Cost Effectiveness of Endovascular Ultrasound Renal Denervation in Patients with Resistant Hypertension.

BACKGROUND: Resistant hypertension (rHTN) is defined as blood pressure (BP) of ≥ 140/90 mmHg despite treatment with at least three antihypertensive medications, including a diuretic. Endovascular ultrasound renal denervation (uRDN) aims to control BP alongside conventional BP treatment with antihypertensive medication. This analysis assesses the cost effectiveness of the addition of the Paradise uRDN System compared with standard of care alone in patients with rHTN from the perspective of the United Kingdom (UK) health care system. METHODS: Using RADIANCE-HTN TRIO trial data, we developed a state-transition model. Baseline risk was calculated using Framingham and Prospective Cardiovascular Münster (PROCAM) risk equations to estimate the long-term cardiovascular risks in patients treated with the Paradise uRDN System, based on the observed systolic BP (SBP) reduction following uRDN. Relative risks sourced from a meta-analysis of randomised controlled trials were then used to project cardiovascular events in patients with baseline SBP ('control' patients); utility and mortality inputs and costs were derived from UK data. Costs and outcomes were discounted at 3.5% per annum. Modelled outcomes were validated against trial meta-analyses and the QRISK3 algorithm and real-world evidence of RDN effectiveness. One-way and probabilistic sensitivity analyses were conducted to assess the uncertainty surrounding the model inputs and sensitivity of the model results to changes in parameter inputs. Results were reported as incremental cost-effectiveness ratios (ICERs). RESULTS: A mean reduction in office SBP of 8.5 mmHg with uRDN resulted in an average improvement in both absolute life-years (LYs) and quality-adjusted life-years (QALYs) gained compared with standard of care alone (0.73 LYs and 0.67 QALYs). The overall base-case ICER with uRDN was estimated at £5600 (€6500) per QALY gained (95% confidence interval £5463-£5739 [€6341-€6661]); modelling demonstrated > 99% probability that the ICER is below the £20,000-£30,000 (€23,214-€34,821) per QALYs gained willingness-to-pay threshold in the UK. Results were consistent across sensitivity analyses and validation checks. CONCLUSIONS: Endovascular ultrasound RDN with the Paradise system offers patients with rHTN, clinicians, and healthcare systems a cost-effective treatment option alongside antihypertensive medication.

Cost-effectiveness of catheter-based radiofrequency renal denervation for the treatment of uncontrolled hypertension: an analysis for the UK based on recent clinical evidence.

AIMS: Catheter-based radiofrequency renal denervation (RF RDN) has recently been approved for clinical use in the European Society of Hypertension guidelines and by the US FDA. This study evaluated the lifetime cost-effectiveness of RF RDN using contemporary evidence. METHODS AND RESULTS: A decision-analytic model based on multivariate risk equations projected clinical events, quality-adjusted life years (QALYs) and costs. The model consisted of seven health states: hypertension alone, myocardial infarction (MI), other symptomatic coronary artery disease, stroke, heart failure (HF), end-stage renal disease, and death. Risk reduction associated with changes in office systolic blood pressure (oSBP) was estimated based on a published meta-regression of hypertension trials. The base case effect size of -4.9 mmHg oSBP (observed vs. sham control) was taken from the SPYRAL HTN-ON MED trial of 337 patients. Costs were based on NHS England data. The incremental cost-effectiveness ratio (ICER) was evaluated against the NICE cost-effectiveness threshold of £20 000-30 000 per QALY gained. Extensive scenario and sensitivity analyses were conducted, including the ON-MED subgroup on three medications and pooled effect sizes. RF RDN resulted in a relative risk reduction in clinical events over 10 years (0.80 for stroke, 0.88 for MI, 0.72 for HF), with an increase in health benefit over a patient's lifetime, adding 0.35 QALYs at a cost of £4 763, giving an ICER of £13 482 per QALY gained. Findings were robust across tested scenarios. CONCLUSION: Catheter-based radiofrequency RDN can be a cost-effective strategy for uncontrolled hypertension in the UK, with an ICER substantially below the NICE cost-effectiveness threshold. Funding: Medtronic Inc.

Patient-Level Pooled Analysis of Endovascular Ultrasound Renal Denervation or a Sham Procedure 6 Months After Medication Escalation: The RADIANCE Clinical Trial Program.

