoring at 6 months Not available CT or MR renal artery angiography at 12 months Not available
• Electrocardiogram
• Renal function (serum creatinine, estimated glomerular filtration rate, proteinuria, etc.)
• CT or MR renal artery angiography at 12 months
RDN techniques and procedures • Four-quadrant ablations required • Four-quadrant ablations required Not available Not available
• Comprehensive renal artery ablations, including branch and accessory arteries, required for radiofrequency RDN • Comprehensive renal artery ablations, including branch and accessory arteries, required for radiofrequency RDN
• Ablations within the inner border of renal parenchyma in renal angiogram
• >2 mm away from the segments with stent or plaque
Clinical Practice Integration Not available Not available Center qualification and structured pathway for RDN are required • A dedicated care pathway for RDN is helpful• An ICD-10 code for uncontrolled hypertension is needed for clinical practice, research, and reimbursement
Words in bold text indicate specific recommendations in the document. ARDeC: Asia Renal Denervation Consortium; BP: Blood pressure; CT: Computed tomography; ESH: European Society of Hypertension; MR: Magnetic resonance; RDN: Renal denervation; SCAI/NKF: Society for Cardiovascular Angiography & Intervention/National Kidney Foundation; THS/TSOC: Taiwan Hypertension Society/Taiwan Society of Cardiology.

Table 2 - Practical tips for the implementation of renal denervation in clinical practice based on shared recommendations among the four consensus documents.
General RDN is an alternative or additive BP-lowering treatment strategy (the third pillar of antihypertensive treatment, besides lifestyle modification and pharmacological therapy)
Patient selection Uncontrolled hypertension confirmed by home or ambulatory BP monitoring;
Patients with hypertensive organ damage or established cardiovascular disease;
Patient preference about RDN
Pre-RDN assessments Secondary hypertension identified (for example, plasma aldosterone-renin ratio) and treated (but BP still not controlled);
CT or MR renal artery angiography (to identify secondary causes and detailed renal artery anatomy)
Post-RDN assessments Adjustment of antihypertensive medications following RDN should be based on average home BP or ambulatory BP (discontinuation of all antihypertensive drugs without BP monitoring is prohibited);
Ambulatory BP monitoring at 6 months (to determine whether patients are responders to RDN); CT or MR renal artery angiography at 12 months (optional)
BP: Blood pressure; CT: Computed tomography; MR: Magnetic resonance; RDN: Renal denervation.

Patient selection

To comprehensively consider and recommend who are the ideal patients for RDN, two factors, such as BP profiles and patient characteristics, should be assessed.

In terms of what BP profiles are suitable for RDN, the THS/TSOC 2019 consensus recommends that RDN can be performed in patients with systolic-diastolic combined hypertension, based on ambulatory BP monitoring irrespective of the use of antihypertensive medications.[10] This recommendation is based on the BP inclusion criteria of all second-generation RDN trials published before 2019. Three points are worth emphasizing. First, ambulatory BP monitoring, rather than office BP, is recommended as the basis of BP profile assessments, as this can exclude the white-coat effect associated with office BP, identify the presence of masked hypertension or masked uncontrolled hypertension,[62] and serve as a reliable measure of the BP-lowering effects of RDN.[63] Second, given that RDN can be performed irrespective of whether antihypertensive medications are used, its role as a stand-alone antihyper-tensive therapy is clear. Third, isolated systolic hypertension is not recommended in the THS/TSOC 2019 consensus due to limited and contradicting publications regarding the efficacy of RDN in patients with isolated systolic hypertension at that time.[64-66] The ARDeC 2020 consensus also recommends that RDN can be performed in patients with resistant hypertension, uncontrolled hypertension, or masked uncontrolled hypertension, because of its “always on” BP-lowering effect. The ARDeC consensus concludes that RDN can be considered as an initial therapeutic option or as a complementary therapy to antihypertensive medications.[59] The ESH 2021 position paper describes RDN as an alternative or additive treatment strategy, but does not mention which BP profiles are more suitable for RDN.[60] In the SCAI/NKF 2021 consensus, RDN is recommended for patients with persistent uncontrolled hypertension despite the prescription of guideline-based therapy. Confirming hypertension using alternative means of BP monitoring (ambulatory or home BP) rather than office BP measurements alone is also emphasized.[61] Isolated systolic hypertension is not considered to be an unfavorable profile in the ESH and SCAI/NKF documents because a recent study showed that patients with isolated systolic hypertension responded equally well compared to patients with other BP profiles.[53] In summary, all consensus documents recommend that RDN can be performed in patients with uncontrolled hypertension, beyond resistant hypertension. Both consensus documents from Asia (THS/TSOC 2019 and ARDeC 2020) are more aggressive in recommending RDN as an initial antihyper-tensive strategy in suitable clinical scenarios (eg, patients with masked hypertension or intolerance to antihyperten-sive medications). Routine ambulatory BP monitoring to confirm and assess BP profiles for patients who will be or have been treated with RDN is only recommended by the THS/TSOC 2019 consensus.

