SYMPLICITY HTN-3 Research Articles

O89 POOLED, LONG-TERM ANALYSIS OF THE GLOBAL SYMPLICITY CLINICAL TRIAL PROGRAM OF RADIOFREQUENCY RENAL DENERVATION FOR THE TREATMENT OF UNCONTROLLED HYPERTENSION

Background/Objective: The Global Symplicity Clinical program is the largest investigation of radiofrequency renal denervation (RDN) to treat uncontrolled hypertension (HTN) to date. Over 4,000 patients enrolled into Spyral First-in-Man, Global SYMPLICITY Registry DEFINE, and multiple randomized, controlled and sham controlled trials including HTN-Japan, Symplicity HTN-3, SPYRAL HTN-OFF and -ON MED studies. We leveraged the entire Symplicity Global Clinical program dataset to develop a multivariate, patient-level, mixed model assessing (1) long-term BP reductions after RDN, and (2) whether specific patient characteristics correlate with future BP reductions after the procedure. Methods: Repeated BP measurements from each patient in the Global Symplicity Clinical program were analyzed using linear mixed models fitted with 24-h ambulatory systolic (S)BP and office SBP as outcome variables. Baseline SBP, baseline number of antihypertensive (AH) medications, and AH medications over time were included as fixed effects. Additional patient characteristics were included as potential significant fixed effects. To account for multiple BP measurements per patient and multiple studies, nested random effects were included using an auto-regressive correlation structure. Results: Data from 4156 patients treated with either the first-generation Symplicity Flex or the next-generation Symplicity Spyral catheter. Estimated, office and 24-h ambulatory SBP changes through 36 months, after adjusting for AH medication effects, were biphasic with a steep reduction after RDN through the first 6 months (Figure), followed by a steady reduction in SBP afterward through 36 months. Higher baseline SBP was correlated with greater BP reductions. AF history (-3.7 mmHg compared to no AF, p=0.0048) and increasing eGFR at baseline (-0.039 mmHg for every 1 ml/min increase in baseline eGFR, p=0.040) significantly correlated with lower 24-h ambulatory SBP. Conclusion: This is the most comprehensive analysis of radiofrequency RDN to date. Higher baseline SBP was strongly correlated with greater BP reductions. The results demonstrate the durability of RDN as an adjunctive therapy to treat HTN. Prospective studies need to validate whether certain patient characteristics are associated with improved response to RDN.

The current state of renal sympathetic denervation in hypertension

This review provides an overview of the efficacy and safety of renal sympathetic denervation as a therapeutic approach for resistant hypertension. While the initial enthusiasm was sparked by the results of early clinical trials, it was dampened by the findings of the Symplicity HTN-3 study. However, recent advances in catheter technology and more refined patient selection criteria have yielded more promising results. Subsequent studies, such as SPYRAL HTN-OFF MED and RADIANCE II, demonstrated significant reductions in blood pressure, even in patients with mild to moderate hypertension. Despite the lack of robust data on major clinical outcomes, investigations into the time in therapeutic range for patients undergoing renal sympathetic denervation suggested potential cardiovascular benefits. Nevertheless, further research is needed to thoroughly understand the long-term impact, assess cost-effectiveness, and accurately identify which patient subgroups may derive the greatest benefits from this therapy.

When Hypertension Gets On One’s Nerves: Has The Time Come For Renal Denervation?

