Renal Denervation for Uncontrolled Hypertension

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A. Decision The Centers for Medicare & Medicaid Services (CMS) will cover radiofrequency renal denervation (rfRDN) and ultrasound renal denervation (uRDN) (collectively, RDN) for uncontrolled hypertension under Coverage with Evidence Development (CED) according to the provisions in sections (B) and (C) below. B. Coverage Criteria RDN is covered for uncontrolled hypertension when furnished according to a Food and Drug Administration (FDA) market-authorized indication, and all the following conditions are met: 1. Patient Criteria The patient meets all the following criteria: (a) Diagnosis of uncontrolled hypertension (≥ 140 mm Hg systolic blood pressure and > 90 mm Hg diastolic blood pressure) despite active management by a clinician with primary responsibility for blood pressure management. (b) Uncontrolled hypertension diagnosed using either ambulatory blood pressure monitoring or serial home blood pressure readings. (c) On lifestyle modifications and stable doses of maximally tolerated guideline-directed medical therapy (GDMT), with assessment of adherence to the prescribed regimen, for at least six weeks before referral for RDN. (d) As clinically appropriate, secondary hypertension must be evaluated and treated before determining that blood pressure remains uncontrolled. At a minimum, patients must be screened for primary aldosteronism, obstructive sleep apnea, and drug or alcohol induced hypertension before referral to RDN. (e) The patient has no contraindications to RDN, consistent with the FDA labeling of the device used. (f) The primary clinicians must coordinate management of the patient for a minimum of six months before referral for RDN, during which the patient had at least three encounters, with no more than two of the three encounters being virtual. (g) No prior RDN procedure. 2. Physician Criteria RDN is furnished by clinicians who meet the following criteria, as applicable: (a) Clinicians referring Medicare beneficiaries must have longitudinal responsibility for hypertension management. (b) Physicians performing RDN must have interventional and endovascular skills to perform effective RDN treatments. Additionally, they must be able to manage potential complications either themselves or with institutional support from colleagues who are immediately available to assist in emergency management. (c) Physicians performing RDN without prior endovascular training or renovascular expertise must complete at least ten supervised cases of diagnostic/therapeutic renovascular procedures, half as primary operator. Additionally, they must complete at least five proctored RDN cases with each approved device used in their practice. (d) Physicians performing RDN with prior endovascular training and active endovascular experience must complete at least five proctored RDN cases with each approved device used in their practice. 3. Facility Criteria The RDN device and related items and services are furnished at facilities meeting the following criteria: (a) Facilities performing RDN must have a hypertension program with contributions from a hypertension clinician with longitudinal patient management responsibility, a hypertension navigator, and access to relevant medical specialties (e.g., internal medicine, endocrinology, sleep medicine, cardiology, and nephrology) as appropriate. (b) Preprocedural imaging capabilities (e.g., ultrasound, Computed Tomography Angiography, Magnetic Resonance Angiography). (c) An appropriate interventional cardiology or radiology suite. 4. CED Study Criteria The RDN device and related items and services are furnished in the context of a CMS-approved CED study. CMS-approved CED study protocols must: include only those patients who meet the criteria in section B.1; furnish items and services only through practitioners who meet the criteria in section B.2; furnish items and services at facilities meeting the criteria in section B.3; and include all of the following: (a) One or more primary outcomes of ambulatory systolic blood pressure (ASBP), ambulatory diastolic blood pressure (ADBP), home systolic blood pressure (HSBP), home diastolic blood pressure (HDBP), office systolic blood pressure (OSBP), office diastolic blood pressure (ODBP), worsening renal function, cerebrovascular accident, acute myocardial infarction, incidence of new-onset heart failure, cardiovascular mortality, all-cause mortality, or a composite of these, through a minimum of 24 months. Each component of a composite outcome must be individually reported. (b) An active comparator. (c) Design sufficient for subgroup analyses by: Age (Stratify <65, 65-74, 75+); Other clinically important patient demographic factors; Chronic kidney disease (Stratify by CKD Stages); Progression of CKD; Hypertension phenotype (e.g., resistant hypertension vs. uncontrolled for any reason); Medication adherence. (d) In addition, CMS-approved CED studies must adhere to the scientific standards (criteria 1-17 below) that have been identified by the Agency for Healthcare Research and Quality (AHRQ) as set forth in Section VI. of CMS’ Coverage with Evidence Development Guidance Document , published August 7, 2024 (the “CED Guidance Document”). Sponsor/Investigator: The study is conducted by sponsors/investigators with the resources and skills to complete it successfully. Milestones: A written plan is in place that describes a detailed schedule for completion of key study milestones, including study initiation, enrollment progress, interim results reporting, and results reporting, to ensure timely completion of the CED process. Study Protocol: The CED study is registered with ClinicalTrials.gov and a complete final protocol, including the statistical analysis plan, is delivered to CMS prior to study initiation. The published protocol includes sufficient detail to allow a judgment of whether the study is fit-for-purpose and whether reasonable efforts will be taken to minimize the risk of bias. Any changes to approved study protocols should be explained and publicly reported. Study Context: The rationale for the study is supported by scientific evidence and study results are expected to fill the specified CMS-identified evidence deficiency and provide evidence sufficient to assess health outcomes. Study Design: The study design is selected to safely and efficiently generate valid evidence of health outcomes. The sponsors/investigators minimize the impact of confounding and biases on inferences through rigorous design and appropriate statistical techniques. If a contemporaneous comparison group is not included, this choice should be justified, and the sponsors/investigators discuss in detail how the design contributes useful information on issues such as durability or adverse event frequency that are not clearly answered in comparative studies. Study Population: The study population reflects the demographic and clinical diversity among the Medicare beneficiaries who are the intended population of the intervention, particularly when there is good clinical or scientific reason to expect that the results observed in premarket studies might not be observed in older adults or subpopulations identified by other clinical or demographic factors. Subgroup Analyses: The study protocol explicitly discusses beneficiary subpopulations affected by the item or service