BACKGROUND: The randomized, sham-controlled RADIANCE-HTN (A Study of the Recor Medical Paradise System in Clinical Hypertension) SOLO, RADIANCE-HTN TRIO, and RADIANCE II (A Study of the Recor Medical Paradise System in Stage II Hypertension) trials independently met their primary end point of a greater reduction in daytime ambulatory systolic blood pressure (SBP) 2 months after ultrasound renal denervation (uRDN) in patients with hypertension. To characterize the longer-term effectiveness and safety of uRDN versus sham at 6 months, after the blinded addition of antihypertensive treatments (AHTs), we pooled individual patient data across these 3 similarly designed trials. METHODS: Patients with mild to moderate hypertension who were not on AHT or with hypertension resistant to a standardized combination triple AHT were randomized to uRDN (n=293) versus sham (n=213); they were to remain off of added AHT throughout 2 months of follow-up unless specified blood pressure (BP) criteria were exceeded. In each trial, if monthly home BP was ≥135/85 mm Hg from 2 to 5 months, standardized AHT was sequentially added to target home BP <135/85 mm Hg under blinding to initial treatment assignment. Six-month outcomes included baseline- and AHT-adjusted change in daytime ambulatory, home, and office SBP; change in AHT; and safety. Linear mixed regression models using all BP measurements and change in AHT from baseline through 6 months were used. RESULTS: Patients (70% men) were 54.1±9.3 years of age with a baseline daytime ambulatory/home/office SBP of 150.5±9.8/151.0±12.4/155.5±14.4 mm Hg, respectively. From 2 to 6 months, BP decreased in both groups with AHT titration, but fewer uRDN patients were prescribed AHT (P=0.004), and fewer additional AHT were prescribed to uRDN patients versus sham patients (P=0.001). Whereas the unadjusted between-group difference in daytime ambulatory SBP was similar at 6 months, the baseline and medication-adjusted between-group difference at 6 months was -3.0 mm Hg (95% CI, -5.7, -0.2; P=0.033), in favor of uRDN+AHT. For home and office SBP, the adjusted between-group differences in favor of uRDN+AHT over 6 months were -5.4 mm Hg (-6.8, -4.0; P<0.001) and -5.2 mm Hg (-7.1, -3.3; P<0.001), respectively. There was no heterogeneity between trials. Safety outcomes were few and did not differ between groups. CONCLUSIONS: This individual patient-data analysis of 506 patients included in the RADIANCE trials demonstrates the maintenance of BP-lowering efficacy of uRDN versus sham at 6 months, with fewer added AHTs. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02649426 and NCT03614260.

Real-world experience with ultrasound renal denervation utilizing home blood pressure monitoring: the Global Paradise System registry study design.

BACKGROUND: Hypertension is a major public health issue due to its association with cardiovascular disease risk. Despite the availability of effective antihypertensive drugs, rates of blood pressure (BP) control remain suboptimal. Renal denervation (RDN) has emerged as an effective non-pharmacological, device-based treatment option for patients with hypertension. The multicenter, single-arm, observational Global Paradise™ System (GPS) registry has been designed to examine the long-term safety and effectiveness of ultrasound RDN (uRDN) with the Paradise System in a large population of patients with hypertension. METHODS: The study aims to enroll up to 3000 patients undergoing uRDN in routine clinical practice. Patients will be recruited over a 4-year period and followed for 5 years (at 3, 6, and 12 months after the uRDN procedure and annually thereafter). Standardized home BP measurements will be taken every 3 months with automatic upload to the cloud. Office and ambulatory BP and adverse events will be collected as per routine clinical practice. Quality-of-Life questionnaires will be used to capture patient-reported outcomes. CONCLUSIONS: This observational registry will provide real-world information on the safety and effectiveness of uRDN in a large population of patients treated during routine clinical practice, and also allow for a better understanding of responses in prespecified subgroups. The focus on home BP in this registry is expected to improve completeness of long-term follow-up and provide unique insights into BP over time. Global Paradise System registry study design. ABP, ambulatory blood pressure; BP, blood pressure; FU, follow-up; M, month; OBP, office blood pressure.

Selecting patients for interventional procedures to treat hypertension.

Purpose: Interventional approaches to treat hypertension are an emerging option that may be suitable for patients whose BP control cannot be achieved with lifestyle and/or pharmacotherapy and possibly for those who do not wish to take drug therapy.Materials and Methods: Interventional strategies include renal denervation with radiofrequency, ultrasound and alcohol-mediated platforms as well as baroreflex activation therapy and cardiac neuromodulation therapy. Presently renal denervation is the most advanced of the therapeutic options and is currently being commercialised in the EU.Results: It is apparent that RDN is effective in both unmedicated patients and patients with more severe hypertension including those with resistant hypertension.Conclusion: However, at present there is no evidence for the use of RDN in patients with secondary forms of hypertension and thus evaluation to rule these out is necessary before proceeding with a procedure. Furthermore, there are numerous pitfalls in the diagnosis and management of secondary hypertension which need to be taken into consideration. Finally, prior to performing an intervention it is appropriate to document presence/absence of hypertension-mediated organ damage.