For centuries, hypertension (HTN) has been a major cause of cardiovascular morbidity and mortality. Even now in 2024, despite all the advances in its understanding, adequate diagnosis and treatment of HTN globally is still sorely lacking. In a 2022 publication it is estimated that as much as 54% of hypertensive patients worldwide are undiagnosed. 42% of the hypertensive patients are both diagnosed and treated, yet only 21% of all hypertensive patients have blood pressure (BP) under control(1). Obviously, on a global scale there are way too many factors and variables that need to be addressed. Yet as practicing clinical physicians we are left to do what we can for the patients we encounter. Assuming there is a program in place to ensure compliance and follow-up, it is estimated that 82% of patients can achieve target BP(2). By simple calculation however, that also means nearly 20% of compliant patients will still not achieve target BP levels despite adequate medical treatment. And amongst those who do, around 20% would be on 3 or 4 anti hypertensive agents(3). This then begs the question… what else can we do for these difficult-to control patients? Renal denervation (RDN) was heralded into the limelight by the SYMPLICITY HTN-1(4) trial which showed RDN provided significant benefit to ambulatory BP readings on follow-up. At that time, RDN seemed poised to achieve a breakthrough in the management of HTN by offering difficult to-control patients another alternative to an ever-increasing number of medications. The RDN train however got derailed when several sham-controlled trials revealed little to no benefit with RDN treated patients compared to control(5,6,7,8). It was not until the second generation RDN technology came around and until RDN technique became much more refined that RDN plus medical therapy was proven to be clearly superior to medical therapy alone. The overall consensus now is that RDN can now provide the same benefits as adding another anti-hypertensive agent(9). And because of this, something that was heretofore unforeseen also occurred. RDN has somehow slowly moved past recommendation guidelines, and has become a therapy of choice for several patient subsets. In more developed countries, a good number of patients who have undergone RDN are those who asked for it. These patients are those who find it difficult to be compliant with medications, patients who are younger, of male gender, have higher ambulatory BP readings, those with concomitant heart failure and those who have numerous side effects from medical treatment for HTN(10). In some countries therefore, it is gradually becoming as mainstream as adding another medicine. As with any new technology, in our local Philippine setting the main barrier is cost. In patients in whom this is not an issue however, it seems the RDN floodgates are about to be opened. And if RDN trends in other countries are any indication, it is only a matter of time before RDN becomes standard therapy for the Philippine hypertensive patient. This consensus statement on RDN therapy by the 2023 Philippine Working Group published by Oliva et al (this issue) highlights what RDN is all about, its indications as well as the subsets of patients that are candidates for RDN. By its mere publication, it serves other purposes. It helps increase awareness about RDN’s availability, and lends more steam to the local RDN locomotive. Next stop? Better and more consistent BP control for the Filipino hypertensive patient!

Is Renal Denervation Effective in Treating Resistant Hypertension?

Resistant hypertension is diagnosed in patients whose blood pressure target is unmet despite the use of three or more antihypertensive medications. Systemic sympathetic hyperactivation is associated with the development of resistant hypertension. As the kidney is largely pervasive of the sympathetic nervous system renal denervation procedure was developed to control blood pressure by attenuating the renal and systemic sympathetic hyperactivity. Renal denervation is a minimally invasive procedure that uses radiofrequency or ultrasound energy waves to reduce the activity of the renal artery nerves. Previous clinical trials have shown conflicting results regarding the efficacy of the procedure. Symplicity HTN-1 and -2 trials showed effective blood pressure lowering results in the renal denervation group with a good safety profile. However, the Symplicity HTN-3 trial showed no difference in blood pressure lowering effect between the renal denervation and control Sham procedure groups. Notwithstanding, some recent clinical trials with Sham control and meta-analysis showed clinical benefits of renal denervation. Other clinical benefits of renal denervation include glucose control, cardiovascular protective effect, reduction of obstructive sleep apnea, and neuralgia control. A subset of patients with satisfactory blood pressure control response to the procedure may experience improved glucose control due to the overall reduced sympathetic activity and insulin resistance. Sympathetic activity control after renal denervation has cardioprotective effects, especially for those with arrhythmia and left ventricular hypertrophy. Also, renal denervation could be helpful in renalorigin pain control. Renal denervation is an effective, safe, non-invasive procedure with many clinical benefits beyond blood pressure control. Further development in the procedure technique and selection of target patients are needed for wider clinical use of renal denervation in resistant hypertension.