under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion requirements effect enrollment of these populations, and a plan for the retention and reporting of said populations in the trial. In the protocol, the sponsors/investigators describe plans for analyzing demographic subpopulations as well as clinically-relevant subgroups as identified in existing evidence. Description of plans for exploratory analyses, as relevant subgroups emerge, are also included. Care Setting: When feasible and appropriate for answering the CED question, data for the study should come from beneficiaries in their expected sites of care. Health Outcomes: The primary health outcome(s) for the study are those important to patients and their caregivers and that are clinically meaningful. A validated surrogate outcome that reliably predicts these outcomes may be appropriate for some questions. Generally, when study sponsors propose using surrogate endpoints to measure outcomes, they should cite validation studies published in peer-reviewed journals to provide a rationale for assuming these endpoints predict the health outcomes of interest. The cited validation studies should be longitudinal and demonstrate a statistical association between the surrogate endpoint and the health outcomes it is thought to predict. Objective Success Criteria: In consultation with CMS and AHRQ, sponsors/investigators establish an evidentiary threshold for the primary health outcome(s) so as to demonstrate clinically meaningful differences with sufficient precision. Data Quality: The data are generated or selected with attention to provenance, bias, completeness, accuracy, sufficiency of duration of observation to demonstrate durability of health outcomes, and sufficiency of sample size as required by the question. Construct Validity: Sponsors/investigators provide information about the validity of drawing warranted conclusions about the study population, primary exposure(s) (intervention, control), health outcome measures, and core covariates when using either primary data collected for the study about individuals or proxies of the variables of interest, or existing (secondary) data about individuals or proxies of the variables of interest. Sensitivity Analyses: Sponsors/investigators will demonstrate robustness of results by conducting pre-specified sensitivity testing using alternative variable or model specifications as appropriate. Reporting: Final results are provided to CMS and submitted for publication or reported in a publicly accessible manner within 12 months of the study’s prim

Decision Memo: Date: October 28, 2025 Table of Contents Decision Decision Coverage Criteria Patient Criteria Physician Criteria Facility Criteria CED Study Criteria Other Uses of RDN Clinical Review Background Hypertension Definition and Classification Epidemiology Treatment and Response to Therapy Renal Denervation Devices Food and Drug Administration Status Evidence Evidence Questions Technology Assessments Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) Clinical Literature Search Assessment of the Evidence Study Quality Assessment Evidence Base and Synthesis of Results Evidence from observational studies/meta-analyses and relevance to Medicare beneficiaries Limitations of Evidence Conclusions Evidence-Based Guidelines Professional Society Recommendations / Consensus Statements / Other Expert Opinios Appropriate Use Criteria Public Comment CMS Coverage Analysis CMS Coverage Authority CMS Analysis for Coverage of RDN for Hypertension Management Benefit Category Patient Evaluation Shared-Decision Making History of Medicare Coverage Current National Coverage Request Timeline of NCA Milestones Appendices Appendix A: Proposed Medicare National Coverage Determinations Manual Language Appendix B: RDN Device Characteristics and Operator Factors Appendix C: Referenced Materials Bibliography Abbreviations used throughout the Decision Memorandum for Renal Denervation (RDN) for Uncontrolled Hypertension ABP – Ambulatory Blood Pressure ABPM – Ambulatory Blood Pressure Monitoring ACC – American College of Cardiology ADBP – Average Daytime Blood Pressure AHA – American Heart Association AHM – Antihypertensive Medications ASBP– Ambulatory Systolic Blood Pressure BCI – Bayesian Credible Interval BMI – Body Mass Index BP – Blood Pressure CED – Coverage with Evidence Development CI – Confidence Interval CKD – Chronic Kidney Disease CTA – Computed Tomography Angiography DBP – Diastolic Blood Pressure eGFR – Estimated Glomerular Filtration Rate FDA – Food and Drug Administration HTN – Hypertension MRA – Magnetic Resonance Angiography NR – Not Reported OBP – Office Blood Pressure OFF MED – Off Medications (in trial contexts) ON MED – On Medications (in trial contexts) PMA – Premarket Approval RCT – Randomized Controlled Trial RDN – Renal Denervation rfRDN – Radiofrequency renal denervation SBP – Systolic Blood Pressure SD – Standard Deviation uRDN – Ultrasound renal denervation US – United States I. Decision A. Decision The Centers for Medicare & Medicaid Services (CMS) will cover radiofrequency renal denervation (rfRDN) and ultrasound renal denervation (uRDN) (collectively, RDN) for uncontrolled hypertension under Coverage with Evidence Development (CED) according to the provisions in sections (B) and (C) below. B. Coverage Criteria RDN is covered for uncontrolled hypertension when furnished according to a Food and Drug Administration (FDA) market-authorized indication, and all the following conditions are met: 1. Patient Criteria The patient meets all the following criteria: (a) Diagnosis of uncontrolled hypertension (≥ 140 mm Hg systolic blood pressure and > 90 mm Hg diastolic blood pressure) despite active management by a clinician with primary responsibility for blood pressure management. (b) Uncontrolled hypertension diagnosed using either ambulatory blood pressure monitoring or serial home blood pressure readings. (c) On lifestyle modifications and stable doses of maximally tolerated guideline-directed medical therapy (GDMT), with assessment of adherence to the prescribed regimen, for at least six weeks before referral for RDN. (d) As clinically appropriate, secondary hypertension must be evaluated and treated before determining that blood pressure remains uncontrolled. At a minimum, patients must be screened for primary aldosteronism, obstructive sleep apnea, and drug or alcohol induced hypertension before referral to RDN. (e) The patient has no contraindications to RDN, consistent with the FDA labeling of the device used. (f) The primary clinicians must coordinate management of the patient for a minimum of six months before referral for RDN, during which the patient had at least three encounters, with no more than two of the three encounters being virtual. (g) No prior RDN procedure. 2. Physician Criteria RDN is furnished by clinicians who meet the following criteria, as applicable: (a) Clinicians referring Medicare beneficiaries must have longitudinal responsibility for hypertension management. (b) Physicians performing RDN must have interventional and endovascular skills to perform effective RDN treatments. Additionally, they must be able to manage potential complications either themselves or with institutional support from colleagues who are immediately available to assist in emergency management. (c) Physicians performing RDN without prior endovascular training or renovascular expertise must complete at least ten supervised cases of diagnostic/therapeutic renovascular procedures, half as primary operator. Additionally, they must complete at least five proctored RDN cases with each approved device used in their practice. (d) Physicians performing RDN with prior endovascular training and active endovascular experience must complete at least five proctored RDN cases with each approved device used in their practice. 