RDN has emerged as a safe and effective approach to treat hypertension with BP lowering efficacy equivalent to antihypertensive monotherapy albeit with guaranteed 'adherence'Presently populations most likely to respond to RDN are not clearly defined but given the costs of the procedure it is likely to be initially made available to those with resistant hypertension and those at highest cardiovascular riskThere is no evidence to support the use of RDN in patients with secondary forms of hypertension and thus this should be thoroughly screened for prior to offering the procedure, especially in the setting of resistant hypertensionOptimisation of lifestyle and drug therapy is key to good hypertension management and should be undertaken prior to an invasive procedure such as RDN being offeredThere are numerous pitfalls in the screening process for secondary hypertension which means that hypertension specialists should be involved in this component of the pathwayRDN can be offered by interventional radiologist, interventional cardiologists or angiologists who have had appropriate trainingClinical pathways for RDN must ultimately involve a multidisciplinary team overview with hypertension specialists, interventionists and imaging specialists combining efforts to ensure appropriate patient selection. This without question must involve patients in the decision-making process.

Endovascular Ultrasound Renal Denervation to Treat Hypertension: The RADIANCE II Randomized Clinical Trial.

Importance: Two initial sham-controlled trials demonstrated that ultrasound renal denervation decreases blood pressure (BP) in patients with mild to moderate hypertension and hypertension that is resistant to treatment. Objective: To study the efficacy and safety of ultrasound renal denervation without the confounding influence of antihypertensive medications in patients with hypertension. Design, Setting, and Participants: Sham-controlled, randomized clinical trial with patients and outcome assessors blinded to treatment assignment that was conducted between January 14, 2019, and March 25, 2022, at 37 centers in the US and 24 centers in Europe, with randomization stratified by center. Patients aged 18 years to 75 years with hypertension (seated office systolic BP [SBP] ≥140 mm Hg and diastolic BP [DBP] ≥90 mm Hg despite taking up to 2 antihypertensive medications) were eligible if they had an ambulatory SBP/DBP of 135/85 mm Hg or greater and an SBP/DBP less than 170/105 mm Hg after a 4-week washout of their medications. Patients with an estimated glomerular filtration rate of 40 mL/min/1.73 m2 or greater and with suitable renal artery anatomy were randomized 2:1 to undergo ultrasound renal denervation or a sham procedure. Patients were to abstain from antihypertensive medications until the 2-month follow-up unless prespecified BP criteria were exceeded and were associated with clinical symptoms. Interventions: Ultrasound renal denervation vs a sham procedure. Main Outcomes and Measures: The primary efficacy outcome was the mean change in daytime ambulatory SBP at 2 months. The primary safety composite outcome of major adverse events included death, kidney failure, and major embolic, vascular, cardiovascular, cerebrovascular, and hypertensive events at 30 days and renal artery stenosis greater than 70% detected at 6 months. The secondary outcomes included mean change in 24-hour ambulatory SBP, home SBP, office SBP, and all DBP parameters at 2 months. Results: Among 1038 eligible patients, 150 were randomized to ultrasound renal denervation and 74 to a sham procedure (mean age, 55 years [SD, 9.3 years]; 28.6% female; and 16.1% self-identified as Black or African American). The reduction in daytime ambulatory SBP was greater with ultrasound renal denervation (mean, -7.9 mm Hg [SD, 11.6 mm Hg]) vs the sham procedure (mean, -1.8 mm Hg [SD, 9.5 mm Hg]) (baseline-adjusted between-group difference, -6.3 mm Hg [95% CI, -9.3 to -3.2 mm Hg], P < .001), with a consistent effect of ultrasound renal denervation throughout the 24-hour circadian cycle. Among 7 secondary BP outcomes, 6 were significantly improved with ultrasound renal denervation vs the sham procedure. No major adverse events were reported in either group. Conclusions and Relevance: In patients with hypertension, ultrasound renal denervation reduced daytime ambulatory SBP at 2 months in the absence of antihypertensive medications vs a sham procedure without postprocedural major adverse events. Trial Registration: ClinicalTrials.gov Identifier: NCT03614260.

Patient-Level Pooled Analysis of Ultrasound Renal Denervation in the Sham-Controlled RADIANCE II, RADIANCE-HTN SOLO, and RADIANCE-HTN TRIO Trials.