HIGHER BASELINE SYSTOLIC BLOOD PRESSURE IS ASSOCIATED WITH GREATER BLOOD PRESSURE REDUCTIONS FOLLOWING RADIOFREQUENCY RENAL DENERVATION IN A POOLED COHORT OF OVER 3900 PATIENTS

Objective: Uncontrolled hypertension (HTN) is the leading global risk factor for cardiovascular disease, and higher systolic blood pressure (SBP) increases this risk. Radiofrequency renal denervation (RF RDN) has been shown to reduce BP effectively in patients with uncontrolled HTN. We investigated the relationship between increasing baseline SBP and its change after RF RDN. Design and method: Patients undergoing RF RDN (N=3974) were pooled from global clinical trials in patients on antihypertensive drugs: SPYRAL First-In-Man, SYMPLICITY HTN-3, HTN-Japan, SPYRAL HTN ON-MED, and the Global SYMPLICITY Registry DEFINE. Office and 24-h ambulatory SBP at baseline and 6 months after RF RDN were evaluated. Linear regression analysis was performed to evaluate the correlation between baseline and SBP change after 6 months (SBP change=intercept+slope∗baseline SBP). Results: The baseline SBP for office and 24-h ambulatory BP were 167±24mmHg and 154±18mmHg, respectively. Patients were prescribed 4.4±1.5 antihypertensive drugs at baseline. After 6 months, prescribed antihypertensive drugs decreased to 4.3±1.5 (p<0.0001). In both office and 24-h ambulatory SBP, baseline SBP correlation with SBP change after 6 months was statistically significant; every 1mmHg increase in baseline office SBP was associated with a 0.59mmHg (r2=0.30; p<0.001) reduction in SBP, and every 1mmHg increase in baseline 24-h ambulatory SBP was associated with a 0.45mmHg (r2=0.19; p<0.001) reduction in SBP at 6 months. According to this linear regression, a baseline office SBP of 160mmHg, 170mmHg and 180mmHg were associated with 6 months office SBP reduction by -9.2mmHg, -15.1mmHg and -21.0mmHg, respectively (Figure). Reductions in SBP of this magnitude have previously been shown to correspond with substantial reductions in the risk of cardiovascular events. Conclusions: A continuous and inverse relationship was observed between baseline SBP and 6 months SBP change in patients with uncontrolled HTN undergoing RF RDN. Higher baseline SBP led to a greater reduction in SBP and may derive greater benefit from an RDN procedure. These findings may help clinicians and patients in their shared decision making regarding their BP management. However, this is a retrospective analysis which needs further prospective validation.

POOLED, LONG-TERM ANALYSIS OF THE GLOBAL SYMPLICITY CLINICAL TRIAL PROGRAM OF RADIOFREQUENCY RENAL DENERVATION FOR THE TREATMENT OF UNCONTROLLED HYPERTENSION

Objective: The Global Symplicity Clinical program is the largest investigation of radiofrequency renal denervation (RDN) to treat uncontrolled hypertension (HTN) to date. Collectively, over 4,000 patients enrolled into Spyral First-in-Man, the Global SYMPLICITY Registry (GSR) DEFINE, and multiple randomized controlled and sham controlled trials including HTN-Japan, Symplicity HTN-3, and the SPYRAL HTN-OFF and ON MED studies. We leveraged the entire Symplicity Global Clinical program patient dataset to develop a multivariate, patient-level, mixed model assessing (1) long-term BP reductions after RDN, and (2) whether specific patient characteristics correlate with future BP reductions after the procedure. Design and method: Repeated BP measurements from each patient in the Global Symplicity Clinical program were analyzed using linear mixed models fitted with 24-h ambulatory systolic (S)BP and office SBP as outcome variables. Baseline SBP, baseline number of antihypertensive (AH) medications, and AH medications over time were included as fixed effects. Additional patient characteristics were included as potential significant fixed effects. To account for multiple BP measurements per patient and multiple studies, nested random effects were included using an auto-regressive correlation structure. Results: The mixed model included data from 4156 patients treated with either the first-generation Symplicity Flex or the next-generation Symplicity Spyral catheter. Estimated, office and 24-h ambulatory SBP changes through 36 months, after adjusting for AH medication effects, were biphasic with a steep reduction after RDN through the first 6 months (Figure), followed by a steady reduction in SBP afterward through 36 months. Higher baseline SBP was correlated with greater BP reductions. History of AF (-3.7 mmHg compared to no AF, p=0.0048) and increasing eGFR at baseline (-0.039 mmHg for every 1 ml/min increase in baseline eGFR, p=0.040) significantly correlated with lower 24-h ambulatory SBP. Conclusions: This is the most comprehensive analysis of radiofrequency RDN to date. Higher baseline SBP was strongly correlated with greater BP reductions. The results demonstrate the durability of RDN as an adjunctive therapy to treat HTN patients. Prospective studies need to validate whether certain patient characteristics are associated with improved response to RDN.