3. Facility Criteria The RDN device and related items and services are furnished at facilities meeting the following criteria: (a) Facilities performing RDN must have a hypertension program with contributions from a hypertension clinician with longitudinal patient management responsibility, a hypertension navigator, and access to relevant medical specialties (e.g., internal medicine, endocrinology, sleep medicine, cardiology, and nephrology) as appropriate. (b) Preprocedural imaging capabilities (e.g., ultrasound, Computed Tomography Angiography, Magnetic Resonance Angiography). (c) An appropriate interventional cardiology or radiology suite. 4. CED Study Criteria The RDN device and related items and services are furnished in the context of a CMS-approved CED study. CMS-approved CED study protocols must: include only those patients who meet the criteria in section B.1; furnish items and services only through practitioners who meet the criteria in section B.2; furnish items and services at facilities meeting the criteria in section B.3; and include all of the following: (a) One or more primary outcomes of ambulatory systolic blood pressure (ASBP), ambulatory diastolic blood pressure (ADBP), home systolic blood pressure (HSBP), home diastolic blood pressure (HDBP), office systolic blood pressure (OSBP), office diastolic blood pressure (ODBP), worsening renal function, cerebrovascular accident, acute myocardial infarction, incidence of new-onset heart failure, cardiovascular mortality, all-cause mortality, or a composite of these, through a minimum of 24 months. Each component of a composite outcome must be individually reported. (b) An active comparator. (c) Design sufficient for subgroup analyses by: Age (Stratify < 65, 65-74, 75+); Other clinically important patient demographic factors; Chronic kidney disease (Stratify by CKD Stages); Progression of CKD; Hypertension phenotype (e.g., resistant hypertension vs. uncontrolled for any reason); Medication adherence. (d) In addition, CMS-approved CED studies must adhere to the scientific standards (criteria 1-17 below) that have been identified by the Agency for Healthcare Research and Quality (AHRQ) as set forth in Section VI. of CMS’ Coverage with Evidence Development Guidance Document , published August 7, 2024 (the “CED Guidance Document”). Sponsor/Investigator: The study is conducted by sponsors/investigators with the resources and skills to complete it successfully. Milestones: A written plan is in place that describes a detailed schedule for completion of key study milestones, including study initiation, enrollment progress, interim results reporting, and results reporting, to ensure timely completion of the CED process. Study Protocol: The CED study is registered with ClinicalTrials.gov and a complete final protocol, including the statistical analysis plan, is delivered to CMS prior to study initiation. The published protocol includes sufficient detail to allow a judgment of whether the study is fit-for-purpose and whether reasonable efforts will be taken to minimize the risk of bias. Any changes to approved study protocols should be explained and publicly reported. Study Context: The rationale for the study is supported by scientific evidence and study results are expected to fill the specified CMS-identified evidence deficiency and provide evidence sufficient to assess health outcomes. Study Design: The study design is selected to safely and efficiently generate valid evidence of health outcomes. The sponsors/investigators minimize the impact of confounding and biases on inferences through rigorous design and appropriate statistical techniques. If a contemporaneous comparison group is not included, this choice should be justified, and the sponsors/investigators discuss in detail how the design contributes useful information on issues such as durability or adverse event frequency that are not clearly answered in comparative studies. Study Population: The study population reflects the demographic and clinical diversity among the Medicare beneficiaries who are the intended population of the intervention, particularly when there is good clinical or scientific reason to expect that the results observed in premarket studies might not be observed in older adults or subpopulations identified by other clinical or demographic factors. Subgroup Analyses: The study protocol explicitly discusses beneficiary subpopulations affected by the item or service under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion requirements effect enrollment of these populations, and a plan for the retention and reporting of said populations in the trial. In the protocol, the sponsors/investigators describe plans for analyzing demographic subpopulations as well as clinically-relevant subgroups as identified in existing evidence. Description of plans for exploratory analyses, as relevant subgroups emerge, are also included. Care Setting: When feasible and appropriate for answering the CED question, data for the study should come from beneficiaries in their expected sites of care. Health Outcomes: The primary health outcome(s) for the study are those important to patients and their caregivers and that are clinically meaningful. A validated surrogate outcome that reliably predicts these outcomes may be appropriate for some questions. Generally, when study sponsors propose using surrogate endpoints to measure outcomes, they should cite validation studies published in peer-reviewed journals to provide a rationale for assuming these endpoints predict the health outcomes of interest. The cited validation studies should be longitudinal and demonstrate a statistical association between the surrogate endpoint and the health outcomes it is thought to predict. Objective Success Criteria: In consultation with CMS and AHRQ, sponsors/investigators establish an evidentiary threshold for the primary health outcome(s) so as to demonstrate clinically meaningful differences with sufficient precision. Data Quality: The data are generated or selected with attention to provenance, bias, completeness, accuracy, sufficiency of duration of observation to demonstrate durability of health outcomes, and sufficiency of sample size as required by the question. Construct Validity: Sponsors/investigators provide information about the validity of drawing warranted conclusions about the study population, primary exposure(s) (intervention, control), health outcome measures, and core covariates when using either primary data collected for the study about individuals or proxies of the variables of interest, or existing (secondary) data about individuals or proxies of the variables of interest. Sensitivity Analyses: Sponsors/investigators will demonstrate robustness of results by conducting pre-specified sensitivity testing using alternative variable or model specifications as appropriate. Reporting: Final results are provided to CMS and submitted for publication or reported in a publicly accessible manner within 12 months of the study’s primary completion date. Wherever