Regarding which patient characteristics are suitable for RDN, the THS/TSOC 2019 consensus provides an acronym “RDNi2” to itemize the five subgroups of hypertensive patients who may benefit the most from RDN.[10] The “R” stands for “Resistant hypertension.” Despite the fact that RDN can be performed in all kinds of hypertensive patients, patients with resistant hypertension are most likely to benefit from the greatest reduction in BP, since pre-treatment BP is the strongest predictor of BP reduction following RDN.[67] The “D” stands for BP-mediated “vasculature or organ Damage.” Patients with organ damage are ideal candidates for RDN given that the reduction in cardiovascular events with a given reduction in systolic BP in mmHg is directly proportional to baseline cardiovascular risk.[68] The “N” and “I” stand for “Non-adherence to antihypertensive medications” and “Intolerance to antihypertensive medications,” respectively. Given the low medication adherence rate in the real world,[9] every effort should be made to improve it. The underlying causes of poor medication adherence, such as drug side effects, should be identified and resolved. Patient preference is one of the main causes of poor adherence,[69] and thus patient preference should be regularly considered when determining which treatment strategies should be provided in the management of all chronic diseases.[69] The “2” stands for “treatment-resistant secondary (2ndary) hypertension.” The presence of secondary causes of hypertension does not guarantee that the identified secondary causes are the only causes of hypertension. If the BP is not controlled following definitive treatment for the secondary causes it is reasonable to recommend RDN, since hypertension is inherently a multifactorial disease.[58] In the ARDeC consensus, patients with suspected higher sympathetic tone, including Asian hypertensive patients,[70] patients with obstructive sleep apnea, and patients with increased 24-h ambulatory heart rate (>74/min),[43,71] and features of salt sensitivity such as asleep hypertension and morning hypertension[59,70] are considered to be ideal candidates for RDN. The ARDeC consensus also recommends that patients with resistant hypertension, those with established cardiovascular disease, and those who are either intolerant or do not adhere to antihypertensive medications are ideal candidates. In both the ESH 2021 and SCAI/NKF documents, the patients’ perspectives and preferences, stage of hypertensive disease, and comorbidities are important determinants for deciding whether RDN should be recommended. In the SCAI/NKF consensus, patients with secondary causes of hypertension are not considered to be suitable for RDN,[61] whereas patients with “treatment-resistant” secondary hypertension are considered to be ideal candidates for RDN in the THS/TSOC consensus.[10] Apart from secondary hypertension, all consensus documents agree that patients with one of the “RDNi” characteristics are ideal candidates for RDN. Patients with features suggesting sympathetic overactivity are only recommended as ideal candidates in the ARDeC consensus. The other consensus documents do not make specific recommendations regarding searching for evidence of sympathetic overactivity because of the following reasons. First, the positive correlation between signs of sympathetic overac-tivity and BP-lowering responses following RDN is still controversial.[10,67] Second, some features of sympathetic overactivity, such as heart rate and obstructive sleep apnea, are affected by pharmacological interventions and lack of well-established diagnostic criteria.[43,71] Third, the role of the sympathetic nervous system may not be evident at the outset due to the presence of multiple counterbalance mechanisms of hypertension.[72]

It is worth emphasizing that patient preference is highly influenced by the information provided by physicians.[69] Hence, balanced, valid, and comprehensive information regarding RDN, thorough assessments of antihypertensive drug adherence, and identification of the reasons for non-adherence by physicians are essential for a legitimate shared decision-making process to facilitate the application of RDN [Figure 1].

F1
Figure 1:
Factors influencing physician and patient perspectives on making decisions regarding whether RDN should be undertaken. Pre- and post-RDN assessment flowchart provided in the THS Consensus. BP: Blood pressure; RDN: Renal denervation; THS: Taiwan Hypertension Society.