Efficacy and safety aspects of renal denervation in treatment of arterial hypertension: a systematic review and meta-analysis

Abstract Introduction Current guidelines for the management of arterial hypertension 2018 of European Society for Cardiology (ESC) do not recommend use of renal denervation (RDN) (as device-based therapy) for treatment of hypertension except as part of clinical studies. However, in the meantime several randomized sham-controlled clinical trials were designed using second generation radiofrequency (RF) (SPYRAL HTN-OFF MED, SPYRAL HTN-ON MED), ultrasound (RADIANCE-HTN SOLO, RADIANCE-HTN TRIO) or alcohol-mediated renal denervation (TARGET BP-OFF) devices. We aimed to perform a comprehensive meta-analysis from all published and unpublished randomized, sham-controlled clinical trials which explored the effects of renal denervation on blood pressure across different devices. Methods We searched MEDLINE and Embase via OVID@ for eligible trials. Of note, we also included unpublished data from the SPYRAL-ON Extension and TARGET BP OFF trials. Pooling the data from all studies, we explored the efficacy (ambulatory and office systolic and diastolic BP) and safety (all cause death, vascular complication, renal artery stenosis >70%, hypertensive crisis) of RDN. Results Analysis included 9 eligible trials (i.e. SYMPLICITY HTN-3, ReSET, SPYRAL HTN OFF MED, Desch et al., RADIANCE-HTN SOLO, RADIANCE-HTN TRIO, RADIANCE, TARGET BP OFF, SPYRAL HTN ON MED extension) comprising 2,091 patients (Table 1). RDN reduced ambulatory systolic (-3.10 mmHg, 95% CI -4.22, -1.97, p<0.00001) and office systolic (-5.15 mmHg, 95% CI -6.65, -3.66, p<0.00001) BP and ambulatory diastolic (-1.58 mmHg, 95% CI -2.54, -0.63, p=0.001) and office diastolic (-2.74 mmHg, 95% CI -3.65, -1.83, p<0.00001) BP compared with sham groups. There was no difference concerning ambulatory SBP reduction between trials with ON medication design (-2.94 mmHg, p<0.0001) and those with OFF medication design (-3.37 mmHg, p<0.0001) (p for interaction 0.69). Similarly, office SBP reduction was comparable between trials with (-4.38 mmHg, p<0.0001) and without concomitant antihypertensive drugs prescription (-6.27 mmHg, p<0.00001) (p for interaction 0.22). The rate of vascular complications (OR 1.21, 95% CI 0.28, 5.25, p=0.80), renal artery stenosis (OR 1.50, 95% CI 0.06, 36.97, p=0.80), hypertensive crisis (OR 1.39, 95% CI 0.50, 3.92, p=0.53) and all cause death (OR 0.52, 95% CI 0.10, 2.83, p=0.45) was not different between treatment and sham groups. Conclusions RDN is associated with clinically significant reductions in ambulatory and office SBP as compared with sham in the presence and absence of antihypertensive medication. The procedure use was not associated with an excess in safety events compared with sham group.

Italian Society of Interventional Cardiology (GISE) and Italian Society of Arterial Hypertension (SIIA) Consensus document on the role of renal denervation in the management of the difficult to treat hypertension

Arterial hypertension is the most prevalent cardiovascular risk factor worldwide. Despite the availability of many and effective antihypertensive medications, the prevalence of uncontrolled blood pressure (BP) remains high. As sympathetic hyperactivity has long been recognized as a major contributor to resistant hypertension, catheter-based renal denervation (RDN) has emerged as a new strategy to reduce BP. RDN aims to interrupt the activity of renal sympathetic nerves by applying radiofrequency (RF) energy, ultrasound (US) energy, or injection of alcohol in the perivascular space. The Symplicity HTN-3 trial, the largest sham-controlled trial using the first-generation RF-based RDN device, failed to significantly reduce BP. Since then, new devices and techniques have been developed and consequently many sham-controlled trials using second-generation RF or US-based RDN devices have demonstrated the BP lowering efficacy and safety of the procedure. A multidisciplinary team involving hypertension experts, interventionalists with expertise in renal interventions and anesthesiologists, plays a pivotal role from the selection of the patient candidate for the procedure to the post-procedural care. The aim of this consensus document is to summarize the current evidence about the use of RDN in difficult to treat hypertension and to propose a management strategy from the selection of the patient candidate for the procedure to the post-procedural care.