possible, the study is submitted for peer review with the goal of publication using a reporting guideline appropriate for the study design and structured to enable replication. If peer-reviewed publication is not possible, results may also be published in an online publicly accessible registry dedicated to the dissemination of clinical trial information such as ClinicalTrials.gov, or in journals willing to publish in abbreviated format (e.g., for studies with incomplete results). Sharing: The sponsors/investigators commit to making study data publicly available by sharing data, methods, analytic code, and analytical output with CMS or with a CMS-approved third party. The study should comply with all applicable laws regarding subject privacy, including 45 CFR § 164.514 within the regulations promulgated under the Health Insurance Portability and Accountability Act of 1996 (HIPAA) and 42 CFR, Part 2: Confidentiality of Substance Use Disorder Patient Records. Governance: The protocol describes the information governance and data security provisions that have been established to satisfy Federal security regulations issued pursuant to HIPAA and codified at 45 CFR Parts 160 and 164 (Subparts A & C), United States Department of Health and Human Services (HHS) regulations at 42 CFR, Part 2: Confidentiality of Substance Use Disorder Patient and HHS regulations at 45 CFR Part 46, regarding informed consent for clinical study involving human subjects. In addition to the requirements under 42 CFR and 45 CFR, studies that are subject to FDA regulation must also comply with regulations at 21 CFR Parts 50 and 56 regarding the protection of human subjects and institutional review boards, respectively. Legal: The study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals, although it is acceptable for a study to test a reduction in toxicity of a product relative to standard of care or an appropriate comparator. For studies that involve researching the safety and effectiveness of new drugs and biological products aimed at treating life-threatening or severely-debilitating diseases, refer to additional requirements set forth in 21 CFR § 312.81(a). Consistent with section 1142 of the Act, AHRQ supports clinical research studies that CMS determines meet all the criteria and standards identified above. C. Other Uses of RDN 1) RDN is not covered for patients outside of a CMS-approved study. 2) Nothing in this NCD would preclude coverage of RDN through NCD 310.1 (Clinical Trial Policy) or through the Investigational Device Exemption (IDE) Policy. See Appendix A for proposed Medicare National Coverage Determinations Manual language. II. Clinical Review A. Background Hypertension Definition and Classification The American Heart Association (AHA) defines blood pressure (BP) as a force that pushes blood through a network of arteries, veins, and capillaries. The blood pressure reading is the result of two forces: systolic pressure occurs as blood pumps out of the heart and into the arteries; diastolic pressure is created as the heart rests between heartbeats (AHA, 2024). Elevated blood pressure, or hypertension (HTN), leads to harm by causing tiny tears in the interior lining (intima) of the arteries and coronary vessels, stimulating a local immune response in the endothelial cells within the arterial walls. In these regions, the arterial intima retains apolipoprotein B, which attracts lipid-rich macrophages (foam cells). These preatherotic lesions develop into atherosclerotic plaques, which become increasingly fibrotic and can form fissures, hematomas, thrombi, and calcifications (Swirski and Nahrendorf, 2013). The result is stiff, thickened arteries that narrow the flow of blood to organs and limbs, which both increases pressure on target organs and limits oxygenation of them. There is also the risk of atherosclerotic plaque rupture, resulting in distal vascular obstruction and ischemia and infarction of end organs, such as stroke in the brain (NIH-NHLBI, 2024). Table 1 , below, outlines the stages of HTN as defined by the AHA. Table 1: Categories of BP in Adults* Blood Pressure Category SBP and/or DBP Normal < 120 mm Hg and < 80 mm Hg Elevated 120 - 129 mm Hg and < 80 mm Hg Hypertension: Stage 1 130 - 139 mm Hg or 80 - 89 mm Hg Hypertension: Stage 2 ≥ 140 mm Hg or ≥ 90 mm Hg *Individuals with SBP and DBP in 2 categories should be designated to the higher BP category. Source: American Heart Association, 2024 DPB: diastolic blood pressure; mm Hg: millimeters of mercury; SBP: systolic blood pressure Uncontrolled HTN is defined as persistently elevated BP above SBP 140 mm Hg and DBP 90 mm Hg (Yaxley and Thambar, 2015; Mancia et al., 2023). Resistant hypertension is defined as BP above goal despite treatment with 3 antihypertensive medications with complementary mechanisms of action, including a diuretic at maximally tolerated doses or BP at goal but requiring > 4 medications (Jones et al., 2025). Epidemiology HTN is a common condition in Westernized countries, affecting approximately 32% of adults and accounting for 8.6% of all primary care visits. Of these cases, about 10% are estimated to be resistant HTN (Yaxley and Thambar, 2015). In the 2013-2016 National Health and Nutrition Examination Survey (NHANES), the prevalence of hypertension (defined at that time as SBP ≥140 or DBP ≥90) in the US was 30.5% (CDC, 2017). The rate of uncontrolled hypertension among known hypertensives was 55.4%. Hypertension was somewhat more prevalent in men than women (31.5% vs. 29.3%, respectively), but men were much more likely to have uncontrolled hypertension (60.9% vs. 46.7%). Blacks had a higher prevalence of hypertension than whites, Latinos, or Asians (42.4%, 29.2%, 29%, and 27%, respectively). By age, 67.4% of women 65-74 years and 78.7% of women 75 years and older had hypertension. Among men, the prevalence was 61.1% and 67.4%, respectively (CDC, 2017). While it is estimated that about 12% to 15% of patients treated for HTN have apparent resistant HTN (Carey et al., 2018), its true prevalence is unknown due to pseudo-resistant HTN. Pseudo-resistant HTN occurs when other factors, such as poor medication adherence, conflicting medications, measurement error, or white coat hypertension, cause what appears to be resistant HTN. Obesity and older age are the strongest risk factors for this condition, though black race, chronic kidney disease, and diabetes are also associated. Cardiovascular disorders such as heart failure, stroke, ischemic heart disease, and renal failure are of great concern for this population, as HTN is a risk factor for these conditions (Carey et al., 2018). Treatment and Response to Therapy Current management of HTN involves both pharmacologic therapy and lifestyle modification, which includes dietary changes, behavioral adjustments such as smoking cessation and decreased alcohol consumption, treatment of sleep apnea, and increased physical activity. There is a dearth of randomized trial data to guide drug treatment for resistant HTN, and since most cases are of unknown etiology, initial management essentially mimics that of essential HTN. Per the 2025 Multispecialty Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults, thiazide diuretics, long acting dihydropyridine calcium channel blockers, and angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers are considered first-line therapy for Stage 1 HTN (Jones et al., 2025). Stage 2 HTN can warrant