Importance: Ultrasound renal denervation (uRDN) was shown to lower blood pressure (BP) in patients with uncontrolled hypertension (HTN). Establishing the magnitude and consistency of the uRDN effect across the HTN spectrum is clinically important. Objective: To characterize the effectiveness and safety of uRDN vs a sham procedure from individual patient-level pooled data across uRDN trials including either patients with mild to moderate HTN on a background of no medications or with HTN resistant to standardized triple-combination therapy. Data Sources: A Study of the ReCor Medical Paradise System in Clinical Hypertension (RADIANCE-HTN SOLO and TRIO) and A Study of the ReCor Medical Paradise System in Stage II Hypertension (RADIANCE II) trials. Study Selection: Trials with similar designs, standardized operational implementation (medication standardization and blinding of both patients and physicians to treatment assignment), and follow-up. Data Extraction and Synthesis: Pooled analysis using individual patient-level data using linear regression models to compare uRDN with sham across the trials. Main Outcomes and Measures: The primary outcome was baseline-adjusted change in 2-month daytime ambulatory systolic BP (dASBP) between groups. Results: A total of 506 patients were randomized in the 3 studies (uRDN, 293; sham, 213; mean [SD] age, 54.1 [9.3]; 354 male [70.0%]). After a 1-month medication stabilization period, dASBP was similar between the groups (mean [SD], uRDN, 150.3 [9.2] mm Hg; sham, 150.8 [10.5] mm Hg). At 2 months, dASBP decreased by 8.5 mm Hg to mean (SD) 141.8 (13.8) mm Hg among patients treated with uRDN and by 2.9 mm Hg to 147.9 (14.6) mm Hg among patients treated with a sham procedure (mean difference, -5.9; 95% CI, -8.1 to -3.8 mm Hg; P < .001 in favor of uRDN). BP decreases from baseline with uRDN vs sham were consistent across trials and across BP parameters (office SBP: -10.4 mm Hg vs -3.4 mm Hg; mean difference, -6.4 mm Hg; 95% CI, -9.1 to -3.6 mm Hg; home SBP: -8.4 mm Hg vs -1.4 mm Hg; mean difference, -6.8 mm Hg; 95% CI, -8.7 to -4.9 mm Hg, respectively). The BP reductions with uRDN vs sham were consistent across prespecified subgroups. Independent predictors of a larger BP response to uRDN were higher baseline BP and heart rate and the presence of orthostatic hypertension. No differences in early safety end points were observed between groups. Conclusions and Relevance: Results of this patient-level pooled analysis suggest that BP reductions with uRDN were consistent across HTN severity in sham-controlled trials designed with a 2-month primary end point to standardize medications across randomized groups. Trial Registration: ClinicalTrials.gov Identifier: NCT02649426 and NCT03614260.

Effects of Renal Denervation vs Sham in Resistant Hypertension After Medication Escalation: Prespecified Analysis at 6 Months of the RADIANCE-HTN TRIO Randomized Clinical Trial.

Importance: Although early trials of endovascular renal denervation (RDN) for patients with resistant hypertension (RHTN) reported inconsistent results, ultrasound RDN (uRDN) was found to decrease blood pressure (BP) vs sham at 2 months in patients with RHTN taking stable background medications in the Study of the ReCor Medical Paradise System in Clinical Hypertension (RADIANCE-HTN TRIO) trial. Objectives: To report the prespecified analysis of the persistence of the BP effects and safety of uRDN vs sham at 6 months in conjunction with escalating antihypertensive medications. Design, Setting, and Participants: This randomized, sham-controlled, clinical trial with outcome assessors and patients blinded to treatment assignment, enrolled patients from March 11, 2016, to March 13, 2020. This was an international, multicenter study conducted in the US and Europe. Participants with daytime ambulatory BP of 135/85 mm Hg or higher after 4 weeks of single-pill triple-combination treatment (angiotensin-receptor blocker, calcium channel blocker, and thiazide diuretic) with estimated glomerular filtration rate (eGFR) of 40 mL/min/1.73 m2 or greater were randomly assigned to uRDN or sham with medications unchanged through 2 months. From 2 to 5 months, if monthly home BP was 135/85 mm Hg or higher, standardized stepped-care antihypertensive treatment starting with aldosterone antagonists was initiated under blinding to treatment assignment. Interventions: uRDN vs sham procedure in conjunction with added medications to target BP control. Main Outcomes and Measures: Six-month change in medications, change in daytime ambulatory systolic BP, change in home systolic BP adjusted for baseline BP and medications, and safety. Results: A total of 65 of 69 participants in the uRDN group and 64 of 67 participants in the sham group (mean [SD] age, 52.4 [8.3] years; 104 male [80.6%]) with a mean (SD) eGFR of 81.5 (22.8) mL/min/1.73 m2 had 6-month daytime ambulatory BP measurements. Fewer medications were added in the uRDN group (mean [SD], 0.7 [1.0] medications) vs sham (mean [SD], 1.1 [1.1] medications; P = .045) and fewer patients in the uRDN group received aldosterone antagonists at 6 months (26 of 65 [40.0%] vs 39 of 64 [60.9%]; P = .02). Despite less intensive standardized stepped-care antihypertensive treatment, mean (SD) daytime ambulatory BP at 6 months was 138.3 (15.1) mm Hg with uRDN vs 139.0 (14.3) mm Hg with sham (additional decreases of -2.4 [16.6] vs -7.0 [16.7] mm Hg from month 2, respectively), whereas home SBP was lowered to a greater extent with uRDN by 4.3 mm Hg (95% CI, 0.5-8.1 mm Hg; P = .03) in a mixed model adjusting for baseline and number of medications. Adverse events were infrequent and similar between groups. Conclusions and Relevance: In this study, in patients with RHTN initially randomly assigned to uRDN or a sham procedure and who had persistent elevation of BP at 2 months after the procedure, standardized stepped-care antihypertensive treatment escalation resulted in similar BP reduction in both groups at 6 months, with fewer additional medications required in the uRDN group. Trial Registration: ClinicalTrials.gov Identifier: NCT02649426.

