Prioritised endpoints for device-based hypertension trials: the win ratio methodology.

In The Journal of Clinical Hypertension, Tino Naduvathumuriyil and colleagues report the results of their single-center registry on the effects of renal denervation (RDN) in resistant hypertension patients. They report that a total of 50 resistant hypertension patients underwent RDN using three different systems. The data from their registry showed that office blood pressure (BP) reductions following RDN were sustained throughout the follow-up periods of up to 3 years. Mean office BP was reduced from 170.6/93.4 mm Hg at baseline to 144.2/84.6 mm Hg at 36 months. Mean changes in office systolic and diastolic BP after 36 months were −26.4 and −8.8 mm Hg (95% CI: −34.6 to −18.2 and −13.5 to −4.2 mm Hg, n = 28), respectively. Patients at the very highest BP level—greater than 180 mm Hg systolic at baseline—appeared to benefit the most from the procedure at three years. Based on office BP, 100% and 82% of patients with grade 3 hypertension were responders at 24 and 36 months, respectively. Additionally, the proportion of patients with an office systolic BP ≥ 180 mm Hg dropped from 30% at baseline to 7.4% at 3 years. Although plasma creatinine increased from 90.6 μmol/L (95% CI: 82.1-99.0 μmol/L) at baseline to 102.1 μmol/L (95% CI: 95.8-108.3 μmol/L) at 36 months (P = .007), no long-term safety concerns were observed following the RDN procedure. The study is an important evidence around RDN as a safe, effective, and long-lasting BP-lowering therapy. The Global SYMPLICITY Registry is the largest study documenting the long-term safety and effectiveness of the Medtronic renal denervation systems in a real-world setting in patients with uncontrolled hypertension.1 This single-center study, as a useful supplement to the Global SYMPLICITY Registry, reconfirmed the long-term efficacy of lowering blood pressure in RDN. The recently published randomized, sham-controlled SPYRAL HTN-OFF MED (Efficacy of catheter-based renal denervation in the absence of antihypertensive medications [SPYRAL HTN-OFF MED Pivotal]: a multicentre, randomised, sham-controlled trial)2 and (Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications [SPYRAL HTN-OFF MED]: a randomised, sham-controlled, proof-of-concept trial),3 SPYRAL HTN-ON MED (Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept randomised trial),4 and RADIANCE SOLO (Endovascular ultrasound renal denervation to treat hypertension [RADIANCE-HTN SOLO]: a multicentre, international, single-blind, randomised, sham-controlled trial)5 trials documented significant and consistent reductions in both office and ambulatory BP in patients with and without concomitant antihypertensive medication, while results are short term. Although the sample size is relatively small, the encouraging findings of this single-center registry support to the clinical application of RDN, a legitimate antihypertensive strategy, for uncontrolled hypertension. This single-center registry showed a substantial reduction in office BP after RDN using 3 different catheter-based radiofrequency ablation systems: the Symplicity RDN system from Medtronic, the EnligHTN RDN system from St. Jude Medical/Abbott, and the Vessix RDN system from Boston Scientific. This first comparison of 3 different radiofrequency ablation RDN systems reveals novel findings. Although the average BP reductions were modest and the number of patients was small, head-to-head comparison showed an advantage for Vessix RDN system perhaps because of the more complete renal nerve ablation. At present, there are a variety of RDN devices with different technologies, but different devices should have different effects. Both radiofrequency and ultrasound endovascular RDN systems have proven clinical efficacy for the treatment of hypertension. The Radiosound-HTN comparative trial has shown that RDN using endovascular ultrasound afforded superior reduction in ambulatory systolic BP in comparison with radiofrequency ablation system.6 Questions that remain open and require further evidence in future studies relate to the long-term safety and efficacy of both the radiofrequency ablation devices and that of other devices with different technologies in larger cohorts. A head-to-head comparison may be useful to determine the potential superiority of all the devices. Selection of suitable patients for RDN therapy is the key to the success of RDN. The ultimate litmus test is to identify responders and nonresponders to RDN therapy. The problem remains unresolved. In this small sample study, patients with grade 3 or higher hypertension had a better response, while the BP response was variable. Although more patients demonstrated BP reduction with RDN than with the sham procedure, there were changes seen in either direction for both groups in SPYRAL HTN-OFF MED, SPYRAL HTN-ON MED, and RADIANCE SOLO trials. In any case, following the positive SPYRAL HTN-OFF MED Pivotal data, these new data provide additional evidence on the safety and efficacy of RDN to help manage uncontrolled hypertension, with study patients experiencing meaningful blood pressure reductions out to several years. None disclaimers.