two first-line therapies of different classes adjusted to the optimal dosages and types. Spironolactone or eplerenone is a preferred add-on therapy to a standard treatment regimen for patients with resistant HTN who do not have concomitant hyperkalemia or renal dysfunction. Aggressive lifestyle modification and discontinuation of contributing medications, such as nonsteroidal anti-inflammatory drugs, are also recommended (Whelton et al., 2018). Despite these widely available antihypertensive agents, drug-resistant hypertension remains a challenging issue in clinical hypertension care. With the decrease in new antihypertensive medication classes available in the clinic (there have been no additions since direct renin inhibitors in 2007), the search for more effective ways to manage drug-resistant hypertension was shifted to revisiting device-based approaches such as renal denervation (RDN; Rey-García and Townsend, 2022). Renal Denervation Devices RDN involves ablating nerves in the renal arteries via a catheter-based radiofrequency or ultrasound procedure. Catheter-based radiofrequency ablation is the most commonly used technique, delivering heat to the intended tissue. Alternatively, intraluminal and extracorporeal high-intensity focused ultrasound delivers high-frequency acoustic energy via a transducer to destroy the tissue; see Appendix B for more on the characteristics and operator factors for the devices considered. There is no evidence of anatomical or functional reinnervation in patients who have undergone catheter-based RDN, but this is an important long-term consideration (Weber et al., 2019). Both functional and anatomical reinnervation of renal nerves has been reported within 12 weeks after surgical RDN in normal rats (Mulder et al., 2013), although renal norepinephrine levels do not return to normal levels by 12 weeks (Rodionova et al., 2016). In normal sheep, both anatomical and functional evidence of afferent and efferent reinnervation was shown at 11 months after RDN (Symplicity Flex catheter), and there was nearly complete recovery of norepinephrine levels by 11 months (Booth et al., 2015). On the other hand, Sharp et al. (2022) demonstrated sustained reductions in renal norepinephrine, cortical axon density, and downstream axonal loss caused by axonal destruction through 180 days post-RDN using Spyral in normotensive pigs, suggesting that functional nerve regrowth after radiofrequency RDN (rfRDN) is unlikely. These results confirmed similar observations by Rousselle et al. (2015) in a similar model also using rfRDN. These studies, together with the experience from the transplantation field, indicate that at least partial anatomical and functional reinnervation is likely to occur after RDN, but the exact timeframe and relevance to sustained BP control are unclear. Nonetheless, evidence from observational studies suggests that blood pressure reductions may persist beyond four years, and functional reinnervation may not be occurring (Mahfoud F et al., 2025). Investigators have found that assessing the adequacy or completeness of RDN is challenging. Currently, no simple physiological or biochemical markers can evaluate the extent of RDN at the time of the procedure; thus, there is no confirmation that the procedure has been successful. Several immediate markers have been proposed, including renal blood flow parameters (Tsioufis et al., 2013), blood levels of brain-derived neurotrophic factor (Dörr et al., 2015), renal norepinephrine spillover (Esler et al., 2010), and the BP response to catheter-based renal nerve stimulation (de Jong et al., 2016). However, none of these are currently used clinically, and both technique and operator experience are important. B. Food and Drug Administration Status On November 2, 2023, the Food and Drug Administration (FDA) approved Recor Medical’s Paradise® Ultrasound Renal Denervation System premarket approval (PMA) application ( P220023 ). Recor Medical’s Paradise ultrasound RDN (uRDN) device utilizes intra-arterial catheters to deliver ultrasound energy through the renal arterial wall to ablate the adjacent sympathetic nerves. The Paradise uRDN System includes the Paradise Catheter with ultrasound transducer, Paradise Generator, Paradise Cartridge, and the Paradise Connection Cable. The Paradise uRDN System is a catheter-based system that delivers ultrasound energy circumferentially to thermally ablate and disrupt renal sympathetic nerve activity to reduce systemic arterial BP. On November 17, 2023, FDA approved Medtronic’s Symplicity Spyral™ Renal Denervation System PMA application ( P220026 ). The Symplicity Spyral rfRDN System consists of two main components: a single-use, disposable catheter (Symplicity Spyral multielectrode renal denervation catheter, also referred to as Symplicity Spyral catheter) and a reusable radiofrequency (RF) generator (Symplicity G3 Renal Denervation RF generator, also referred to as Symplicity G3 RF generator). The generator includes an optional remote control and power cord. Medtronic previously studied an earlier version of their RDN device, the Symplicity Flex RDN, in a series of clinical trials: HTN-1 (Esler et al., 2014); HTN-2 (Esler et al., 2010, Esler et al., 2014, Esler et al., 2012); and HTN-3 (Bakris et al., 2015, Bhatt et al., 2014, Bhatt et al., 2022). HTN-3 was a multicenter, sham-controlled trial of 535 patients. It met its primary safety endpoint, but the primary and secondary effectiveness endpoints (a significant reduction in BP compared to sham controls) were not met. Potential contributors to the nil result in HTN-3 include prescribed medication changes in 39% of patients during the study period, despite the protocol mandating no medication changes, and a larger than expected decrease in office and ambulatory systolic BP in the control group. Additionally, incomplete ablation might result in inadequate denervation and was cited as a potential contributor to the nil result in HTN-3. Following HTN-3, Medtronic redesigned its RDN device with a spiral configuration of multiple RF electrodes to deliver more effective circumferential RDN. The Symplicity multi-electrode radiofrequency RDN system’s safety and performance were tested in a prospective, non-randomized, open-label, feasibility study that enrolled 50 subjects (Whitbourn et al., 2015). The results of this feasibility study indicated that the Symplicity multi-electrode RDN system was associated with a statistically significant, although highly variable, reduction in office SBP (OSBP) from baseline at 12 months post-procedure (-19.2±25.2 mm Hg), with minimal complications. The indication for both RDN devices is to reduce BP as an adjunctive treatment in patients with hypertension in whom lifestyle modifications and antihypertensive medications do not adequately control BP. III. Evidence This section provides a summary of the evidence we considered during our review. The evidence presented here includes the published medical literature on pertinent clinical research of endovascular RDN (radiofrequency energy or high-focused ultrasound energy) for resistant hypertension. This assessment does not address other methods of RDN, such as surgical renal denervation or chemical ablation using alcohol injections into the perivascular space of the renal artery. A. Evidence Questions The following questions guided our clinical literature search, review, and analysis of the evidence on RDN for resistant HTN. We answer these questions in Section IV.B. 6 . following the CMS coverage analysis. Q1. Is the evidence sufficient to conclude that RDN for hypertension meaningfully improves health outcomes for Medicare beneficiaries? Q2. Do specific characteristics or comorbidities make patients more or less likely to benefit from RDN in hypertension management? Q3. Are specific treatment conditions necessary to achieve outcomes with the use of RDN for hypertension management similar to those demonstrated in the clinical studies reviewed in this analysis? B. Technology Assessments CMS did not request an external technology assessment on this topic. Our review did not identify any Cochrane or Evidence-based Practice Center (EPC) reviews of RDN for uncontrolled HTN. C. Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) A MEDCAC meeting was not convened on this topic. D. Clinical Literature Search A systematic literature review addressed the above evidence questions and focused on RDN for resistant HTN, population risk factors, and endpoints. Literature searches were conducted in PubMed and Embase with search terms related to the following topics: (1) “hypertension,” (2) “anti-hypertensive therapy,” (3) “kidney denervation system,” or (4) “anti-hypertensive devices.” The review included all published, peer-reviewed English language clinical studies and systematic reviews from the databases' inception to Oct 10, 2024. We excluded clinical studies with fewer than 30 patients, editorials, and conference abstracts. Of the references identified in the searches, 26 were deemed eligible for inclusion. These publications reported on a total of seven randomized controlled trials (RCTs), which served as the primary basis for our analysis. We note that additional results were published shortly before publication of this coverage analysis (Kandzari et al., 2025). Although they are not part of the evidence base, we have briefly summarized those results, and the findings in the recent publication do not change our decision. The primary studies are summarized in Table 2 . Table 2. Key Studies 1 for RDN for Hypertension Study Patients Endpoint Author Year Study design Inclusion N Age (yr) Female (%) Blinding Additional AHM allowed Follow-up Primary findings 2 Urdn On-Medication Azizi et al. (RADIANCE-HTN SOLO) 2018 RCT Mild to moderate 74: 72 54.4; 53.8 30; 46 Blinded No 2 mo ∆ Daytime ASBP: -6.3 (-9.4 to -3.1); p= 0.0001 Azizi et al. (Follow-up of RADIANCE-HTN SOLO) 2019 69: 71 54.1; 53.8 37.7; 45.1 Blinded Yes, Standardized 6 mo ∆ Daytime ASBP: -4.3 (-7.9 to -0.6); p= 0.024 Azizi et al. (Follow-up of RADIANCE-HTN SOLO) 2020 65: 67 54.3; 54.1 33.9; 47.8 Unblinded Yes, Standard of Care 12 mo ∆ Daytime ASBP: -2.3 (-5.9 to 1.3); p=0.201 ∆ OSBP: -6.3 (-11.1 to -1.5); p=0.010 Rader et al, (Follow-up of RADIANCE-HTN SOLO) 2022 Single-arm follow-up 51: n/a 53.9: n/a 33.3:n/a Unblinded Yes, Standard of Care 36 mo ∆ OSBP from baseline to 36 months: Mean:18; SD:15 mmHg; p < 0.001 Azizi et al. (RADIANCE-II) 2023 RCT Stage 2 HTN 150: 74 55.1; 54.9 31.3; 23.0 Blinded No 2 mo ∆ Daytime ASBP: -6.3 (-9.3 to -3.2); p < 0.001 ∆ OSBP: -5.4 (-9.0 to -1.8); p= 0.004 On Medication Azizi et al. (RADIANCE-HTN TRIO) 2021 RCT Resistant 69: 67 52.3; 52·8 19; 21 Blinded Yes, Standardized 2 mo ∆ Daytime ASBP: -4.5 (-8.5 to -0.3); p= 0.022 ∆ OSBP: -7.0 (-13.0 to 0.0); p= 0.037 Azizi et al. (Follow-up of RADIANCE-HTN TRIO) 2022 RCT Resistant 65: 64 51.9; 53.0 18.5; 20.3 Blinded Yes, Standardized 6 mo ∆ Daytime ASBP: -0.0 (-4.6 to 4.5); p= 0.65 ∆ OSBP: -0.7 (-5.3 to 6.6); p= 0.93 Bloch et al. (Follow-up of RADIANCE-HTN TRIO) 2024 Single-arm follow-up Resistant 49: n/a 53.0: n/a 18: n/a Unblinded Yes 36 mo ∆ OSBP from screening: Mean: -14.5; SD: 26.1; p < 0.001 ∆ OSBP from baseline: Mean: -8.0; SD: 24.5; p= 0.007 Kario et al. (REQUIRE) 2022 RCT Resistant 69: 67 50.7; 55.6 30.4; 20.9 Single-blind Yes, Not standardized 3 mo ∆ 24-hour ASBP: LSMD: -0.1; SEM: 2.1; p=0.971 ∆ 24-hour OSBP: LSMD: -2.0; SEM: 3.0; p= 0.511 RfRDN Off Medication SPYRAL HTN-OFF MED Pivotal Böhm et al. Includes patients enrolled in Townsend et al., 2017 2020 RCT Un-controlled 166:165 51.4; 52.5 36.7; 33.3 Blinded No 3 mo ∆ 24-hour SBP: -4.0 (95% BCI -6.2 to -1.8); pps > 0.999 ∆ OSBP: -6.6 (95% BCI -9.6 to -3.5); pps > 0.999 On Medication Kandzari et al. (SPYRAL HTN-ON MED Expansion) Includes patients enrolled in Kandzari et al. 2018 2023 RCT Un-controlled 206: 131 55.2; 54.6 19; 21 Blinded Yes 6 mo ∆ 24-hour ASBP: -0.03 (95% BCI: -2.82 to 2.77); pps= 0.51 ∆ OSBP: -4.9 (-7.9 to -1.9); p= 0.0015 Kandzari et al. (Follow-up of SPYRAL HTN-ON MED) 3 2025 RCT Un-controlled 206: 131 4 (ITT) 187: 35 (Per-protocol) 55.2; 54.6 19; 21 Patients and physicians unblinded Outcome assessors for OSBP blinded Yes 12 mo ∆ 24-hour ASBP: -0.6; p=0.71 ∆ OSBP: -3.1; p=0.15 24 mo ∆ 24-hour ASBP: -5.7; p=0.039 ∆ OSBP: -8.7; p=0.0034 Mahfoud et al. (SPYRAL HTN-ON MED proof-of-concept) 2022 RCT Un-controlled 38: 42 53.9; 53.0 13.2; 19 Unblinded Yes 36 mo ∆ 24-hour ASBP: -10.0 (-16.6 to -3.3); p=0.0039 ∆ OSBP: -8.2 (-17.1 to 0.8); p= 0.073 1 There are multiple subtrials and analyses reported within this document. Table 2 reflects the findings of the main trials. 2 Findings are reported as baseline-adjusted MD in mm Hg (95% CI) unless otherwise indicated. 3 The 24 month follow-up of SPYRAL HTN-ON MED was published subsequent to the evidence review but is included here for completeness. 4 Patients were able to cross over to the RDN group (n=66) after the primary endpoint measure at 6-months. Patients in the sham condition who crossed over to RDN were censored, meaning that no data from these patients were carried forward. AHM: antihypertensive medications; ASBP: ambulatory systolic blood pressure; BCI: Bayesian credible interval; CI: confidence interval; ITT: intention-to-treat population; MD: mean difference; n/a: not applicable; OSBP: office systolic blood pressure; pps: posterior probability of superiority; RCT: randomized controlled trial; rfRDN: radiofrequency renal denervation; SBP: systolic blood pressure; SD: standard deviation; SEM: standard error of the mean; uRDN: ultrasound renal denervation E. Assessment of Evidence The seven RCTs considered as evidence consisted of various designs to evaluate renal denervation systems in patients with hypertension. Three trials—RADIANCE-HTN SOLO, RADIANCE-HTN TRIO, and RADIANCE II—were randomized, double-blind, sham-controlled studies conducted at multiple centers across Europe and the United States. The REQUIRE trial, conducted in Japan and South Korea, was a randomized, single-blind, sham-controlled study. Additionally, two multicenter, sham-controlled, single-blind trials, SPYRAL HTN-OFF and SPYRAL HTN-ON, were conducted across the US, Canada, Japan, Europe, and Australia. The RADIOSOUND-HTN trial was a 3-arm study, conducted in Germany, comparing uRDN, and rfRDN ablation of either the main renal artery or of both the main renal artery, branches, and accessory arteries to each other. The RADIANCE-HTN SOLO, RADIANCE-HTN TRIO, RADIANCE II, and REQUIRE trials evaluated the safety and efficacy of the uRDN system. These studies were conducted in groups of patients who were either not using (Off Med) or who were using (On Med) antihypertensive drugs. The SPYRAL HTN-OFF and HTN-ON trials assessed the safety and efficacy of the rfRDN system, incorporating an adaptive Bayesian design with a pilot study followed by