Late outcomes of renal denervation are more favourable than early ones: facts or fancies?

Following second-generation randomized trials, there is evidence that renal denervation (RDN) decreases blood pressure (BP), although to a lesser extent than suggested in the initial controlled and observational studies. The recent publication of the 36-month follow-up of the Symplicity HTN-3 trial has raised expectations, suggesting increasing, late benefits of the procedure, despite initially negative results. These findings come after those obtained at 36months in the sham-controlled trial SPYRAL HTN-ON MED and in the Global Symplicity Registry. However, they are susceptible to biases inherent in observational studies (after unblinding for sham-control) and non-random, substantial attrition of treatment groups at 36 months, and used interpolation of missing BPs. More importantly, in SPYRAL HTN-ON MED and Symplicity HTN-3, long-term BP changes in patients from the initial RDN group were compared with those in a heterogeneous control group, including both control patients who did not benefit from RDN and patients who eventually crossed over to RDN. In crossover patients, the last BP before RDN was imputed to subsequent follow-up. In Symplicity HTN-3, this particular approach led to the claim of increasing long-term benefits of RDN. However, comparison of BP changes in patients from the RDN group and control patients who did not undergo RDN, without imputation of BPs from crossover patients, does not support this view. The good news is that despite the suggestion of sympathetic nerve regrowth after RDN in some animal models, there is no strong signal in favour of a decreasing effect of RDN over time, up to 24 or even 36months. Still, current data do not support a long-term increase in the effect of RDN and the durability of RDN-related BP reduction remains to be formally demonstrated.

SYMPLICITY HTN-3: failure at 6 months, success at 3 years?

In The Lancet, Deepak L Bhatt and colleagues report long-term outcomes of renal artery denervation in patients denervated by single-electrode radiofrequency within the SYMPLICITY HTN-3 study. 1 Bhatt DL Vaduganathan M Kandzari DE et al. Long-term outcomes after catheter-based renal artery denervation for resistant hypertension: final follow-up of the randomised SYMPLICITY HTN-3 Trial. Lancet. 2022; (published online Sept 18.)https://doi.org/10.1016/S0140-6736(22)01787-1 Summary Full Text Full Text PDF Scopus (2) Google Scholar This large sham-controlled trial recruited 535 patients (210 [39%] women and 325 [61%] men; mean age in renal denervation group 57·9 years [SD 10·4]) with treatment-resistant hypertension enrolled in 88 centres in the USA. The trial was expected to provide definitive evidence of the efficacy of renal denervation in patients with treatment-resistant hypertension but did not meet its primary 6-month efficacy endpoint, 2 Bhatt DL Kandzari DE O'Neill WW et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014; 370: 1393-1401 Crossref PubMed Scopus (1592) Google Scholar raising an unprecedented wave of scepticism about renal denervation. 3 Persu A Jin Y Fadl Elmula FE Jacobs L Renkin J Kjeldsen S Renal denervation after Symplicity HTN-3: an update. Curr Hypertens Rep. 2014; 16: 460 Crossref PubMed Scopus (29) Google Scholar Long-term outcomes after catheter-based renal artery denervation for resistant hypertension: final follow-up of the randomised SYMPLICITY HTN-3 TrialThis final report of the SYMPLICITY HTN-3 trial adds to the totality of evidence supporting the safety of renal artery denervation to 36 months after the procedure. From 12 months to 36 months after the procedure, patients who were originally randomly assigned to receive renal artery denervation had larger reductions in blood pressure and better blood pressure control compared with patients who received sham control. Full-Text PDF

Long-term outcomes after catheter-based renal artery denervation for resistant hypertension: final follow-up of the randomised SYMPLICITY HTN-3 Trial