Objectives We assessed a novel approach to percutaneous renal denervation for uncontrolled hypertension consisting of ablation beyond the proximal main renal artery (Y-pattern), including the primary branches, and compared it to the standard procedure applied only within the main vessel. We also assessed the safety and practicality of a brachial access approach. Methods and results Renal denervation was performed on 119 consecutive patients (60±13 years). In 68 of the patients, femoral arterial vascular approach was used and in 51 brachial. In 80 patients treated with the standard ablation, 12.0±3.0 total ablations (both sides) were applied while 20.4±3.9 total ablations were delivered for the group of 39 patients with Y-pattern denervation (P<0.001). Technically successful renal denervation was achieved in all patients. Office blood-pressure levels at baseline were 170±17/93±10 mm Hg for the standard group and 169±13/96±9 mm Hg for the Y-pattern group. No major adverse events occurred during the procedure or in the postprocedural in-hospital period. Renal denervation was associated with significant decreases in both office and ambulatory systolic and diastolic blood pressure in both groups. The reduction in 24-hour mean ambulatory systolic blood pressure at 6 months was significantly greater (P=0.002) for the Y-Pattern group (−22.1±15.4 mm Hg) compared to the Standard group (−11.8±16.2 mm Hg). Changes in diastolic office and ambulatory pressure were also significantly greater at 6 months in the Y-pattern ablation group. Indices of blood pressure variability improved in both groups. Between group comparison of blood pressure and other parameters at follow up Standard Y-Pattern P (Standard vs Y) Change in Office Diastolic Blood Pressure (mmHg) 1 Month −8.0±13.2* −9.8±8.5* 0.49 3 Months −6.3±6.9* −6.4±9.0* 0.96 6 Months −5.0±9.0* −9.9±10.8* 0.01 Change in Ambulatory Diastolic Pressure (mmHg) 24-Hour −5.2±8.4* −6.2±10.0* 0.61 Daytime −3.2±9.4* −5.6±10.0* 0.24 Night Time −7.6±8.4* −6.5±11.5* 0.56 Antihypertensive Medication Classes 4.9±1.1* 5.3±0.8* 0.07 otal Number of Lesions† 12.0±3.0 20.4±3.9 <0.001 Conclusion Renal denervation using a Y-pattern ablation strategy combined with a greater number of lesions is safe and resulted in significant greater decreases in mean 24-hour ambulatory systolic and diastolic blood pressure compared to the conventional

