CADTH Health Technology Review

Renal Denervation for Uncontrolled Hypertension

Rapid Review

What Is the Issue?

• It is estimated that 23% of adults in Canada have hypertension. About 1/3 of this population have uncontrolled hypertension, a condition in which (BP) blood pressure levels continue to remain high despite treatment. People with high BP despite being prescribed 3 or more blood pressure-lowering (antihypertensive) medicines are considered to have uncontrolled resistant hypertension.

• Renal denervation is a therapy that involves disrupting activity in the sympathetic nerves in the renal artery using a minimally invasive catheter-based procedure to treat high BP.

• We wanted to know if renal denervation would effectively and safely reduce BP in people with uncontrolled hypertension.

What Did We Do?

• We identified and summarized the literature comparing the clinical effectiveness and safety of renal denervation in individuals with uncontrolled hypertension to help guide decisions on the use of this intervention.

• An information specialist searched for peer-reviewed and grey literature sources published between January 1, 2019, and February 5, 2024. The search was limited to English-language documents. One reviewer screened articles for inclusion based on predefined criteria, critically appraised the included studies, and narratively summarized the findings.

What Did We Find?

• The evidence for this report was based on 2 systematic reviews and 3 randomized controlled trials (RCTs).

• Renal denervation could lead to a reduction in BP compared to sham in adults with uncontrolled nonresistant hypertension.

• It is uncertain if renal denervation is an effective treatment for resistant hypertension and suspected hypertensive heart disease due to the methodological limitations of the included studies.

• Serious side effects of renal denervation were rare.

What Does This Mean?

• Our findings agree with evidence-based guidelines and real-world evidence that suggest renal denervation can be considered a treatment option for patients with uncontrolled nonresistant hypertension. Other factors, including costs and resources, equity, acceptability, and patient selection, should be considered when implementing renal denervation in Canada, where it remains an emerging medical technology.

• Future research should assess important patient outcomes, such as quality of life.

Context and Policy Issues

What Is Uncontrolled Hypertension?

In Canada, approximately 5.8 million people, or 23% of adults had hypertension in the 2016 to 2017 Canadian Health Measures Survey.¹ Currently, 1/3 of people in Canada living with hypertension have uncontrolled hypertension,^1,2 most commonly defined as office systolic BP between 150 mm Hg and 180 mm Hg, mean 24-hour ambulatory systolic BP between 140 mm Hg and 170 mm Hg, and taking 3 or less antihypertensive medications.³ The terms “uncontrolled hypertension” and “resistant hypertension” are often used interchangeably but are not synonymous. Resistant hypertension, typically defined as office systolic BP over 140 mm Hg despite taking 3 or more BP-lowering drugs at optimal doses (with 1 being a diuretic),^3-6 is 1 of the causes of uncontrolled hypertension.⁴ Other causes include patient nonadherence to antihypertensive medications, adverse effects of medications, socioeconomic factors (e.g., medication costs), inadequate treatment regimens, lack of patient education, physician inertia to initiate or intensify therapy, and white coat effect (when office BP is above the threshold, but out-of-office BP is below threshold).^1,2 Patients with uncontrolled hypertension are at greater risk of cardiovascular disease and kidney disease.⁷

What Is the Current Practice?

The current approach to managing hypertension consists of lifestyle and diet modifications and pharmacological interventions. Hypertension Canada’s 2020 guidelines⁸ recommend weight reduction, physical exercise, and decreasing alcohol and sodium intake as first-line interventions for hypertension. Medications such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, and longer-acting thiazide-like diuretics are considered for adults with uncontrolled hypertension.⁸ Hypertension Canada8 recommends drugs such as spironolactone, bisoprolol, doxazosin, amiloride, eplerenone, or clonidine as an adjunct treatment for patients with resistant hypertension.

What Is Renal Denervation?

Renal denervation (RDN) is a minimally invasive procedure that reverses the activation of sympathetic nerves in the renal artery using a catheter that releases energy (typically low-dose radiofrequency or focused ultrasound) to disrupt their activity, which can lower BP.^9,10 The renal sympathetic nervous system innervates several organ systems, including major structural components of the kidneys. Increased activity of the renal sympathetic nervous system, through a chain of pathophysiological changes, results in an increased volume of blood in the circulatory system as well as increased resistance of blood vessels, and subsequently increased BP.⁹

Why Is It Important to Do This Review?

Large observational studies have shown that roughly half of participants stop taking their antihypertensive drugs within a year for various reasons, including poor patient adherence, adverse effects of drug therapy, and socioeconomic factors.⁹ A systematic review (SR)¹¹ published in 2020 reported that the prevalence of medication nonadherence was 35% in patients with resistant hypertension. Therefore, additional or alternative therapy is required for patients who cannot take medication or do not adhere to their prescribed regimen.⁹ RDN could be a complementary or alternative device-based BP-lowering therapy for those patients.⁹

Early research demonstrated that RDN reduced BP at 6 months in patients with persistent hypertension without major complications.¹² However, this evidence came from observational, uncontrolled studies with short-term follow-up, small sample sizes, and high heterogeneity in BP measurement.¹³ RCTs did not find statistically significant benefits of RDN compared to placebo or standard therapy for uncontrolled hypertension.¹³ Initial and subsequent RCTs evaluating RDN compared to sham reported varying results.¹⁴ In 2022, CADTH produced a Horizon Scan¹⁵ that summarized the available information on Symplicity Spyral, a second-generation RDN system that uses multi-electrode catheter and radiofrequency generator to treat uncontrolled hypertension. In recent years, new RCTs and SRs evaluating the clinical effectiveness of different RDN systems compared to sham procedures have been published. Therefore, a review of the most current evidence is warranted.

Objective

To support decision-making about RDN for individuals with uncontrolled hypertension, we prepared this Rapid Review to summarize and critically appraise the available evidence regarding the clinical effectiveness of RDN versus sham.

Research Question

What is the clinical effectiveness of renal denervation in individuals with uncontrolled hypertension?