Pre-RDN assessments

To improve the treatment quality of RDN, standardization of the whole procedure, including pre- and post-procedure assessments, is required. In the THS/TSOC 2019 consensus, an acronym, “RAS,” is provided to highlight the three essential aspects of pre-RDN assessments [Figure 2]. The “ R” stands for “computed tomography (CT) or magnetic resonance (MR) Renal artery angiography,” to assess anatomic eligibility, complete roadmap, and plaque distribution of renal arteries. The presence of accessory renal arteries should be carefully examined since they are present in approximately 30% of individuals and are highly innervated, and thus should be ablated.[22-24] The “A” stands for “24-h Ambulatory BP monitoring.” To reliably assess the BP-lowering effects of antihypertensive medications and RDN, the THS/TSOC consensus emphasizes that 24-h ambulatory BP monitoring should be done after the “witnessed” intake of antihypertensive medications.[62] The “S” stands for “Secondary hypertension identified and treated.” The THS/TSOC consensus recommends routine screening for primary aldosteronism by checking the plasma aldosterone-renin ratio, defined as plasma aldosterone concentration divided by plasma renin activity.[73] Blood samples collected in the morning are recommended. The most commonly used cutoff value is >30 when the plasma aldosterone concentration is reported in ng/dL and plasma renin activity in ng·mL−1 h−1.[73] In patients with documented secondary causes of hypertension, including obstructive sleep apnea, who have been treated for ≥3 months, RDN can be recommended if their ambulatory BP remains uncontrolled, as suggested in the THS/TSOC consensus.[10] In the ARDeC consensus, the value of pre-RDN CT or MR renal artery angiography for pre-procedural planning is recognized. Neither the ESH 2021 nor SCAI/NKF documents make recommendations on pre-RDN assessments.

F2
Figure 2:
Pre- and post-RDN assessment flowchart provided in the THS Consensus. BP: Blood pressure; CT: Computed tomography; ECG: Electrocardiography; K: Potassium; MR: Magnetic resonance; RDN: Renal denervation; SCr: Serum creatinine; THS: Taiwan Hypertension Society; UACR: Urinary albumin to creatinine ratio.

Post-RDN assessments

In the THS/TSOC consensus, post-RDN assessments include: (1) 24-h ambulatory BP monitoring 6 months following RDN, since reductions in BP usually continue for 6 months;[53-56] (2) electrocardiography 12 months following RDN, and then yearly, since the change in QRS voltage is a surrogate of left ventricular mass, which is closely related to long-term BP burden and of prognostic significance[2,3]; (3) renal function assessments, including serum creatinine, estimated glomerular filtration rate, and potassium and urine dipstick or albumin to creatinine ratio, 1 to 2 weeks and every 6 months following RDN; and (4) CT or MR renal artery angiography 12 months following RDN to evaluate whether there is any evidence of renal artery stenosis, which may not be evident clinically. Neither the ARDeC nor SCAI/NKF documents address issues regarding post-RDN assessments. The ESH 2021 position paper mentions that imaging studies 1 year following RDN to re-examine renal arteries is requested by the Food and Drug Administration of the United States.[60]

Technical and procedural requirements

In both the THS/TSOC and ARDeC documents, four-quadrant ablations of the renal arteries and comprehensive renal artery ablations including branch and accessory renal arteries with diameters of ≥3 mm during radiofrequency RDN are emphasized, since previous studies have demonstrated that the number of ablations, four-quadrant ablations, and branch and accessory artery ablations were associated with more significant BP reductions.[74] The THS/TSOC consensus also provides some technical tips, including: (1) the tip of the radiofrequency ablation catheter should not exceed the inner border of the renal parenchyma in renal angiogram [Figure 3]; (2) radio-frequency ablation should be performed >2 mm away from the stented segments or segments with plaques; and (3) either diluted iodinated contrast with dose restriction or CO2 angiography can be used during RDN in patients with advanced chronic kidney disease (stages ≥3b). Neither the ESH nor SCAI/NKF documents address issues regarding RDN techniques and procedures.

F3
Figure 3:
Inner border of the renal parenchyma in a renal angiogram. The red dotted line shows the inner border of the renal parenchyma. The blue dots indicate candidate ablation points.

Clinical practice integration

In the ESH 2 21 position paper, the authors emphasize the importance of establishing a structured pathway for the clinical use of RDN in daily practice. They recommend establishing a transparent method of qualifying centers to perform RDN. The SCAI/NKF 2 21 consensus recommends that RDN should be performed at an experienced interventional center and that an ICD-10 code specific for uncontrolled hypertension is crucial for clinical practice, research, and reimbursement. Neither the THS/TSOC nor ARDeC documents specifically mention issues regarding a structured clinical pathway. However, both documents provide important technical tips for RDN, which they consider to be key factors to ensure optimal RDN.