The SYMPLICITY HTN-3 (Renal Denervation in Patients With Uncontrolled Hypertension) trial showed the safety but not efficacy of the Symplicity system (Medtronic, Santa Rosa, CA, USA) at 6 months follow-up in patients with treatment-resistant hypertension. This final report presents the 36-month follow-up results. SYMPLICITY HTN-3 was a single-blind, multicentre, sham-controlled, randomised clinical trial, done in 88 centres in the USA. Adults aged 18-80 years, with treatment-resistant hypertension on stable, maximally tolerated doses of three or more drugs including a diuretic, who had a seated office systolic blood pressure of 160 mm Hg or more and 24 h ambulatory systolic blood pressure of 135 mm Hg or more were randomly assigned (2:1) to receive renal artery denervation using the single electrode (Flex) catheter or a sham control. The original primary endpoint was the change in office systolic blood pressure from baseline to 6 months for the renal artery denervation group compared with the sham control group. Patients were unmasked after the primary endpoint assessment at 6 months, at which point eligible patients in the sham control group who met the inclusion criteria (office blood pressure ≥160 mm Hg, 24 h ambulatory systolic blood pressure ≥135 mm Hg, and still prescribed three or more antihypertensive medications) could cross over to receive renal artery denervation. Changes in blood pressure up to 36 months were analysed in patients in the original renal artery denervation group and sham control group, including those who underwent renal artery denervation after 6 months (crossover group) and those who did not (non-crossover group). For comparisons between the renal artery denervation and sham control groups, follow-up blood pressure values were imputed for patients in the crossover group using their most recent pre-crossover masked blood pressure value. We report long-term blood pressure changes in renal artery denervation and sham control groups, and investigate blood pressure control in both groups using time in therapeutic blood pressure range analysis. The primary safety endpoint was the incidence of all-cause mortality, end stage renal disease, significant embolic event, renal artery perforation or dissection requiring intervention, vascular complications, hospitalisation for hypertensive crisis unrelated to non-adherence to medications, or new renal artery stenosis of more than 70% within 6 months. The trial is registered with ClinicalTrials.gov, NCT01418261. From Sep 29, 2011, to May 6, 2013, 1442 patients were screened, of whom 535 (37%; 210 [39%] women and 325 [61%] men; mean age 57·9 years [SD 10·7]) were randomly assigned: 364 (68%) patients received renal artery denervation (mean age 57·9 years [10·4]) and 171 (32%) received the sham control (mean age 56·2 years [11·2]). 36-month follow-up data were available for 219 patients (original renal artery denervation group), 63 patients (crossover group), and 33 patients (non-crossover group). At 36 months, the change in office systolic blood pressure was -26·4 mm Hg (SD 25·9) in the renal artery denervation group and -5·7 mm Hg (24·4) in the sham control group (adjusted treatment difference -22·1 mm Hg [95% CI -27·2 to -17·0]; p≤0·0001). The change in 24 h ambulatory systolic blood pressure at 36 months was -15·6 mm Hg (SD 20·8) in the renal artery denervation group and -0·3 mm Hg (15·1) in the sham control group (adjusted treatment difference -16·5 mm Hg [95% CI -20·5 to -12·5]; p≤0·0001). Without imputation, the renal artery denervation group spent a significantly longer time in therapeutic blood pressure range (ie, better blood pressure control) than patients in the sham control group (18% [SD 25·0] for the renal artery denervation group vs 9% [SD 18·8] for the sham control group; p≤0·0001) despite a similar medication burden, with consistent and significant results with imputation. Rates of adverse events were similar across treatment groups, with no evidence of late-emerging complications from renal artery denervation. The rate of the composite safety endpoint to 48 months, including all-cause death, new-onset end-stage renal disease, significant embolic event resulting in end-organ damage, vascular complication, renal artery re-intervention, and hypertensive emergency was 15% (54 of 352 patients) for the renal artery denervation group, 14% (13 of 96 patients) for the crossover group, and 14% (10 of 69 patients) for the non-crossover group. This final report of the SYMPLICITY HTN-3 trial adds to the totality of evidence supporting the safety of renal artery denervation to 36 months after the procedure. From 12 months to 36 months after the procedure, patients who were originally randomly assigned to receive renal artery denervation had larger reductions in blood pressure and better blood pressure control compared with patients who received sham control. Medtronic.