Methods

Literature Search Methods

An information specialist conducted a literature search on key resources including MEDLINE, Embase, the Cochrane Database of Systematic Reviews, the International HTA Database, the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search approach was customized to retrieve a limited set of results, balancing comprehensiveness with relevancy. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. Search concepts were developed based on the elements of the research questions and selection criteria. The main search concepts were renal denervation and hypertension. CADTH-developed search filters were applied to limit retrieval to health technology assessments, systematic reviews, meta-analyses, or indirect treatment comparisons, and RCT or controlled clinical trials. The search was completed on February 5, 2024 and limited to English-language documents published since January 1, 2019.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full text articles was based on the inclusion criteria presented in Table 1.

Table 1: Selection Criteria

Exclusion Criteria

The following were excluded:

• articles that did not meet the selection criteria outlined in Table 1

• duplicate publications

• articles published before 2019

• RCTs that were captured in an included SR

• SRs in which all relevant studies were captured in other more recent or more comprehensive SRs.

Critical Appraisal of Individual Studies

The included publications were critically appraised by 1 reviewer using the following tools as a guide: A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2)¹⁶ for SRs and the Downs and Black checklist¹⁷ for RCTs. Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively.

Summary of Evidence

Quantity of Research Available

This report includes 5 studies presented in 6 publications.^14,18-22 These were 2 SRs^14,18,19 (there were 2 publications^14,18 of 1 SR) and 3 RCTs.^20-22 Study selection details are presented in Appendix 1.

Appendix 6 presents additional references of potential interest related to RDN for uncontrolled hypertension. These included SRs in which all relevant primary studies were captured in at least 1 of the 2 included SRs^14,18,19 and 2 cost-effectiveness studies.

Summary of Study Characteristics

Detailed characteristics of included publications are provided in Appendix 2.

Study Design

One SR¹⁹ queried the electronic databases from inception to March 2023 and the other SR^14,18 from January 2000 to October 2021. There were 11 RCTs published between 2014 and 2023 identified across both SRs.^14,18,19 The 2 SRs^14,18,19 included overlapping primary studies, with 8 RCTs included in both SRs^18,19 (refer to Appendix 6 for details regarding overlap). To avoid duplication of results, outcome data from the individual RCTs is only reported once.

The RCT by Heradien et al.²² published in 2022 was a single-centre patient- and assessor-blinded trial. The other 2 RCTs^20,21 were published in 2023 and used an international, multicentre, patient- and assessor-blinded design. One of them, the SPYRAL HTN-ON MED trial was reported by Kandzari et al.²⁰ and included the findings from both the pilot trial (n = 80) and the extension trial (n = 257). The SPYRAL HTN-ON MED pilot trial was also included in the 2 SRs.^14,18,19 To avoid duplication of results, outcome data on the SPYRAL HTN-ON MED pilot trial is reported only once in the current report.

The RCTs were carried out in Australia,²⁰ Austria,²⁰ Belgium,²¹ Canada,²⁰ France,^20,21 Germany,^20,21 Greece,²⁰ Ireland,²⁰ Japan,²⁰ South Africa,²² UK,^20,21 and US.²¹ The 2 SRs^14,18,19 (both by authors in the US) did not report the countries in which the included trials were carried out.

Population

The population in the included studies^14,18-22 were adults with uncontrolled hypertension. The 2 SRs^14,18,19 categorized participants as having resistant hypertension (defined as uncontrolled BP despite being on 3 or more antihypertensive medications) and nonresistant hypertension (or essential hypertension, defined as BP above the goal while taking less than 3 antihypertensive medications). The participants in the RCT by Heradien et al.²² were also at high risk of experiencing subclinical atrial fibrillation (suspected hypertensive heart disease). The number of participants across primary studies in the 2 SRs^14,18,19 ranged from 51 to 535, and mean ages ranged from 53 to 62 years. The number of participants in the 3 RCTs^20-22 ranged from 81²² to 257,²⁰ and mean ages ranged from 54²¹ to 64²² years.

Intervention and Comparators

The interventions in the included studies were RDN using radiofrequency,^14,18-20,22 ultrasound ablation^14,18,19 or alcohol-mediated;²¹ and included both first-generation^14,18,19 and second-generation RDN.^14,18-22 First-generation RDN used a single-tip radiofrequency catheter, made fewer lesions that were placed randomly in the main renal artery, while second-generation systems used multi-electrode catheters and newer ablation techniques, and placed lesions in the distal segments of the renal arteries, achieving a greater degree of RDN.⁵ The types of RDN systems used in the studies included Kona Surround Sound,¹⁴ Paradise,¹⁴ Peregrine,²¹ Simplicity Flex,¹⁴ Simplicity G3,^14,20 Symplicity Spyral,^14,20,22 and Vessex.¹⁴

The sham comparator was renal angiography alone in 2 RCTs^20,21 and prerecorded renal denervation generator sounds to simulate the RDN procedure in the other RCT.²² The 2 SRs^14,18,19 did not report any details about the sham comparisons in their included studies.

Two RCTs^20,22 assessed the effectiveness of RDN in the presence of antihypertensive medications, as an adjunct therapy, while the other RCT²¹ assess the effectiveness of RDN in the absence of antihypertensive medications, as a pharmacotherapy replacement (following a medication washout period).

Outcomes

Clinical effectiveness outcomes assessed in the studies included 24-hour ambulatory systolic and diastolic BP;^18-22 office systolic and diastolic BP;^14,19-22 daytime systolic and diastolic BP (measured 7:00 to 21:59);^14,19 nighttime systolic and diastolic BP (measured 22:00 to 6:59),^14,23,24 estimated glomerular filtration rate (eGFR, to measure level of kidney function),²¹ antihypertensive medication utilization (measured by the mean number of prescribed antihypertensive medications),^20,21 and antihypertensive medication burden.^20,21 Safety was assessed by adverse events.^19-22

Across the studies, the follow-up period ranged from 2 months^14,18,19 to 2 years.²²

Summary of Critical Appraisal

Systematic Reviews

The 2 SRs^14,18,19 clearly stated their review objective and inclusion criteria. The authors of the 2 SRs^14,18,19 performed literature searches in 2 or more electronic databases and provided the search strategies^18,19 or key search terms.¹⁹ This increases the transparency and reproducibility of the literature searches and article selection process. Both SRs^18,19 presented a flow chart illustrating the study selection process. Data extraction was performed in duplicate; thus, decreasing the possibility of errors in the 2 SRs^14,18,19 In both SRs,^14,18,19 the authors used the Cochrane tool to assess the risk of bias of the included studies. The 2 SRs^14,18,19 performed random-effects meta-analysis using the inverse variance method to estimate mean difference with a 95% confidence interval. Both SRs^18,19 conducted sensitivity analyses by systematically excluding 1 RCT at a time to investigate the effect on the results. The authors of both SRs^14,18,19 reported no conflicts of interest and no funding was received for the review.