Guidance for the Interpretation of Continual Cuffless Blood Pressure Data for the Diagnosis and Management of Hypertension.

Hypertension remains the leading risk factor for death worldwide. Despite its prevalence, success of blood pressure (BP) management efforts remains elusive, and part of the difficulty lies in the tool still used to diagnose, measure, and treat hypertension: the sphygmomanometer introduced by Samuel Siegfried Karl von Basch in 1867. In recent years, there has been an explosion of devices attempting to provide estimates of BP without a cuff, overcoming many limitations of cuff-based BP monitors. Unfortunately, the differences in underlying technologies between traditional BP cuffs and newer cuffless devices, as well as hesitancy of changing a well-implemented standard, still generate understandable skepticism about and reluctance to adopt cuffless BP monitors in clinical practice. This guidance document aims to navigate the scientific and medical communities through the types of cuffless devices and present examples of robust BP data collection which are better representations of a person's true BP. It highlights the differences between data collected by cuffless and traditional cuff-based devices and provides an initial framework of interpretation of the new cuffless datasets using, as an example, a CE-marked continual cuffless BP device (Aktiia BP Monitor, Aktiia, Switzerland). Demonstration of novel BP metrics, which have the potential to change the paradigm of hypertension diagnosis and treatment, are now possible for the first time with cuffless BP monitors that provide continual readings over long periods. Widespread adoption of continual cuffless BP monitors in healthcare will require a collaborative and thoughtful process, acknowledging that the transition from a legacy to a novel medical technology will be slow. Finally, this guidance concludes with a call to action to international scientific and expert associations to include cuffless BP monitors in original scientific research and in future versions of guidelines and standards.

Clinical Trial Design Principles and Outcomes Definitions for Device-Based Therapies for Hypertension: A Consensus Document From the Hypertension Academic Research Consortium.

The clinical implications of hypertension in addition to a high prevalence of both uncontrolled blood pressure and medication nonadherence promote interest in developing device-based approaches to hypertension treatment. The expansion of device-based therapies and ongoing clinical trials underscores the need for consistency in trial design, conduct, and definitions of clinical study elements to permit trial comparability and data poolability. Standardizing methods of blood pressure assessment, effectiveness measures beyond blood pressure alone, and safety outcomes are paramount. The Hypertension Academic Research Consortium (HARC) document represents an integration of evolving evidence and consensus opinion among leading experts in cardiovascular medicine and hypertension research with regulatory perspectives on clinical trial design and methodology. The HARC document integrates the collective information among device-based therapies for hypertension to better address existing challenges and identify unmet needs for technologies proposed to treat the world's leading cause of death and disability. Consistent with the Academic Research Consortium charter, this document proposes pragmatic consensus clinical design principles and outcomes definitions for studies aimed at evaluating device-based hypertension therapies.

Plasma renin and aldosterone concentrations related to endovascular ultrasound renal denervation in the RADIANCE-HTN SOLO trial.