Renal denervation (RDN) has demonstrated clinically relevant reductions in blood pressure (BP) among individuals with uncontrolled hypertension despite lifestyle intervention and medications. The safety and effectiveness of alcohol-mediated RDN have not been formally studied in this indication. TARGET BP I is a prospective, international, sham-controlled, randomized, patient- and assessor-blinded trial investigating the safety and efficacy of alcohol-mediated RDN. Patients with office systolic BP (SBP) ≥150 and ≤180 mm Hg, office diastolic BP ≥90 mm Hg, and mean 24-hour ambulatory SBP ≥135 and ≤170 mm Hg despite prescription of 2 to 5 antihypertensive medications were enrolled. The primary end point was the baseline-adjusted change in mean 24-hour ambulatory SBP 3 months after the procedure. Secondary end points included mean between-group differences in office and ambulatory BP at additional time points. Among 301 patients randomized 1:1 to RDN or sham control, RDN was associated with a significant reduction in 24-hour ambulatory SBP at 3 months (mean±SD, -10.0±14.2 mm Hg versus -6.8±12.1 mm Hg; treatment difference, -3.2 mm Hg [95% CI, -6.3 to 0.0]; P=0.0487). Subgroup analysis of the primary end point revealed no significant interaction across predefined subgroups. At 3 months, the mean change in office SBP was -12.7±18.3 and -9.7±17.3 mm Hg (difference, -3.0 [95% CI, -7.0 to 1.0]; P=0.173) for RDN and sham, respectively. No significant differences in ambulatory or office diastolic BP were observed. Adverse safety events through 6 months were uncommon, with one instance of accessory renal artery dissection in the RDN group (0.7%). No significant between-group differences in medication changes or patient adherence were identified. Alcohol-mediated RDN was associated with a modest but statistically significant reduction in 24-hour ambulatory SBP compared with sham control. No significant differences between groups in office BP or 6-month major adverse events were observed. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02910414.

Background Orthostatic blood pressure (BP) adaptations are associated with the risk of adverse cardiovascular events. This study aimed to evaluate the effect of catheter-based renal denervation (RDN) on orthostatic BP adaptations in patients with uncontrolled hypertension. Methods The Iberis-HTN Trial is a randomized, sham-controlled, multicenter study conducted at 16 centers in China. Eligible patients were randomly assigned to undergo either radiofrequency RDN or a sham procedure. As one of the participating centers in the Iberis-HTN trial, BP and heart rate (HR) changes during a 3-min orthostatic challenge from supine to standing were measured at baseline and 6 months after randomization. Results Between March 2018 and January 2022, a total of 30 patients were assigned to the RDN group (n = 15) and sham group (n = 15). Of these 30 patients, 10 in the RDN group and 12 in the sham group completed orthostatic BP measurements at both baseline and 6 months. At 6 months, the RDN group exhibited a significantly greater reduction in ambulatory blood pressure, office systolic blood pressure (SBP) and BP in both supine and standing positions compared to the sham group. The changes in orthostatic SBP and diastolic blood pressure (DBP) at 3 minutes, and the maximum changes during a 3-min orthostatic test at 6 months were smaller in the RDN group than in the sham group after adjusting for baseline values (3 min: SBP -9.4 mmHg [95%CI: -16.0 to -2.8], P = 0.008; DBP -6.7 mmHg [95%CI: -12.4 to -1.1], P = 0.022. Maximum: SBP -10.9 mmHg [95%CI: -21.1 to -0.6], P = 0.039; DBP -9.2 mmHg [95%CI: -16.2 to -2.1], P = 0.013). The orthostatic HR changes at 6 months were similar between the RDN and sham group. Conclusions Catheter-based radiofrequency RDN significantly reduced office BP, ambulatory BP, and BP in both supine and standing positions during active standing at 6 months compared to the sham group. Additionally, RDN mitigated the inappropriate increase in orthostatic BP and partly restored the normal response pattern to orthostatic challenges. Further studies are warranted to investigate whether the differential effects of RDN on orthostatic BP correlated with long-term cardiovascular outcomes.