There were limitations in the 2 SRs.^18,19 Both SRs^14,18,19 did not report the establishment of an a priori method or development of a review protocol. A preestablished review method is important for informing the conduct of reviews and allows readers to assess any protocol deviations that could introduce potential risk of bias to the review's findings. Neither SR^14,18,19 reported whether there were publication restrictions in their searches, nor did they incorporate searches of the grey literature or trial registries, nor did they provide a list of excluded studies. One publication¹⁸ on the SR by Ahmed et al. did not report the I-squared statistic (estimate of heterogeneity between studies) in their meta-analyses. Publication bias might account for some of the effects observed in the 2 SRs; ^14,18,19 however, this was not investigated in either SR.^14,18,19

Randomized Controlled Trials

The 3 RCTs^20-22 clearly reported the study objective, inclusion and exclusion criteria, intervention, and demographics of included participants. Because RDN and sham were administered by study personnel, it was assumed that adherence to the intervention or comparator was reliable for each RCT.^20-22 The methods of randomization and allocation concealment were appropriate, reducing the risk of selection bias. The participants and outcome assessors were blinded to the interventions, reducing the risk of performance and detection bias. There were no significant losses to follow-up of randomized patients in the 3 RCTs.^20-22 All the predefined outcomes were relevant and valid, and adequately reported. All RCTs^20-22 were analyzed on an intention-to-treat basis. The 3 RCTs^20-22 reported adverse events or complications associated with the intervention.

The RCTs^20-22 had overall low risk of bias. However, it was uncertain if the participants were representative of the entire population from which they were recruited in all RCTs.^20-22 For example, in the TARGET BP OFF-MED trial, 70% of patients who consented to participation in the trial were not randomized because they did not meet inclusion criteria before or after the run-in period, were excluded during run-in period for other reasons, were lost or withdrawn before randomization, or were not willing to stop antihypertensive medications. The authors did not report any baseline characteristics for this group compared to those who were randomized.²¹ Two RCTs^21,22 were not powered for statistical comparisons of clinical effectiveness outcomes. Two RCTs^20,21 were fully funded by the manufacturer of the RDN device being investigated and the other RCT²² was partially funded by the device manufacturer. In 1 RCT,²⁰ the funding body identified clinical sites in collaboration with the executive committee and was responsible for data collection, monitoring, and data analysis. The funder also assisted in generating the figures and tables, copyediting, and formatting.²⁰ In another RCT,²² the funder had no role in writing the protocol, executing the trial, handling the data or statistical analysis, and had no veto power over the manuscript’s content. In the third RCT,^21, the role of the funder was not described. The statement of conflicts of interest also helps readers to understand the potential bias from study funders. Most of the authors of each RCT^20-22 disclosed potential conflicts of interest, specifically ties with the device manufacturer or other industries (e.g., speaker honorariums, consulting fees, institutional grants, study fees to enrol patients). Direct funding from industry for the 3 RCTs^20-22 and potential conflicts of interest with RDN manufacturers^20-22 could potentially have led to publication, performance, or other bias in favour of the intervention.

Additional details regarding the strengths and limitations of the included publications are provided in Appendix 3.

Summary of Findings

The main study findings are provided in Appendix 4.

24-Hour Ambulatory BP

There were statistically significant reductions in 24-hour ambulatory systolic and diastolic BP with RDN compared to sham procedure in:

• patients with nonresistant hypertension (uncontrolled hypertension on less than 3 antihypertensive medications) at 2 to 6 months (meta-analyses in 1 SR)¹⁸

• patients with uncontrolled hypertension not taking any hypertensive medications at 2 months (1 RCT in 1 SR).¹⁹

Based on a clinically important difference of 2.0 mm Hg,^23-25 these reductions appear to be clinically significant.

There were no statistically significant differences between RDN and sham in 24-hour ambulatory systolic and diastolic BP in:

• patients with resistant hypertension (uncontrolled hypertension despite taking 3 or more hypertensive medications at 2 to 6 months; meta-analyses in 1 SR)¹⁸

• patients with uncontrolled hypertension taking 1 to 3 hypertensive medications at 6 months (for 24-hour ambulatory systolic BP only since 24-hour ambulatory diastolic BP was not reported, 1 RCT)²⁰

• patients with suspected hypertensive heart disease on 3 or more hypertensive medications at 6 months (1 RCT).^22.

At 1 year, RDN statistically and clinically significantly increased 24-hour ambulatory diastolic BP compared to sham, but had no statistically significant effect on 24-hour ambulatory systolic BP in patients with uncontrolled hypertension not taking any hypertensive medications (1 RCT).²¹ The authors suggested that these results may have been effected by COVID-19 pandemic; i.e., BP outcomes may have been sensitive to COVID-19 stressors and public health measures which also impacts lifestyle and social living.²¹

Office BP

There were statistically significant reductions in office systolic BP with RDN compared to sham procedure in:

• patients with uncontrolled nonresistant hypertension at 2 to 12 months (meta-analyses in 1 SR)¹⁹

• patients with uncontrolled hypertension on 1 to 3 hypertensive medications at 6 months (1 RCT).²⁰

Based on a clinically important difference of 5 mm Hg,²⁵ these reductions in office systolic BP appear to be clinically significant.