Knowledge gaps

All four documents provide areas with knowledge gaps in RDN, which can be summarized into the following seven aspects [Table 3]. The first aspect is regarding the predictors of BP-lowering responses to RDN, which include clinical and intra-procedural predictors. No predictor except pre-treatment BP has yet been widely validated.[10,67] This is important because the average BP reductions achieved in second-generation RDN trials, around 10 mmHg in office systolic BP and 6 to 9 mmHg in 24-h ambulatory systolic BP, are equivalent to the effect of one or two antihypertensive medications at most.[33] However, a few patients are super-responders to RDN. In the RADIANCE-HTN SOLO trial, 40% and 30% of the participants treated with RDN had daytime ambulatory systolic BP reductions of 10 and 15 mmHg, respectively, from the baseline average level of 150 mmHg.[39] For super-responders, RDN can be viewed as a definitive, or even curative, treatment strategy. From this perspective, the search for predictors of super-responders is strategically essential. The second aspect is regarding the identification of RDN procedural endpoints. Without a definite endpoint indicative of the immediate procedural success of RDN, it is hard to interpret results regarding different BP-lowering efficacy between various RDN strategies (comprehensive ablation vs. focused) and modalities.[75]

Table 3 - Knowledge gaps in renal denervation.
Aspects Specific contents
Predictors of blood pressure-lowering responses to renal denervation Clinical predictors;
Intra-procedural predictors;
Predictors of super-responders (ambulatory systolic blood pressure reduction >10 or >15 mmHg) to renal denervation
Renal denervation procedural endpoints Definition of procedural success
Expanding indications for renal denervation Conditions indicative of sympathetic overactivity: atrial fibrillation, obstructive sleep apnea, heart failure, chronic kidney disease, ventricular arrhythmia, metabolic syndrome, white-coat hypertension, and wide blood pressure variability;
Conditions indicative of salt sensitivity: asleep hypertension, early morning hypertension, and Asian hypertensive patients
Longer-term (>3 years) safety and durability Non-invasive monitoring of regional (renal) sympathetic activity
Patient preference and patient-reported outcome measures towards renal denervation
Cost-effectiveness analysis
Effects of renal denervation on clinical hard endpoints (stroke, myocardial infarction, and mortality)

The third aspect is regarding expanding the indications for RDN. Several conditions associated with or possibly caused by sympathetic activation are considered to be further indications for the use of RDN, including atrial fibrillation, obstructive sleep apnea, heart failure, chronic kidney disease, ventricular arrhythmia, and metabolic syndrome.[59-61] The fourth aspect is regarding the safety and durability of RDN beyond 3 years. In addition to longer-term follow-up data to validate the safety and durability of RDN, a non-invasive monitoring tool that can detect regional (renal) sympathetic activity is required to identify not only whether there is functional reinnervation but also increased sympathetic activity at baseline before RDN.[76] The fifth aspect is regarding patient preference and patient-reported outcome measures. These should be assessed in RDN trials and considered in clinical decision-making. The sixth aspect is regarding the cost-effectiveness of RDN. Finally, the seventh aspect is regarding the effect of RDN on clinical hard endpoints, including stroke, myocardial infarction, and mortality. This is the most important aspect that needs to be thoroughly researched and clarified.

Conclusions

Given the unsatisfactory hypertension control rates and high rates of non-adherence to antihypertensive medications worldwide, device therapy that can safely provide durable clinically meaningful efficacy can fulfill the unmet need. A series of second-generation randomized sham-controlled RDN trials have demonstrated the efficacy and safety of RDN in a wide range of hypertensive patients. The four representative consensus documents on RDN detailed in this study consistently recommend RDN as an alternative or complementary treatment strategy for patients with uncontrolled hypertension. In addition, both consensus documents from Asia recommend that RDN can be used as an initial treatment strategy for drug-naïve hypertensive patients. There is still inconsistency regarding whether ambulatory BP monitoring should be used routinely both before and after RDN, and whether patients with secondary causes of hypertension can be treated with RDN if their BP remains uncontrolled after definitive treatment (treatment-resistant secondary hypertension). The consensus document from Taiwan (China) provides acronyms to summarize key aspects of patient selection (RDNi2) and pre-RDN assessments (RAS). The ARDeC consensus recommends that RDN can be considered in patients with BP profiles indicative of increased salt sensitivity (asleep hypertension and morning hypertension) and conditions of sympathetic overactivity (such as atrial fibrillation and obstructive sleep apnea). Both consensus documents from Asia provide detailed technical and procedural requirements, while the documents from Europe and America recommend establishing structured pathways for clinical practice and issues regarding reimbursement. All documents identify knowledge gaps in RDN, from identifying the predictors of super-responders to demonstrating the effects on cardiovascular events. Research to fill these gaps is urgently needed to facilitate the wider application of this device therapy for hypertension.

Conflicts of interest

None.

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Keywords:

Consensus; Hypertension; Guideline; Patient; Renal Denervation

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