Renal denervation is a promising new non-pharmacological treatment for resistant hypertension. However, there is a lack of data from Asian patients. The REQUIRE trial investigated the blood pressure-lowering efficacy of renal denervation in treated patients with resistant hypertension from Japan and South Korea. Adults with resistant hypertension (seated office blood pressure ≥150/90 mmHg and 24-hour ambulatory systolic blood pressure ≥140 mmHg) with suitable renal artery anatomy were randomized to ultrasound renal denervation or a sham procedure. The primary endpoint was change from baseline in 24-hour ambulatory systolic blood pressure at 3 months. A total of 143 patients were included (72 renal denervation, 71 sham control). Reduction from baseline in 24-hour ambulatory systolic blood pressure at 3 months was not significantly different between the renal denervation (−6.6 mmHg) and sham control (−6.5 mmHg) groups (difference: −0.1, 95% confidence interval −5.5, 5.3; p = 0.971). Reductions from baseline in home and office systolic blood pressure (differences: –1.8 mmHg [p = 0.488] and −2.0 mmHg [p = 0.511], respectively), and medication load, did not differ significantly between the two groups. The procedure-/device-related major adverse events was not seen. This study did not show a significant difference in ambulatory blood pressure reductions between renal denervation and a sham procedure in treated patients with resistant hypertension. Although blood pressure reduction after renal denervation was similar to other sham-controlled studies, the sham group in this study showed much greater reduction. This unexpected blood pressure reduction in the sham control group highlights study design issues that will be addressed in a new trial.Clinical trial registrationNCT02918305 (http://www.clinicaltrials.gov).

Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept randomised trial

Objective: The blood pressure (BP) lowering effect of renal sympathetic denervation (RDN) in treatment resistant hypertension (TRH) shows variation among the few randomized studies. The duration of antihypertensive effect and long-term effect and safety of RDN require further follow-up. We aimed to report the office and ambulatory (BP) changes and long-term safety at 12-month follow-up. Design and Method: Patients with apparent TRH (n = 65) were referred specifically for RDN and those with secondary and spurious hypertension (n = 26) were excluded. TRH was defined as office systolic BP>140 mmHg despite maximally tolerated doses of at least 3 antihypertensive drugs including a diuretic. Additionally, ambulatory daytime systolic BP > 135 mmHg following witnessed intake of antihypertensive drugs was required, after which 20 patients had normalized BP, indicating poor drug adherence. Patients with true TRH were randomized and underwent RDN with Symplicity catheter (n = 9) versus adjusted drug treatment (n = 10). Results: 24-hour ambulatory systolic and diastolic BPs in the drug adjustment group changed from 151 ± 13/84 ± 7 mmHg (±SD) at baseline to 131 ± 12/75 ± 5 mmHg at 12 months (p < 0.0005 for all), and in the RDN group from 149 ± 9/89 ± 7 to 141 ± 11/83 ± 5 mmHg (p = 0.07 and p = 0.04, respectively). The absolute difference in change between groups in systolic BP was significantly higher in favor of the drug adjustment group (p = 0.01). Office, daytime and nighttime ambulatory BPs changed in parallel to the 24-hour ambulatory BPs. However 2 patients in RDN group considered as a responder since they have sustained reduction of 24-hour ambulatory systolic BP by more than 15 mmHg. There were no significant changes in renal arteries assessed by MRI or CT scans after 12 months follow-up. No deterioration of renal function was found. Conclusions: RDN has inferior BP lowering effects compared to adjusted drug treatment in patients with TRH. However, RDN is safe and this encourages future research to identify characteristics of patients who might respond to RDN.

Objective: Studies on the blood pressure lowering effect of renal denervation (RDN) in resistant hypertensive patients have produced conflicting results. Change in medication usage during the studies may be responsible for this inconsistency. To eliminate the effect of medication usage on blood pressure we focused on unmedicated hypertensive patients who underwent RDN. Design and method: Our study reports on a cohort of patients who were not on blood pressure lowering drugs at baseline and during follow-up from eight tertiary centers. Data of patients were used when they were treated with RDN and had a baseline office systolic blood pressure (SBP) of at least 140 mmHg and/or 24-hour ambulatory SBP of at least 130 mmHg. Our primary outcome was defined as change in office and 24-hour SBP at 12 months after RDN, compared to baseline. Results: Fifty-three patients were included. There were three different reasons for not using blood pressure lowering drugs: 1) documented intolerance or allergic reaction (57%); 2) temporary cessation of medication for study purposes (28%); and 3) reluctance to take antihypertensive drugs (15%). Mean change in 24-hour SBP was −5.7 mmHg (95% confidence interval [CI] −11.0 to −0.4; P = 0.04). Mean change in office SBP was −13.1 mmHg (95% CI −20.4 to −5.7; P = 0.001). Figure 1 represents individual changes in blood pressure after RDN. No changes were observed in other variables, such as eGFR, body–mass-index and urinary sodium excretion. Conclusions: This explorative study in hypertensive patients, who were not on blood pressure lowering medication, suggests that at least in some patients RDN lowers blood pressure.