There was a statistically significant reduction in office diastolic BP with RDN compared to sham procedure in patients with uncontrolled nonresistant hypertension at 2 to 12 months, but this effect was not clinically significant (meta-analyses in 1 SR).¹⁹

A statistically significant, but not clinically important (< 5 mm Hg), reduction in office diastolic BP at 2 to 12 months was found with RDN versus sham in patients with resistant hypertension; and the reduction in office systolic BP was not statistically or clinically significant (meta-analyses in 1 SR).¹⁹

There were no statistically significant differences between RDN and sham in office systolic and diastolic BP in:

• patients with resistant hypertension at 3 and 6 months (2 RCTs in 1 SR)¹⁴

• patients with suspected hypertensive heart disease at 6 months (1 RCT)²²

• patients with uncontrolled hypertension off hypertensive medications at 1 year (1 RCT).²¹

Daytime BP

There were statistically and clinically significant reductions in daytime ambulatory systolic and diastolic BP with RDN compared to sham in patients with uncontrolled nonresistant hypertension at 2 to 12 months (meta-analysis in 1 SR).¹⁹

In patients with resistant hypertension, a meta-analysis in 1 SR¹⁹ found that RDN statistically and clinically significantly reduced daytime ambulatory systolic BP, but had no effect on daytime ambulatory diastolic BP, compared to sham at 2 to 12 months (meta-analysis in 1 SR).¹⁹ However, 1 RCT in another 1 SR¹⁸ reported no statistically or clinically significant differences between RDN and sham in daytime systolic and diastolic BP in patients with resistant hypertension at 3 months. It is possible that the difference in findings is because meta-analyses have higher statistical power and are likely able to detect between-group differences more precisely.

Nighttime BP

In patients with uncontrolled hypertension (regardless of antihypertensive medication usage), there was no statistically significant difference in change from baseline of nighttime ambulatory systolic and diastolic BP between RDN and sham at 2 to 6 months (meta-analysis in 1 SR).¹⁴

Estimated Glomerular Filtration Rate

There was a statistically significant difference in change from baseline of eGFR between RDN and sham at 12 months; eGFR remained stable in the RDN group but decreased in the sham group (1 RCT).²¹ However, the clinical importance of this finding is unclear.

Antihypertensive Medication Utilization

Patients taking antihypertensive medications at baseline who received RDN compared to sham were prescribed statistically significantly fewer antihypertensive medications at 6 months (1 RCT). ²⁰ Patients who received RDN in the absence of antihypertensives (at baseline) were also prescribed statistically significantly fewer antihypertensive medications at 12 months compared to the sham group (1 RCT).²¹

In patients taking antihypertensive medications at baseline, medication burden was statistically significantly lower in the RDN group compared to the sham group at 6 months (1 RCT).²⁰ In patients not taking antihypertensives at baseline, medical burden was statistically significantly lower with RDN compared to sham at 12 months (1 RCT).²¹

Adverse Events

In patients with uncontrolled hypertension, there were no significant differences in major adverse events with RDN versus sham procedure (1 RCT included in 1 SR,¹⁹ 2 RCTs).^20,21 In patients with suspected hypertensive heart disease, there was a statistically significant reduction in subclinical atrial fibrillation with RDN compared to sham at 2-year follow-up (1 RCT).²²

Limitations

Certainty of the Evidence

Risk of Bias of Included Studies in SRs

Of the 8 included trials in both SRs,^14,18,19 the review authors of 1 SR¹⁹ assessed the 8 trials as high risk of bias related to allocation concealment; whereas, the authors of the other SR¹⁸ assessed 7 trials as having some concerns about allocation concealment, 2 studies had some concerns related to blinding, 1 with some concerns with incomplete outcome data, and all 8 studies as having some concerns related to industry funding. Of the 3 trials included in either 1 of the SRs (i.e., non-overlapping studies),^14,18,19 as assessed by the review authors, 1 study had high risk of bias related to allocation concealment; another study had some concerns regarding allocation concealment, blinding of patients and personnel, and industry funding, and high risk of bias related to incomplete outcome data; and the third study had some concerns regarding blinding and industry funding. Therefore, there is some uncertainty in the evidence from the SRs^14,18,19 due to risk of bias.

Generalizability

Of the included primary studies, only the RCT evaluating the Symplicity Spyral RDN system²⁰ had a study site in Canada. Thus, the generalizability of the effectiveness of other RDN systems (not yet available in Canada) may not be generalizable to the health care context in Canada. The 2 SRs^14,18,19 did not identify the countries in which their included studies were conducted; therefore, the generalizability (or directness) of their findings is unknown.

Heterogeneity

There was variability in patient populations (e.g., different inclusion criteria, number of comorbidities, types of hypertensives taken), interventions (e.g., first- or second-generation device, energy source, expertise of physicians performing RDN), and time periods (e.g., length of follow-up, during or not during the COVID-19 pandemic) across included studies. Patient adherence to antihypertensive medications was monitored in some included studies (e.g., with urine and plasma testing)^14,18-21 but not others,^14,18,19,22 which may have led to inconsistencies in categorizing patients as having resistant or nonresistant hypertension.^14,18,19

Imprecision

Two RCTs^21,22 had small sample sizes. Effect estimates for several outcomes had wide confidence intervals.^18,19 One RCT²⁰ did not report the confidence intervals for the effect estimates.

Conclusions and Implications for Decision- or Policy-Making

This report comprises 2 SRs^14,18,19 and 3 RCTs^20-22 on the clinical effectiveness of RDN compared to sham for uncontrolled hypertension.

Clinical Effectiveness of Renal Denervation Compared to Sham

In adults with uncontrolled nonresistant hypertension, RDN compared to sham may have a favourable effect on 24-hour ambulatory BP, office systolic BP, and daytime BP at 2 to 12 months following treatment, but these findings are uncertain due to risk of bias, imprecision and potential indirectness.^18,19 In adults with resistant hypertension, RDN compared to sham had no effect on 24-hour ambulatory BP, office systolic BP, and daytime diastolic BP at 2 to 12 months following treatment, but these findings have some uncertainty due to risk of bias and potential indirectness.^18,19 The effect of RDN compared to sham on office diastolic BP and daytime systolic BP is uncertain due to conflicting findings across studies.^18,19

In adults with uncontrolled hypertension on antihypertensive medications, RDN compared to sham may have no effect on 24-hour systolic ambulatory BP, but a favourable effect on office systolic BP and medication burden, at 6 months following treatment, but these findings are uncertain due to unknown precision.²⁰

In adults with uncontrolled hypertension not taking antihypertensive medications, RDN compared to sham may have a favourable effect on 24-hour ambulatory BP at 2 months¹⁹ and following treatment and no effect on office BP at 12 months (despite statistically significantly lower medication burden in the RDN group),²¹ but these findings are uncertain due to risk of bias, imprecision, and potential indirectness.^19,21 In patients with suspected hypertensive heart disease, RDN compared to sham may a favourable impact on subclinical atrial fibrillation but no effect on 24-hour ambulatory BP and office BP, at 6 months following treatment, but these findings are uncertain due to imprecision and indirectness.²²