Renal denervation in resistant hypertension: a review of clinical trials and future perspectives.

A previous report using the National Health and Nutrition Examination Survey demonstrated an increase in the prevalence of resistant hypertension, which does not respond to traditional therapy and medication. Studies using various animal hypertensive models have demonstrated significant blood pressure (BP) reduction following renal artery denervation (RDN). Catheter-based RDN became available in clinical trials as a possible treatment option for resistant hypertension. Although first clinical trials of RDN have demonstrated the efficacy and safety of this treatment mortality for lowering BP in patients with resistant hypertension, the role of RDN has been questioned since the results of the Symplicity HTN-3 trial. Considering the ethnic differences demonstrated in the Symplicity HTN-Japan and Global Symplicity registry, by contrast, RDN might be an effective for resistant hypertension in Asian population. Here, we discuss RDN applications and technology, the old and new clinical evidence of RDN, patients' selection of RDN responder, and optimization of RDN procedure in this review. The available evidence demonstrates that RDN could be effective in carefully selected patients with resistant hypertension, paving the way for future research in this area.

Role of renal denervation in the treatment of arterial hypertension: a review

Regardless of the fact that arterial hypertension is the focus of modern cardiology, resistance to therapy is still an important public health problem with adverse medical, social, and economic consequences. Aim of study: systematizing the available results of studies of the effectiveness of renal denervation in the treatment of patients with resistant AH. Search within databases (PubMed, Cochrane Library) was performed for randomized controlled studies of second-generation catheterassisted renal denervation and sham-controlled studies. We have used PRISMA protocol for preparing our paper. The neutral results of the SYMPLICITY HTN-3 study significantly weakened the interest of practical cardiology in this procedure, however recently published data from the EnligHTNed IDE, SPYRAL HTN OFF MED, and SPYRAL HTN-ON MED studies confirmed the effectiveness and safety of the technique. As the result the second-generation catheters (multielectrode catheters) used for renal denervation confirmed the effectiveness and safety of the procedure, and also expanded the technique usage beyond resistant hypertension. However, the question of the reliability of long-term effects of the procedure still remains, as well as establishing mechanisms to identify predictors of planned intervention responsiveness.

Renal arteries denervation: from the treatment of resistant hypertension to the treatment of atrial fibrillation.

Renal denervation (RDN) is a therapeutic strategy for patients with uncontrolled arterial hypertension characterized by considerable fluctuations during its progression. After initial strong enthusiasm, the procedure came to an abrupt halt following the publication of the Symplicity HTN-3 study results. The results of recently published studies highlight the reduction in blood pressure values after RDN and justify the inclusion in the Guidelines of new recommendations for the use of RDN in clinical practice, in selected patients. Additionally, RDN findings are summarized in view of other potential indications such as atrial fibrillation. Six prospective, randomized studies are presented that evaluated RDN as an adjunct therapy to pulmonary vein isolation for the treatment of atrial fibrillation. In five studies, patients had uncontrolled hypertension despite therapy with three antihypertensive drugs. The analysis of these studies showed that RDN reduced the recurrence of atrial fibrillation (AF) by 57% compared to patients with pulmonary vein isolation (PVI) only. Modulation of the autonomic nervous system by RDN has been shown not only to reduce blood pressure but also to have an antiarrhythmic effect in symptomatic AF patients when the strategy is combined with PVI, thus opening up new therapeutic scenarios.

Current Status and Future Perspectives of Renal Denervation.

Catheter-based renal denervation (RDN) therapy, a new procedure that uses radiofrequency ablation to interrupt efferent and afferent renal sympathetic nerve fibers, is a complementary or alternative treatment to antihypertensive medications for optimal control of blood pressure (BP). Although several single-arm early proof-of-concept studies showed significant BP reduction, the largest sham-controlled study using the first-generation RDN device (SYMPLICITY HTN-3) failed to significantly reduce BP in patients with resistant hypertension who were taking the guideline-based combination of antihypertensive medications. Since then, new devices and techniques have been developed to improve the efficacy and safety of RDN procedures. Sham-controlled trials using second-generation RDN devices (radiofrequency- and ultrasound-based) have provided solid evidence for their BP-lowering efficacy with and without the use of concomitant antihypertensive medication. Moreover, the safety profile of RDN in several registries and clinical trials appears to be excellent. This review summarizes the current evidence for RDN and discusses its current issues, future trials, Asian perspectives, and potential roles in both hypertension and other morbidities.