the cumulative sodium retention. Furthermore, this renal denervation was shown to prevent, markedly attenuate or delay the development of hypertension in a diverse number of models of elevated blood pressure. 4 These promising experimental results of renal sympathetic nerve denervation for the treatment of hypertension prompted the establishment of the first clinical trial of this approach as a proof-of-principle study. 3 In brief, in 45 patients with resistant hypertension a catheter connected to a radiofrequency generator was introduced into renal arteries via femoral access and up to six discrete radiofrequency ablations were delivered within each renal artery. The major aims of this study were to assess firstly the efficacy of blood pressure lowering and s econdly the safety of this procedure. The initial blood pressure in these patients who had been treated with four to seven anti-hypertensive medications was 177/101 mmHg. The highly significant average reduction in office measured systolic/diastolic blood pressure at 1 month after the renal sympathetic denervation procedure was 14/10 mmHg. Blood pressure was further reduced at 3 months by 22/10 mmHg, with this effect persisting on s ubsequent assessments with the reduction 12 months after the procedure being 27/17 mmHg. Only six out of 45 patients did not benefit from this treatment, defined as a s ystolic blood pressure reduction of less than 10 mmHg. In 12 patients, 24 hour ambulatory blood pressure monitoring was performed before and after the denervation procedure. The change in office systolic blood pressure correlated closely with the change in mean ambulatory blood pressure (r 2 50.62, p50.002). Furthermore, renal sympathetic denervation was associated with an increase in the number of n octurnal dippers in the group of patients that had responded to this treatment. The effectiveness of the radiofrequency method in achieving efferent renal denervation was assessed in a subgroup of patients (n 51 0) by measuring renal Arterial hypertension is a major risk factor for an array of cardiovascular diseases, particularly in the context of concomitant diabetes. Furthermore, elevated blood pressure is at least twice as prevalent in type 2 diabetes as in the g eneral population. Clinical data suggest that lower blood pressure may induce even greater cardiovascular benefits in diabetic subjects than in individuals without diabetes. With respect to renal disease, recent data from the Action in Diabetes and Vascular Disease (ADVANCE) study indicate that there is no lower threshold for blood pressure reduction when one is aiming to reduce the burden of renal disease. 1 So far, the major therapeutic strategy for arterial hypertension has focused on pharmacological treatments. Despite the abundance of available antihypertensive drugs, arterial hypertension remains undertreated, in particular in diabetes and specifically in the setting of associated chronic kidney disease. Clinical trials involving patients with diabetes or renal impairment have demonstrated that achieving lower blood pressure goals requires treatment with on average at least three different antihypertensive agents. 2 Moreover, it has been shown that with current standard antihypertensive therapies only one of out seven patients with type 2 diabetes can achieve a target blood pressure of less than 130/80 mmHg. Recently, a multi-centre prospective cohort study has demonstrated the efficacy of a non-pharmacological, minimally invasive percutaneous radiofrequency catheter-based treatment to disrupt renal sympathetic nerves in the management of patients with resistant hypertension, which included a significant subgroup with type 2 diabetes. 3 The rationale for renal sympathetic nerves denervation as a treatment strategy for systemic hypertension lies in the hypothesis that abnormal excretory function is crucial for the initiation, p rogression and maintenance of primary hypertension with sodium and water balance considered to be of central importance in the long-term control of systemic blood pressure. In addition, in animal models it has been confirmed that renal sympathetic nerve stimulation results in a substantial increase in the renin secretion rate and promotes antinatriuresis without affecting glomerular filtration rate and renal plasma flow. Moreover, in animal models renal sympathetic denervation has been used to demonstrate that renal sympathetic nerve activity is responsible for approximately 40% of