an expansion cohort. Like the RADIANCE trials, these studies were conducted in groups of patients who were either not using (Off Med) or who were using (On Med) antihypertensive drugs. Finally, the RADIOSOUND-HTN trial employed a prospective, randomized design to directly compare the different renal denervation methods in patients with resistant hypertension. Participants who were considered medication-adherent were admitted into the study and continued with their antihypertensive medications during the trial, with therapeutic adjustments as needed. Study Quality Assessment Study quality for RCTs was assessed using the US Preventive Services Task Force’s (USPSTF) Criteria for Assessing Internal Validity of Individual Studies. We rated the quality of the primary RCTs, and it should be noted that most studies were unblinded during the follow-up period, which could impact the findings. All Radiance trials were sponsored by Recor, and all SPYRAL trials were sponsored by Medtronic. REQUIRE was funded by JIMRO Co. and Korea Otsuka Pharmaceutical. RADIOSOUND-HTN was funded by the Leipzig Heart Institute. All studies except RADIOSOUND-HTN received editorial or trial design input or medical writing support from the manufacturers, and all studies had declarations of support (e.g., receiving speaker or consulting fees) from manufacturers for one or more authors. uRDN The RADIANCE trials, including SOLO, TRIO, and RADIANCE II, were rated as “Good.” There was adequate randomization and allocation of participants for RADIANCE II, SOLO, and TRIO, adequate blinding of patients (for 6 months), and outcome assessors. Intention-to-treat (ITT) analysis was conducted, and overall attrition was low. Retention in the SOLO trial was 100%, 95%, and 90% at the 2-, 6-, and 12-month follow-up visits, respectively. Retention in the TRIO trial was 100% and 95% at the 2- and 6-month follow-up visits, respectively. RADIANCE II has reported 2-month results with no loss to follow-up at this time. The REQUIRE trial received a rating of “Poor.” The authors reported the possibility of patient sampling error such that a significant number of patients with uncontrolled hypertension and poor drug adherence may have been enrolled in the study and may have improved their drug adherence during the study. Although patients were blinded, clinical staff were not blind to treatment condition, which is a critical study limitation under the USPSTF framework. There was no standardization of AHM. Additionally, authors reported poor drug adherence in nearly half the patients during the study. There were no other major methodological concerns. Randomization and allocation concealment were adequate, as was the blinding of participants and outcome assessors. No ITT analysis was performed, but attrition was low (~95% retention). rfRDN The PYRAL HTN OFF MED and SPYRAL HTN ON MED trials received ratings of "Good." Randomization and allocation concealment were adequate. There was adequate blinding of participants across studies. In both HTN OFF MED and HTN ON MED, pilot cohort participants remained blinded for 12 months, and expansion cohort participants remained blinded for 6 months. There was adequate blinding of outcome assessors. ITT analyses were performed, and there were no other major methodological concerns. The RADIOSOUND-HTN was rated “Poor” as only the participants were blinded. Under the USPSTF framework, the lack of blinding of outcome assessors is considered a critical design limitation. Additionally, there was no standardization of AHM, and adherence was not tested. Randomization was adequate, and while no ITT analysis was performed, attrition was low (~95% retention). Evidence Base and Synthesis of Results A total of 1,465 patients were enrolled across seven RCTs, with 506 participants in the RADIANCE trials, 366 in the HTN OFF MED trial, 337 in the HTN ON MED trial, 136 in the REQUIRE trial, and 120 in the RADIOSOUND trial. Follow-up periods for participants ranged from 2 to 36 months. Across all trials, the mean age of participants ranged from 51.4 years in the HTN OFF MED trial to 64.6 years in the RADIOSOUND trial. However, the overall proportion of patients aged 65 and older was not reported. Overall, these seven trials represented a broad spectrum of hypertensive populations, ranging from mild to resistant forms of hypertension. The RADIANCE-HTN trials targeted two distinct patient groups: those with mild to moderate hypertension not on medications at the time of enrollment (SOLO and RADIANCE II) and those with resistant hypertension (TRIO). In contrast, the SPYRAL HTN-OFF and HTN-ON trials focused on patients with mild to moderate hypertension, and HTN-OFF was further limited to patients able to discontinue AHMs, while HTN-ON included patients on stable regimens of 1-3 AHMs. These two trials were conducted in two phases: an initial Pilot Cohort to assess feasibility and an Expansion Cohort utilizing an adaptive Bayesian design. The REQUIRE and RADIOSOUND trials both studied patients with resistant hypertension. Across all trials, baseline characteristics between the RDN (uRDN or rfRDN) and sham groups were generally well-balanced, with minor variations. Key parameters such as age, sex, BMI, and BP showed close alignment in most studies. For instance, age and BMI were comparable across groups in trials like SOLO, Radiance II, and HTN-OFF. BP, both office and 24-hour measurements, also showed similar baseline levels between the RDN and sham groups, ensuring fair comparisons. Minor differences included slightly higher male representation in the sham groups of some trials, such as Radiance II and REQUIRE. Racial and ethnic status, however, was not always thoroughly reported, and enrollment of different racial and ethnic groups was limited across studies, with most participants being white. In the studies where racial backgrounds were properly reported (RADIANCE SOLO, RADIANCE II, and TRIO), the proportion of African Americans in these studies was similar to their overall proportion in the general US population. However, resistant hypertension is more prevalent in African Americans (Sarafidis et al., 2013). Hispanics and Asian Americans were generally underrepresented in these studies. Despite this, the racial distribution within each trial (when reported) was generally balanced between the groups. Background medical therapy was not standardized in SPYRAL HTN ON MED, and it was not in the form of single-pill combination therapy in the RADIANCE HTN TRIO trial. This study design left room for adding or withdrawing medications during the studies. Below, we describe the main outcomes for safety and efficacy as reported in the RCTs investigating RDN. Please refer to the tables in Appendix C for baseline characteristics across all trials. Ultrasound Renal Denervation (uRDN) Inclusion Criteria and Setting The RADIANCE studies enrolled individuals aged 18 to 75 years with a documented history of hypertension, suitable renal anatomy for the renal denervation procedure confirmed by recent renal CTA (computed tomography angiography) or MRA (magnetic resonance angiography), and the ability to comply with study procedures. The studies RADIANCE-HTN SOLO (Azizi et al., 2018), RADIANCE-HTN TRIO (Azizi et al., 2021), and RADIANCE II (Azizi et al., 2023) were conducted at multiple centers across Europe and the United States. The REQUIRE trial was conducted in Japan and South Korea (Kario et al., 