Major adverse events (including cardiovascular events) following treatment with RDN were rare.^19-22

Clinical Effectiveness of Renal Denervation at Longer Follow-Up

All included studies investigated short-term effects of RDN, with follow-up periods ranging from 2 to 12 months for clinical effectiveness outcomes^14,18-22 and up to 2 years for safety outcomes.²² Three publications of 2 RCTs^26-28 included in the 2 SRs^14,18,19 reported longer-term effects of RDN versus sham on BP outcomes, time in therapeutic BP range, and safety in patients with treatment-resistant hypertension. While we did not critically appraise these primary studies, we present a summary of their findings in Table 10. The authors of these publications^26,27 concluded that patients in the RDN group had statistically significantly larger reductions from baseline to 3-year follow-up in 24-hour ambulatory, office, morning, and nighttime BP compared with the sham control group.^26,27 The RDN group spent approximately twice as much time in a therapeutic BP range compared with the sham control group.²⁷ Additionally, there were no late-emerging complications with RDN at 3-²⁷ and 4-year follow-up.²⁸

Guidelines and Real-World Evidence on the Use of Renal Denervation for Uncontrolled Hypertension

Findings of this review appear to be generally consistent with that of guidelines and real-world evidence regarding RDN for uncontrolled hypertension. Although we did not formally review and appraise the real-world evidence and evidence-based guidelines, a brief summary is provided in this section. Additional details are presented in Appendix 5.

While Hypertension Canada’s 2020 guidelines⁸ do not include recommendations about the use of RDN, we identified 3 evidence-based guidelines^29-31 that include recommendations about the use of RDN for uncontrolled hypertension. The European Society of Hypertension,²⁹ the National Institute for Health and Care Excellence (NICE),³⁰and the Taiwan Hypertension Guidelines²⁹ recommend that RDN can be considered as a treatment option for patients with uncontrolled hypertension. The European Society of Hypertension²⁹ and NICE³⁰ provide further recommendations regarding patient selection and RDN performance. A summary of the guideline recommendations is presented in Table 11.

The Medtronic-funded Global SYMPLICITY registry is an international, multicentre, prospective, open-label, observational study to evaluate real-world effectiveness and safety after treatment with the Symplicity RDN system using either the single-electrode Symplicity Flex or the multi-electrode Symplicity Spyral radiofrequency catheter systems.^32,33 As of March 2023, over 3,000 patients from 45 countries have been enrolled.³³ According to the published results, there was a statistically significant decrease from baseline in 24-hour and office systolic BP at 3 years in patients with uncontrolled hypertension and with resistant hypertension.^32,33 The authors concluded that radiofrequency RDN reduced BP consistently up to 36 months independent of the number of baseline antihypertensive medications³³ and that RDN-induced reductions in BP were associated with fewer strokes and other adverse cardiovascular events within 3 years.³² Recent real-world studies with smaller populations have also demonstrated decreases in 24-hour ambulatory and office BP values with RDN in patients with resistant hypertension over 12 months¹⁰ and 9 years without adverse renal function effects.² While we did not critically appraise these primary studies, we present a summary of their findings, a summary of the findings of real-world studies is presented in Table 12.

Considerations for Future Research

As the findings of ongoing sham-controlled RCTs on RDN using newer ablation techniques³⁴ and alcohol-based methods³⁵ become available, they should be combined with the evidence in this Rapid Review. Future RCTs should measure patient-important outcomes, such as quality of life and patient preferences, with longer follow-up periods, larger sample sizes, and more standardized procedural methods. The finding that RDN compared to sham may reduce atrial fibrillation independent of its effect on BP²² should be confirmed in trials with a larger population. Future work should also focus on the development of a periprocedural marker for successful renal nerve ablation,³⁶ common to all RDN methods, and predictors of significant response to RDN to identify patient populations who will benefit most from treatment, factors leading to improved procedural efficacy, and direct comparison of different RDN techniques.³⁷

To help address health equity concerns in future studies, researchers should consider collecting equity-relevant population characteristics (e.g., gender, education, socioeconomic status, place of residence) to assess potential health inequities related to RDN for uncontrolled hypertension.

Implications for Clinical Practice

Although the findings of this report are not conclusive, they do suggest a potential short-term benefit of RDN for uncontrolled nonresistant hypertension without negative major adverse events. RDN remains an emerging technology in Canada, with approval from Health Canada pending at the time of authoring this report. Decision-makers should consider factors such as cost of RDN, potential health care resource need required for the procedure,³⁸ possible long wait times, and concerns related to equity of access. In addition, as per the NICE guidelines,³⁰ patients who receive RDN should be selected by a multidisciplinary team and health care providers should audit and review clinical outcomes for all RDN procedures. The evidence does not support decision-making in favour of the use of RDN for resistant hypertension and suspected hypertensive heart disease currently.

References

1.Leung AA, Williams JVA, McAlister FA, et al. Worsening hypertension awareness, treatment, and control rates in Canadian women between 2007 and 2017. Can J Cardiol. 2020;36(5):732-739. PubMed

2.Sesa-Ashton G, Nolde JM, Muente I, et al. Catheter-based renal denervation: 9-year follow-up data on safety and blood pressure reduction in patients with resistant hypertension. Hypertension. 2023;80(4):811-819. PubMed

3.Silverwatch J, Marti KE, Phan MT, et al. Renal denervation for uncontrolled and resistant hypertension: Systematic review and network meta-analysis of randomized trials. J Clin Med. 2021;10(4):16. PubMed

4.Townsend RR. Definition, risk factors, and evaluation of resistant hypertension. In: Post TW, ed. UpToDate. Waltham (MA): UpToDate; 2023: http://www.uptodate.com. Accessed 2024 Feb 29.