OBJECTIVE: The RADIANCE-HTN SOLO trial demonstrated a greater reduction in daytime ambulatory SBP at 2 months by endovascular ultrasound renal denervation than sham procedure. We hypothesized that plasma renin and aldosterone concentrations would be associated with the SBP response to renal denervation. METHODS: Hypertensive patients were randomized to renal denervation (n = 74) or sham (n = 72) after a 4-week washout of antihypertensive medications. In a 53-patient subset, 2-month and 6-month plasma renin and aldosterone concentration were measured. Dietary sodium was not controlled. RESULTS: Mean age of the 29 treatment and 24 sham patients was 54 years; 62% were men; 17% black. Daytime ambulatory SBP fell in the denervation but not the sham group at 2 months (-7.8 ±â€Š10.7 vs. -0.1 ±â€Š10.1 mmHg; P = 0.048). Baseline plasma renin and aldosterone concentrations were in the low-normal range, did not change significantly at 2 months in either group and did not predict response to renal denervation. At 6 months, after the addition of antihypertensive medications, there was a significant rise in renin in the sham but not the denervation group. CONCLUSION: Although renal denervation but not sham resulted in a decrease in daytime ambulatory SBP at 2 months, renin and aldosterone concentrations did neither predict the BP response to renal denervation; nor did they fall after denervation. A rise in renin at 6 months in the sham group likely represents confounding from antihypertensive medications. Whether the BP-lowering effect of renal denervation depends on reducing local intrarenal renin release requires further study.

Predictors of blood pressure response to ultrasound renal denervation in the RADIANCE-HTN SOLO study.

The blood pressure (BP) lowering response to renal denervation (RDN) remains variable with about one-third of patients not responding to ultrasound or radiofrequency RDN. Identification of predictors of the BP response to RDN is needed to optimize patient selection for this therapy. This is a post-hoc analysis of the RADIANCE-HTN SOLO study. BP response to RDN was measured by the change in daytime ambulatory systolic blood pressure (dASBP) at 2 months post procedure. Univariate regression was used initially to assess potential predictors of outcome followed by multivariate regression analysis. In the univariate analysis, predictors of response to RDN were higher baseline daytime ambulatory diastolic blood pressure (dADBP), the use of antihypertensive medications at screening, and presence of orthostatic hypertension (OHTN) whilst the presence of untreated accessory arteries was a negative predictor of response. Multivariate analysis determined that dADBP and use of antihypertensive medications were predictors of response to RDN with a trend for OHTN to predict response. Obese females also appeared to be better responders to RDN in an interaction model. RDN is more effective in patients with elevated baseline dADBP and those with OHTN, suggesting increased peripheral vascular resistance secondary to heightened sympathetic tone. These assessments are easy to perform in clinical setting and may help in phenotyping patients who will respond better to RDN.

Dysautonomia Causing Severe Orthostatic Hypotension: An Important, Early Finding in Neurodegenerative Disorders.

Orthostatic hypotension is common and dangerous; it has neurogenic and nonneurogenic causes. We present the case of a 40-year-old man with severe neurogenic hypotension, caused by young-onset multiple system atrophy. In patients presenting with neurogenic orthostatic hypotension, underlying neurodegenerative diseases should always be considered. (Level of Difficulty: Advanced.).

Changes in blood pressure after crossover to ultrasound renal denervation in patients initially treated with sham in the RADIANCE-HTN SOLO trial.

BACKGROUND: The multicentre, randomised, sham-controlled RADIANCE-HTN SOLO trial reported the blood pressure (BP)-lowering efficacy and safety of ultrasound renal denervation (RDN) in the absence (2 months) and presence (6 and 12 months) of antihypertensive medications in patients with mild-to-moderate hypertension. AIMS: The aim of this report was to evaluate patients originally assigned to the sham group who crossed over to RDN. METHODS: After the primary endpoint was met, patients in the sham arm who remained uncontrolled were allowed to cross over to receive RDN. All patients were unblinded and treated with standard of care medications at the time of crossover. Ambulatory BP was evaluated 2 and 6 months after crossover. RESULTS: Among 72 subjects of the sham arm, 33 underwent ultrasound RDN after an average follow-up of 23±6 months. Prior to crossover, patients had a daytime ambulatory BP of 144.1±10.1/89.9±8.4 mmHg and received 1.2±0.8 antihypertensive medications. Mean change in daytime ambulatory BP from pre-crossover to 2 and 6 months post RDN was -11.2±13.7/-7.1±8.9 mmHg (n=33; p<0.001; p<0.001) and -10.8±17.3/-7.8±11.6 mmHg (n=27; p=0.002; p<0.001). The number of antihypertensive medications did not change from pre-crossover baseline to 2 and 6 months. Eighteen of 33 (54.5%) patients had their daytime ambulatory BP controlled (<135/85 mmHg) at 2 months and 44.4% (12/27) at 6 months post RDN. No major procedure-related adverse events occurred. CONCLUSIONS: During unblinded long-term follow-up of the RADIANCE-HTN SOLO study, patients originally assigned to a sham procedure who remained uncontrolled had significant reductions in BP following crossover treatment with ultrasound RDN.