Orthostatic function after renal sympathetic denervation in patients with resistant hypertension

Renal denervation (RDN) can lower blood pressure (BP) in patients with hypertension in both the presence and absence of medication. This is a sham-controlled trial investigating the safety and efficacy of RDN in China. This prospective, multicenter, randomized, patient- and outcome-assessor-blinded, sham-controlled trial investigated radiofrequency RDN in patients with hypertension on standardized triple antihypertensive therapy. Eligible patients were randomized 1:1 to undergo RDN using a multi-electrode radiofrequency catheter (Iberis; Shanghai Angiocare Medical Technology, Shanghai, China) or a sham procedure. The primary efficacy outcome was the between-group difference in baseline-adjusted change in mean 24-hour ambulatory systolic BP from randomization to 6 months. Of 217 randomized patients (mean age, 45.3±10.2 years; 21% female), 107 were randomized to RDN and 110 were randomized to sham control. At 6 months, there was a greater reduction in 24-hour systolic BP in the RDN (-13.0±12.1 mm Hg) compared with the sham control group (-3.0±13.0 mm Hg; baseline-adjusted between-group difference, -9.4 mm Hg [95% CI, -12.8 to -5.9]; P<0.001). Compared with sham, 24-hour diastolic BP was lowered by -5.0 mm Hg ([95% CI, -7.5 to -2.4]; P<0.001) 6 months after RDN, and office systolic and diastolic BP was lowered by -6.4 mm Hg ([95% CI, -10.5 to -2.3]; P=0.003) and -5.1 mm Hg ([95% CI, -8.2 to -2.0]; P=0.001), respectively. One patient in the RDN group experienced an access site complication (hematoma), which resolved without sequelae. No other major device- or procedure-related safety events occurred through follow-up. In this trial of Chinese patients with uncontrolled hypertension on a standardized triple pharmacotherapy, RDN was safe and reduced ambulatory and office BP at 6 months compared with sham. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02901704.

Cardiorespiratory Response to Exercise After Renal Sympathetic Denervation in Patients With Resistant Hypertension

Renal denervation (RDN) is a promising treatment based on catheter intervention for patients with refractory hypertension. However, the effect in patients with isolated systolic hypertension (ISH) remains controversial. The aim of this meta-analysis was to determine the blood pressure lowing effect of RDN in patients with ISH compared with combined systolic/diastolic hypertension (CH) patients. PubMed, Embase, Cochrane and ClinicalTrials.gov were searched for prospective clinical studies that included RDN. The outcomes of interest were the change of 24-hour ambulatory systolic blood pressure (SBP) from baseline. We used the fixed effects model to calculate weighted mean difference (WMD) with 95% confidence interval (CI). Six trials were included, with 1405 participants, including 597 patients with ISH and 808 patients with CH. Mean follow-up was five months. The reduction of 24-hour ambulatory SBP was significantly greater for the CH patients than the ISH patients (WMD = 3.89, 95% CI: 2.32-5.45, P < 0.0001). RDN also showed a greater reduction in office SBP in the CH patients compared to the ISH patients (WMD = 10.24, 95% CI: 4.24-15.74, P = 0.0003). And the effect was independent of age, length of follow-up, and ablation device. RDN provides superior blood pressure control in the CH patients compared with the ISH patients, and the CH patients may be the best suitable population for which RDN is indicated.

Catheter-Based Renal Denervation in ADPKD: Just for Pain Control?

Does the Presence of Accessory Renal Arteries Affect the Efficacy of Renal Denervation?