5.Stavropoulos K, Patoulias D, Imprialos K, et al. Efficacy and safety of renal denervation for the management of arterial hypertension: A systematic review and meta-analysis of randomized, sham-controlled, catheter-based trials. J Clin Hypertens (Greenwich). 2020;22(4):572-584. PubMed

6.Filippone EJ, Naccarelli GV, Foy AJ. Controversies in hypertension IV: Renal denervation. Am J Med. 2023;136(9):857-868. PubMed

7.Hiremath S, Sapir-Pichhadze R, Nakhla M, et al. Hypertension Canada's 2020 evidence review and guidelines for the management of resistant hypertension. Can J Cardiol. 2020;36(5):625-634. PubMed

8.Rabi DM, McBrien KA, Sapir-Pichhadze R, et al. Hypertension Canada's 2020 comprehensive guidelines for the prevention, diagnosis, risk assessment, and treatment of hypertension in adults and children. Can J Cardiol. 2020;36(5):596-624. PubMed

9.Choi KH, Choi SH. Current status and future perspectives of renal denervation. Korean Circ J. 2021;51(9):717-732. PubMed

10.Rodriguez-Leor O, Segura J, Garcia Donaire JA, et al. Renal denervation for the treatment of resistant hypertension in Spain. The Flex-Spyral Registry. Rev Esp Cardiol (Engl Ed). 2020;73(8):615-622. PubMed

11.Bourque G, Ilin JV, Ruzicka M, Davis A, Hundemer G, Hiremath S. The prevalence of non-adherence in patients with resistant hypertension: A systematic review and meta-analysis [non peer-reviewed preprint]. medRxiv. 2020. https://www.medrxiv.org/content/10.1101/2020.08.14.20175125v1. Accessed 2024 Feb 29.

12.Davis MI, Filion KB, Zhang D, et al. Effectiveness of renal denervation therapy for resistant hypertension: A systematic review and meta-analysis. J Am Coll Cardiol. 2013;62(3):231-241. PubMed

13.Pisano A, Iannone LF, Leo A, Russo E, Coppolino G, Bolignano D. Renal denervation for resistant hypertension. Cochrane Database Syst Rev. 2021;11:CD011499. PubMed

14.Ahmed M, Nudy M, Bussa R, et al. A systematic review, meta-analysis, and meta regression of the sham controlled renal denervation randomized controlled trials. Trends Cardiovasc Med. 2023;33(8):490-498. PubMed

15.Kumar D, Loshak H. CADTH horizon scan: Renal denervation for people with hypertension. Can J Health Technol. 2022;2(1). https://canjhealthtechnol.ca/index.php/cjht/article/view/en0038/en0038. Accessed 2024 Feb 29. PubMed

16.Shea BJ, Reeves BC, Wells G, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017;358:j4008. PubMed

17.Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health. 1998;52(6):377-384. PubMed

18.Ahmed M, Nudy M, Bussa R, Naccarelli GV, Filippone EJ, Foy AJ. A subgroup meta-analysis comparing the renal denervation sham-controlled randomized trials among those with resistant and nonresistant hypertension. Am J Cardiol. 2023;191:119-124. PubMed

19.Singh S, Rout A, Garg A. Renal denervation in hypertension: An updated meta-analysis of the randomized controlled trials. Catheter Cardiovasc Interv. 2023;102(4):663-671. PubMed

20.Kandzari DE, Townsend RR, Kario K, et al. Safety and efficacy of renal denervation in patients taking antihypertensive medications. J Am Coll Cardiol. 2023;82(19):1809-1823. PubMed

21.Pathak A, Rudolph UM, Saxena M, et al. Alcohol-mediated renal denervation in patients with hypertension in the absence of antihypertensive medications. EuroIntervention. 2023;19(7):602-611. PubMed

22.Heradien M, Mahfoud F, Greyling C, et al. Renal denervation prevents subclinical atrial fibrillation in patients with hypertensive heart disease: Randomized, sham-controlled trial. Heart Rhythm. 2022;19(11):1765-1773. PubMed

23.Whelton PK, He J, Appel LJ, et al. Primary prevention of hypertension: clinical and public health advisory from The National High Blood Pressure Education Program. JAMA. 2002;288(15):1882-1888. PubMed

24.Makai P, IntHout J, Deinum J, Jenniskens K, Wilt GJV. A network meta-analysis of clinical management strategies for treatment-resistant hypertension: Making optimal use of the evidence. J Gen Intern Med. 2017;32(8):921-930. PubMed

25.Bhatt DL, Kandzari DE, O'Neill WW, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370(15):1393-1401. PubMed

26.Kario K, Mahfoud F, Kandzari DE, et al. Long-term reduction in morning and nighttime blood pressure after renal denervation: 36-month results from SPYRAL HTN-ON MED trial. Hypertens Res. 2023;46(1):280-288. PubMed

27.Bhatt DL, Vaduganathan M, Kandzari DE, et al. Long-term outcomes after catheter-based renal artery denervation for resistant hypertension: Final follow-up of the randomised SYMPLICITY HTN-3 Trial. Lancet. 2022;400(10361):1405-1416. PubMed

28.Mahfoud F, Kandzari DE, Kario K, et al. Long-term efficacy and safety of renal denervation in the presence of antihypertensive drugs (SPYRAL HTN-ON MED): A randomised, sham-controlled trial. Lancet. 2022;399(10333):1401-1410. PubMed

29.Mancia G, Kreutz R, Brunstrom M, et al. 2023 ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension: Endorsed by the International Society of Hypertension (ISH) and the European Renal Association (ERA). J Hypertens. 2023;41(12):1874-2071. PubMed

30.National Institute for Health and Care Excellence. Percutaneous transluminal renal sympathetic denervation for resistant hypertension (NICE interventional procedures guidance IPG754). 2023; https://www.nice.org.uk/guidance/ipg754/. Accessed 2024 Feb 13.

31.Wang TD, Chiang CE, Chao TH, et al. 2022 Guidelines of the Taiwan Society of Cardiology and the Taiwan Hypertension Society for the Management of Hypertension. Acta Cardiologica Sin. 2022;38(3):225-325. PubMed

32.Schmieder RE, Mahfoud F, Mancia G, et al. Clinical event reductions in high-risk patients after renal denervation projected from the global SYMPLICITY registry. Eur Heart J Qual Care Clin Outcomes. 2023;9(6):575-582. PubMed

33.Mahfoud F, Mancia G, Schmieder RE, et al. Outcomes following radiofrequency renal denervation according to antihypertensive medications: Subgroup analysis of the Global SYMPLICITY Registry DEFINE. Hypertension. 2023;80(8):1759-1770. PubMed

34.Otsuka Medical Devices Co., Ltd. Japan. A Clinical Study of the Paradise™ Renal Denervation System in Patients With Hypertension (RADIANCE‐HTN DUO). ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine: https://clinicaltrials.gov/study/NCT05326230. Accessed 2024 Feb 28.