Catheter-based alcohol-mediated renal denervation for the treatment of uncontrolled hypertension: design of two sham-controlled, randomized, blinded trials in the absence (TARGET BP OFF-MED) and presence (TARGET BP I) of antihypertensive medications.

BACKGROUND: Arterial hypertension is a common and life-threatening condition and poses a large global health burden. Device-based treatments have been developed as adjunctive or alternative therapy, to be used with or without antihypertensive medication for treating uncontrolled hypertension. The safety and feasibility of chemical renal denervation (RDN) using the Peregrine Catheter and alcohol were demonstrated in a first-in-man and open-label clinical trials, prompting the initiation of the ongoing TARGET BP OFF-MED and TARGET BP I trials. DESIGN: The TARGET BP trials are randomized, blinded, sham-controlled trials designed to assess the safety and efficacy of alcohol-mediated RDN for the treatment of uncontrolled hypertension in the absence of antihypertensive medications (TARGET BP OFF-MED) or in addition to prescribed antihypertensive medications (TARGET BP I). Subjects with confirmed uncontrolled hypertension and suitable renal artery anatomy are randomized (1:1) to receive either RDN using the Peregrine Kit with alcohol (0.6 mL per renal artery) infused through the Peregrine Catheter or diagnostic renal angiography only (sham procedure). TARGET BP OFF-MED completed enrollment and randomized 96 subjects. TARGET BP I will randomize approximately 300 subjects and will transition to an open-label safety cohort of approximately 300 subjects receiving RDN once the primary efficacy endpoint of the Randomized Controlled Trial (RCT) cohort has been met. Primary endpoints are change in mean 24-hour ambulatory systolic blood pressure from baseline to 8 weeks (TARGET BP OFF-MED) and 3 months (TARGET BP I) post-procedure. CONCLUSION: The TARGET BP trials are the first large-scale, international, randomized trials aimed to investigate the safety and BP lowering efficacy of a novel RDN method, with perivascular alcohol delivery using the Peregrine Kit.

Ultrasound renal denervation for hypertension resistant to a triple medication pill (RADIANCE-HTN TRIO): a randomised, multicentre, single-blind, sham-controlled trial.

BACKGROUND: Endovascular renal denervation reduces blood pressure in patients with mild-to-moderate hypertension, but its efficacy in patients with true resistant hypertension has not been shown. We aimed to assess the efficacy and safety of endovascular ultrasound renal denervation in patients with hypertension resistant to three or more antihypertensive medications. METHODS: In a randomised, international, multicentre, single-blind, sham-controlled trial done at 28 tertiary centres in the USA and 25 in Europe, we included patients aged 18-75 years with office blood pressure of at least 140/90 mm Hg despite three or more antihypertensive medications including a diuretic. Eligible patients were switched to a once daily, fixed-dose, single-pill combination of a calcium channel blocker, an angiotensin receptor blocker, and a thiazide diuretic. After 4 weeks of standardised therapy, patients with daytime ambulatory blood pressure of at least 135/85 mm Hg were randomly assigned (1:1) by computer (stratified by centres) to ultrasound renal denervation or a sham procedure. Patients and outcome assessors were masked to randomisation. Addition of antihypertensive medications was allowed if specified blood pressure thresholds were exceeded. The primary endpoint was the change in daytime ambulatory systolic blood pressure at 2 months in the intention-to-treat population. Safety was also assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02649426. FINDINGS: Between March 11, 2016, and March 13, 2020, 989 participants were enrolled and 136 were randomly assigned to renal denervation (n=69) or a sham procedure (n=67). Full adherence to the combination medications at 2 months among patients with urine samples was similar in both groups (42 [82%] of 51 in the renal denervation group vs 47 [82%] of 57 in the sham procedure group; p=0·99). Renal denervation reduced daytime ambulatory systolic blood pressure more than the sham procedure (-8·0 mm Hg [IQR -16·4 to 0·0] vs -3·0 mm Hg [-10·3 to 1·8]; median between-group difference -4·5 mm Hg [95% CI -8·5 to -0·3]; adjusted p=0·022); the median between-group difference was -5·8 mm Hg (95% CI -9·7 to -1·6; adjusted p=0·0051) among patients with complete ambulatory blood pressure data. There were no differences in safety outcomes between the two groups. INTERPRETATION: Compared with a sham procedure, ultrasound renal denervation reduced blood pressure at 2 months in patients with hypertension resistant to a standardised triple combination pill. If the blood pressure lowering effect and safety of renal denervation are maintained in the long term, renal denervation might be an alternative to the addition of further antihypertensive medications in patients with resistant hypertension. FUNDING: ReCor Medical.