2022). Findings The efficacy of uRDN for lowering BP was mixed between the Off Med (SOLO and RADIANCE II) studies and between the Off Med and On Med (TRIO and REQUIRE) studies. Use of uRDN in the Off Med SOLO and RADIANCE II trials showed consistent reductions in office systolic BP and daytime ASBP compared to the sham intervention at 2 months follow-up in patients with mild-to moderate HTN and patients with Stage 2 HTN, although the evidence is more varied at later time points, and the evidence is limited for durability of effect. In patients with resistant HTN, findings differed between the two On Med trials. In TRIO, uRDN reduced daytime ASBP statistically, but not meaningfully, more than the sham procedure at 2 months but not at 6 months. The smaller REQUIRE trial found no difference in ASBP changes between uRDN and sham at the 3-month follow-up. There were relatively few treatment-related adverse events across studies. Mild-to-Moderate Hypertension In patients with mild-to-moderate hypertension (SOLO; Azizi et al., 2018), at 2 months the uRDN group (n=74) achieved a clinically significantly greater reduction in office systolic BP (SBP) relative to the sham group (n=72), with a baseline-adjusted difference (AD) between groups of -6.5 mm Hg (95% CI: -11.3 to -1.8; p=0.007) as well as daytime ASBP (-6.3 mm Hg; 95% CI: -9.4 to -3.1; p=0.0001). At 6 months, patients in the SOLO trial were still blinded to treatment condition (Azizi et al., 2019) and had received recommended and standardized stepped-care antihypertensive treatment since the 2-month follow-up if home BP control did not achieve the target range (home BP ≥135/85 mm Hg). At the 6-month time point, 65.2% of patients in the uRDN group were treated with antihypertensive medications (AHM) versus 84.5% in the sham group (p=0.008), the number of medications used and the defined daily dose (DDD) were lower in the uRDN group relative to the sham group (AHM: 0.9 ± 0.9 vs 1.2 ± 0.9, p=0.043 and DDD: 1.4 ± 1.5 vs 2.0 ± 1.8, p = 0.018; respectively). Reductions in OSBP did not differ between the groups (AD: -3.7 mm Hg; 95% CI: -8.1 to 0.7 mm Hg; p=0.102; adjusted for baseline value and AHM). However, reductions in ASBP were statistically different between the groups (AD: -4.3 mm Hg; 95% CI: -7.9 to -0.6 mm Hg; p = 0.024; adjusted for baseline value and AHM), but this difference may not be clinically meaningful. At the 12-month follow-up (Azizi et al., 2020), patients were no longer blind to treatment condition and were treated with AHM according to standard-of-care (i.e., not standardized). The number of medications (1.0 vs. 1.4; p=0.015), and DDD (1.4 vs. 2.2; p=0.007) were less with uRDN versus sham. There was no difference in daytime ASBP between the groups (AD: -2.3 mm Hg; 95% CI: -5.9 to 1.3; p=0.201; adjusted for baseline value and AHM), but OSBP was clinically meaningfully decreased (AD: -6.3 mm Hg; 95% CI: -11.1 to -1.5 mmHg; p=0.010). Regarding safety outcomes, the SOLO trial reported no major adverse events in either group at 30 days or 6 months (Azizi et al., 2019). At the 12-month follow-up, one patient in the sham group died (suicide), and one experienced a cerebrovascular event. Neither group had any other major adverse events (Azizi et al., 2020). Twelve-month imaging was available in 63 RDN patients. One patient underwent renal artery stent placement at 6 months after mild progression of ostial renal artery plaque. No new renal artery stenosis > 70% was detected on CTA or MRA of the renal arteries at 12 months, and the calculated eGFR remained stable from baseline to 12 months in the RDN group (Azizi et al., 2020). Of note, the SOLO trial was not designed or powered to demonstrate a difference in BP between the uRDN and the sham beyond 2 months, and sham patients with persistent uncontrolled hypertension were eligible to crossover and receive uRDN. A single-arm follow-up study of patients who remained in the uRDN arm from randomization reported findings at 36 months (Rader et al., 2022). In patients with uncontrolled BP at screening (n=36), office systolic BP decreased by 10.8 mm Hg (no estimate of variability; p < 0.001) at 36 months. This is a small subset of patients, and these findings regarding durability should be interpreted in that context. No new adverse events were deemed related to the procedure at this follow-up. Stage 2 Hypertension In patients with stage 2 HTN (RADIANCE II; Azizi et al., 2023) those randomized to uRDN (n=150) versus sham (n=74) demonstrated a clinically meaningful reduction in OSBP with a between-group difference of -5.4 mm Hg (95% CI: -9.0 to -1.8; p=0.004) and in daytime ASBP (AD: -6.3 mm Hg; 95% CI: -9.3 to -3.2; p < 0.001) at two months follow-up with no major adverse events in either group. This study’s follow-up is short, and planned observational data at 6 and 12 months have yet to be reported. Resistant Hypertension The findings in patients with resistant HTN are mixed. Both studies were conducted in patients receiving concomitant antihypertensive drug therapy. In the TRIO trial, patients with resistant hypertension on fixed-dose, triple combination therapy (Azizi et al., 2021), uRDN (n=69) reduced OSBP (unadjusted median difference: -7.0: 95% CI: -13.0 to 0.0; adjusted p=0.037) and daytime ASBP (unadjusted median difference: -4.5 mm Hg; 95% CI -8.5 to -0.3; adjusted p=0.022) more than sham (n=67). These findings are statistically different but may not be clinically meaningful. However, at 6 months, the per-protocol analysis indicated no significant difference between treatment conditions in either OSBP (AD: 0.7; 95% CI: -5.3 to 6.6; p=0.93) or daytime ASBP (AD: -0.0 mm Hg; 95% CI: -4.6 to 4.5; p = 0.65; Azizi et al., 2022). In REQUIRE, patients with resistant hypertension and standard-of-care medication therapy (Kario et al., 2022), uRDN (n=69) and sham (n=67) treatments did not differ at 3-month follow-up for either OSBP (Least Squares Mean Difference [LSMD]: -2.0; Standard Error of the Mean (SEM): 3.0; 95% CI: not reported; p=0.511) or 24-hour ASBP (LSMD: -0.1, SEM: 2.1; 95% CI: -5.5 to 5.3; p=0.971). Regarding safety outcomes, three adverse events were reported in the TRIO trial after uRDN within 30 days of the procedure (Azizi et al., 2022). Six other cardiovascular or kidney events through 6 months were reported in four patients in each group, and eGFR decreased slightly and similarly from baseline to 6 months in the 2 groups. No new 50% or greater kidney artery stenosis was detected on non-invasive imaging in either group at 6 months (Azizi et al., 2022). REQUIRE did not report any major procedure- or device-related adverse events. However, vasospastic angina was seen in one patient, and a puncture site hemorrhage occurred in another during the RDN procedure (Kario et al., 2022). It should be noted that the patient populations differed between TRIO and REQUIRE. Patients enrolled in TRIO were primarily white and residing in Western countries (e.g., the United States, the United Kingdom, Germany, and France), whereas patients enrolled in REQUIRE were Asian and resided in Japan or South Korea. Baseline enrollment criteria differed between the two studies, with TRIO enrolling patients with office BP of at least 140/90 mm Hg despite using three or more medications, including a diuretic. Participants in TRIO received a standardized fixed-dose triple-drug regimen. REQUIRE enrolled patients with a seated office BP of at least 150/90 mm Hg