35.Ablative Solutions, Inc. TARGET BP I Clinical Trial (TARGET BP I). ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2023: https://clinicaltrials.gov/study/NCT02910414. Accessed 2024 Feb 28.

36.Azizi M, Schmieder RE, Mahfoud F, et al. Six-month results of treatment-blinded medication titration for hypertension control after randomization to endovascular ultrasound renal denervation or a sham procedure in the RADIANCE-HTN SOLO trial. Circulation. 2019;139(22):2542-2553. PubMed

37.Shah RT, Wang BX. Effectiveness of renal denervation in the treatment of hypertension: A literature review. Clin Hypertens. 2022;28(1):11. PubMed

38.Marcusohn E, Tobe SW, Dueck A, Madan M. Renal denervation for uncontrolled hypertension. CMAJ. 2023;195(43):E1475-E1480. PubMed

Appendix 1: Selection of Included Studies

Figure 1: Selection of Included Studies

Appendix 2: Characteristics of Included Publications

Note that this appendix has not been copy-edited.

Table 2: Characteristics of Included Systematic Reviews

ABP = ambulatory blood pressure; AH = antihypertensive; BP = blood pressure; CAD = coronary artery disease; DBP = diastolic blood pressure; DM = diabetes mellitus; HTN = hypertension; MA = meta-analyses; NR = not reported; RCT = randomized controlled trial; RDN = renal denervation; SBP = systolic blood pressure.

Table 3: Characteristics of Included Randomized Controlled Trials

ABP = ambulatory blood pressure; BP = blood pressure; CAD = coronary artery disease; CCS = chronic coronary syndrome; DBP = diastolic blood pressure; eGFR = estimated glomerular filtration rate; HTN = hypertension; NR = not reported; RDN = renal denervation; RCT = randomized controlled trial; SBP = systolic blood pressure; SD = standard deviation.

Appendix 3: Critical Appraisal of Included Publications

Note that this appendix has not been copy-edited.

Table 4: Strengths and Limitations of Systematic Reviews Using AMSTAR 2¹⁶

AMSTAR 2 = A MeaSurement Tool to Assess systematic Reviews 2; RCT = randomized controlled trial; ROB = risk of bias.

Table 5: Strengths and Limitations of Randomized Controlled Trials Using the Downs and Black Checklist¹⁷

Appendix 1: Main Study Findings

Table 6: Summary of Findings by Outcome — Blood Pressure Outcomes

AH = antihypertensive; CI = confidence interval; DBP = diastolic blood pressure; MA = meta-analysis; MD = mean difference; NA = not applicable; NR = not reported; RCT = randomized controlled trial; RDN = renal denervation; SD = standard deviation; SR = systematic review; SBP = systolic blood pressure.

^aPatients whose BP remains above the goal and are taking < 3 AH medications were described as having nonresistant uncontrolled HTN.^14,18,20

^bPatients whose BP remains above the goal and are taking ≥ 3 AH medications were described as having resistant HTN.^14,18,20

^cOne RCT (RADIANCE II trial) was not reported in the SR by Ahmed et al.^14,18 Therefore, data from this trial is presented separately, rather than the MA reported in this SR to avoid duplicate reporting.¹⁹

^dAdjusted for baseline values.²²

^eTwo RCTs (REQUIRE and WAVE IV trials) were not reported in the SR by Singh et al.¹⁹ Therefore, data from these trials is presented separately, rather than the MA reported in this SR to avoid duplicate reporting.

^fOne RCT (REQUIRE trial) was not reported in the SR by Singh et al.¹⁹ Therefore, data from this is presented separately, rather than the MA reported in this SR to avoid duplicate reporting.¹⁴

Note that this appendix has not been copy-edited.

Table 7: Summary of Findings by Outcome — Estimated glomerular filtration rate

AH = antihypertensive; CI = confidence interval; eGFR = estimated glomerular filtration rate; NR = not reported; RCT = randomized controlled trial; RDN = renal denervation; SD = standard deviation.

Table 8: Summary of Findings by Outcome — Antihypertension Medication Utilization

AH = antihypertensive; CI = confidence interval; NA = not applicable; RCT = randomized controlled trial; RDN = renal denervation; SD = standard deviation.

^aP values used ANCOVA adjusted for baseline values.

^bComposite index based on the doses of medications but multiplies this result by the number of prescribed medications. AH medication burden was calculated for all AH medication prescribed at study specified follow-up visits for each patient and added to yield a single, summative score.²⁰

^cComposite index based on the doses of medications and is a proportional measure of prescribed to maximum daily dose, as recommended by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, calculated for each antihypertensive medication.²¹

Table 9: Summary of Findings by Outcome — Adverse Events

CI = confidence interval; HR = hazard ratio; NR = not applicable; RR = relative risk; RCT = randomized controlled trial; RDN = renal denervation.

^aVascular complications included requiring surgical repair, intervention procedure, thrombin injection, or blood transfusion.

^bRenal function complications included renal artery stenosis, renal artery perforation or dissection requiring intervention, serum creatinine elevation > 50%, or new-onset end-stage renal disease.

^cHypertensive crisis.

^dVascular complication (the patient developed a small subcutaneous hematoma; aneurysma spurium was subsequently diagnosed).

Appendix 5: Summary of Findings from Other Publications of Interest

Note that this appendix has not been copy-edited.

Table 10: Summary of Findings — Longer Follow-Up Periods

AH = antihypertensive; CI = confidence interval; DBP = diastolic blood pressure; MD = mean difference; RCT = randomized controlled trial; RDN = renal denervation; SD = standard deviation; SBP = systolic blood pressure; TTR = time in therapeutic range.

^aMorning is defined as 7:00 a.m. to 9:00 a.m.

^bNighttime is defined as 1:00 a.m. to 6:00 a.m.

^cDefined as a composite of all-cause mortality, end-stage renal disease, embolic event resulting in end-organ damage, renal artery perforation requiring reintervention, renal artery dissection requiring reintervention, vascular complications, hospitalization for hypertensive crisis or emergency, or new renal artery stenosis > 70%.

^dOne patient had a hypertension crisis and stroke at 427 days after the procedure; the patient presented to the emergency department with weakness on the left side and elevated BP (193 mm Hg over 123 mm Hg), received inpatient treatment, and was discharged in a stable condition.