Device Therapy of Hypertension.

In the past decade, efforts to improve blood pressure control have looked beyond conventional approaches of lifestyle modification and drug therapy to embrace interventional therapies. Based upon animal and human studies clearly demonstrating a key role for the sympathetic nervous system in the etiology of hypertension, the newer technologies that have emerged are predominantly aimed at neuromodulation of peripheral nervous system targets. These include renal denervation, baroreflex activation therapy, endovascular baroreflex amplification therapy, carotid body ablation, and pacemaker-mediated programmable hypertension control. Of these, renal denervation is the most mature, and with a recent series of proof-of-concept trials demonstrating the safety and efficacy of radiofrequency and more recently ultrasound-based renal denervation, this technology is poised to become available as a viable treatment option for hypertension in the foreseeable future. With regard to baroreflex activation therapy, endovascular baroreflex amplification, carotid body ablation, and programmable hypertension control, these are developing technologies for which more human data are required. Importantly, central nervous system control of the circulation remains a poorly understood yet vital component of the hypertension pathway and mandates further investigation. Technology to improve blood pressure control through deep brain stimulation of key cardiovascular control territories is, therefore, of interest. Furthermore, alternative nonsympathomodulatory intervention targeting the hemodynamics of the circulation may also be worth exploring for patients in whom sympathetic drive is less relevant to hypertension perpetuation. Herein, we review the aforementioned technologies with an emphasis on the preclinical data that underpin their rationale and the human evidence that supports their use.

Alcohol-Mediated Renal Sympathetic Neurolysis for the Treatment of Hypertension: The Peregrine™ Infusion Catheter.

Renal sympathetic denervation using conventional non-irrigated radiofrequency catheters has potential technical shortcomings, including limited penetration depth and incomplete circumferential nerve damage, potentially impacting therapeutic efficacy. Against this background, second generation multi-electrode, radiofrequency and ultrasound renal denervation systems have been developed to provide more consistent circumferential nerve ablation. Irrigated catheters may allow deeper penetration while minimizing arterial injury. In this context, catheter-based chemical denervation, with selective infusion of alcohol, a potent neurolytic agent, into the perivascular space, may minimize endothelial, intimal and medial injury while providing circumferential neurolysis. Animal studies demonstrate pronounced renal norepinephrine level reductions and consistent renal nerve injury after perivascular alcohol infusion using the Peregrine Catheter. Early clinical studies demonstrated significant blood pressure reductions and a reasonable safety profile. Randomized sham-controlled trials (NCT03503773, NCT02910414) are underway to examine whether the aforementioned theoretical advantages of alcohol-medicated denervation with the Peregrine System™ Kit translate into clinical benefits.

Ambulatory Blood Pressure Monitoring to Predict Response to Renal Denervation: A Post Hoc Analysis of the RADIANCE-HTN SOLO Study.

Renal denervation (RDN) is effective in lowering blood pressure (BP) in patients with hypertension. The issue remains how to best identify potential responders. Ambulatory BP monitoring may be useful. Baseline nighttime systolic BP (SBP) ≥136 mm Hg and its variability (SD) ≥12 mm Hg in DENER-HTN trial or 24-hour heart rate ≥73.5 bpm in SPYRAL HTN-OFF MED Trial were shown to predict the BP response to RDN. We applied these criteria to the patients with hypertension in the sham-controlled RADIANCE-HTN SOLO trial to predict the BP response to ultrasound RDN at 2 months while patients were maintained off medications. BP responders were defined as: clinical with 24-hour SBP <130 mm Hg (RDN: 22/64 versus sham: 7/58); meaningful with 24-hour SBP reduction ≥10 mm Hg (RDN: 24/64, sham: 7/58); and extreme with 24-hour SBP reduction above mean+2 SD of the SBP decrease in the sham group, that is, ≥16.5 mm Hg (RDN: 10/64 versus sham: 2/58). The predictive criteria reported above were tested for sensitivity, specificity, and positive and negative predictive values. The predictive value varied according to the definition of response, with the clinical definition being strongly influenced by regression to the mean. Baseline nighttime SBP and its variability, especially when combined, offered good specificity (>90% irrespective of definition) but low sensitivity (from 9.1% to 30% depending on the definition) to predict responders; the heart rate criterion had insufficient predictive value. This analysis suggests the potential role of nighttime SBP and its variability to predict BP response to RDN in patients with hypertension. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02649426.