^eOne cardiovascular death occurred 693 days after the procedure; the patient was found unconscious at home, and an autopsy was not performed; therefore, cause of death is unknown.

_f Crossover group included patients randomized to sham, who underwent RDN after 6 months.

^gNoncrossover group included patients randomized to sham, who did not receive RDN.

Table 11: Summary of Recommendations in Guidelines

ASCVD = atherosclerotic cardiovascular diseases; BP = blood pressure; CV = cardiovascular; eGFR = estimated glomerular filtration rate; ESH = European Society of Hypertension; RDN = renal denervation; NICE = National Institute for Health and Care Excellence.

Table 12: Summary of Findings — Real-World Evidence

AH = antihypertensive; DBP = diastolic blood pressure; MD = mean difference; NS = not statistically significant; RDN = renal denervation; SD = standard deviation; SBP = systolic blood pressure.

^aFull population included patients with a mean age of 61 years, 42% female gender, 47% with a history of cardiovascular disease, and mean 4.6 prescribed AH medications.³³

^bPopulation included patients with a mean age of 56 years, 41% female gender, and 12% with previous ischemic heart disease and mean 4.9 prescribed AH medications.¹⁰

^cPopulation included patients with a mean age of 61 years, 16% female gender, and mean 4.2 prescribed AH medications.²

^dIncluded myocardial infarction, cardiovascular deaths, all-cause deaths, and hospitalization for heart disease.³³

^eThe 4 events were 3 nonfatal strokes and 1 nonfatal myocardial infarction. Sixty-two participants reported no adverse major cardiovascular events; however, 3 additional patients received coronary artery stents following the discovery of notable coronary stenosis. One participant noted they had begun dialysis treatment on a background of significant preexisting chronic kidney disease before RDN.

Appendix 6: Overlap Between Included SRs

Note that this appendix has not been copy-edited.

Table 13: Overlap in Relevant Primary Studies Between Included Systematic Reviews

Appendix 7: References of Potential Interest

Previous CADTH Reports

Kumar D, Loshak H. CADTH horizon scan: Renal denervation for people with hypertension. Can J Health Technol. 2022;2(1). https://canjhealthtechnol.ca/index.php/cjht/article/view/en0038/en0038. PubMed

Systematic Reviews

Systematic Reviews in Which All Relevant Studies Were Captured in Systematic Reviews Included in the Report

Ahmed M, Nudy M, Bussa R, Filippone EJ, Foy AJ. A systematic review and meta-analysis of all sham and placebo controlled trials for resistant hypertension. Eur J Intern Med. 2023;113:83-90. PubMed

Agasthi P, Shipman J, Arsanjani R, et al. Renal denervation for resistant hypertension in the contemporary era: A systematic review and meta-analysis. Sci Rep. 2019;9(1):6200. PubMed

Cheng X, Zhang D, Luo S, Qin S. Effect of catheter-based renal denervation on uncontrolled hypertension: A systematic review and meta-analysis. Mayo Clin Proc. 2019;94(9):1695-1706. PubMed

Dahal K, Khan M, Siddiqui N, et al. Renal denervation in the management of hypertension: A meta-analysis of sham-controlled trials. Cardiovasc Revasc Med. 2020;21(4):532-537. PubMed

Clinical evidence assessment: Paradise Renal Denervation System (ReCor Medical, Inc.) for treatment-resistant hypertension. Plymouth Meeting (PA): ECRI Institute; 2024: www.ecri.org. Accessed 2024 Feb 5.

Maqsood MH, Rubab K, Anwar F, et al. A systematic review of randomized controlled trials comparing renal sympathetic denervation versus sham procedure for the management of uncontrolled hypertension. J Cardiovasc Pharmacol. 2021;77(2):153-158. PubMed

Pisano A, Iannone LF, Leo A, Russo E, Coppolino G, Bolignano D. Renal denervation for resistant hypertension. Cochrane Database Syst Rev. 2021;11():CD011499.

Silverwatch J, Marti KE, Phan MT, et al. Renal denervation for uncontrolled and resistant hypertension: Systematic review and network meta-analysis of randomized trials. J Clin Med. 2021;10(4):782. PubMed

Sardar P, Bhatt DL, Kirtane AJ, et al. Sham-controlled randomized trials of catheter-based renal denervation in patients with hypertension. J Am Coll Cardiol. 2019;73(13):1633-1642. PubMed

Stavropoulos K, Patoulias D, Imprialos K, et al. Efficacy and safety of renal denervation for the management of arterial hypertension: A systematic review and meta-analysis of randomized, sham-controlled, catheter-based trials. J Clin Hypertens (Greenwich). 2020;22(4):572-584. PubMed

Syed M, Osman M, Alhamoud H, et al. The state of renal sympathetic denervation for the management of patients with hypertension: A systematic review and meta-analysis. Catheter Cardiovasc Interv. 2021;97(4):E438-E445. PubMed

Tian Z, Vollmer Barbosa C, Lang H, Bauersachs J, Melk A, Schmidt BMW. Efficacy of pharmacological and interventional treatment for resistant hypertension-a network meta-analysis. Cardiovasc Res. 2023;27():27.

Wales Health Technology. Renal denervation to treat people with resistant hypertension [Evidence Appraisal Report]. 2023: https://healthtechnology.wales/wp-content/uploads/2022/02/EAR042-Renal-Denervation-WEB.pdf Accessed 2024 Feb 13.

Yang X, Liu H, Chen S, Dong P, Zhao D. Intravascular renal denervation reduces ambulatory and office blood pressure in patients with essential hypertension: A meta-analysis of randomized sham-controlled trials. Kidney Blood Press Res. 2022;47(6):363-374. PubMed

Economic Evaluations

Sharp ASP, Cao KN, Esler MD, et al. Cost-effectiveness of catheter-based radiofrequency renal denervation for the treatment of uncontrolled hypertension: An analysis for the UK based on recent clinical evidence. Eur Heart J Qual Care Clin Outcomes. 2024; 09:qcae001. PubMed

Taylor RS, Bentley A, Metcalfe K, et al. Cost effectiveness of endovascular ultrasound renal denervation in patients with resistant hypertension. Pharmacoeconom Open. 2024;30:30. PubMed