Renal denervation: a new life of the technology

Renal denervation (RDN) is a method of the sympathetic nervous system modulation which has been specifically developed for the treatment of resistant hypertension. Initial reports demonstrating high efficiency of RDN in such patients propelled the development of the technology, yet a specific randomised controlled trial Symplicity HTN-3 did not show its benefits. Data from the subsequent RCTs SPYRAL HTN-OFF MED and SPYRAL HTN-ON MED have shown that RDN reduces both office and daily blood pressure, does not depend on the patient adherence, and is efficient in patients with uncontrolled hypertension even in the absence of drug therapy. This review summarises the data on the efficacy and safety of the technology, its organoprotective effects, and also discusses the benefits of the RDN in different patient groups.

A Systematic Review of Randomized Controlled Trials Comparing Renal Sympathetic Denervation Versus Sham Procedure for the Management of Uncontrolled Hypertension.

The efficacy of renal sympathetic denervation (RSD) in the treatment of uncontrolled hypertension (HTN) remains uncertain. A systematic review of randomized controlled trials was performed to evaluate the efficacy and safety of RSD for resistant HTN. PubMed, EMBASE, MEDLINE, Cochrane, Directory of Open Access Journals, CINAHL, and Google Scholar were searched from January 01, 2001, through July 30, 2020. Randomized controlled trials comparing RSD with the sham procedure for uncontrolled HTN were selected. The primary efficacy outcome was the reduction in ambulatory systolic blood pressure. We used random-effects models. Nine prospective clinical trials met the inclusion criteria. The ReSet and Symplicity HTN-3 Trial showed no significant changes because of discrepancies in complete circumferential ablation during RSD. The Relief study, The Radiance HTN solo, and the SPYRAL HTN OFF medical trials showed a significant reduction in systolic blood pressure in the group that had undergone the intervention compared with the sham group attributed to rigorous trial design. In conclusion, our systematic review suggests that efficacy of RSD seems to be superior to sham-controlled interventions provided circumferential denervation is performed. However, difference in efficacy is marginal.

Renal denervation – not an easy road to treatment of arterial hypertension and concomitant diseases

Percutaneous renal denervation (RDN) has been introduced in clinical trials as the possible interventional method of treatment of resistant hypertension more than one decade ago. The results of trials: SYMPLICITY HTN-1 (single-arm), HTN-2 (randomized, single-blinded) and HTN-3 (with sham procedure) are summarized in this article. The author presents the results of second-generation trials with new technologies: Spyral catheter (radiofrequency RDN) and Paradise system (ultrasound RDN). The favorable results of these studies justify the revision of the current recommendations, limiting this method only to clinical trials. Also the studies on RDN applied in atrial fibrillation and obstructive sleep apnea – diseases related to sympathetic nervous system activity – are discussed.

New opportunities of renal denervation

Radiofrequency renal artery denervation (RND) was introduced as a method of interventional treatment of resistant hypertension almost ten years ago. The first studies demonstrated the effectiveness of this procedure. This has led to growing interest in this area and the rapid development of the method. However, the results of the first randomized trial of SYMPLICITY HTN-3 questioned the role of RND in the treatment of resistant hypertension, this fact conducted to the decrease in the recommendation class and level of evidence in the Guidelines of the European Society of Cardiology and the European Society of Hypertension in 2018. To date, the medical community is actively discussing the results of recently published trials such as SPYRAL HTN-OFF MED, SPYRAL HTN-ON MED, RADIANCE-HTN SOLO and RADIOSOUND-HTN.

Recent advances in understanding and managing resistant/refractory hypertension.

The management of resistant hypertension presents several challenges in everyday clinical practice. During the past few years, several studies have been performed to identify efficient and safe pharmacological and non-pharmacological options for the management of such patients. The Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2) trial demonstrated significant benefits with the use of spinorolactone as a fourth-line drug for the treatment of resistant hypertension over doxazosin and bisoprolol. In addition, recent data support that spironolactone may demonstrate superiority over central acting drugs in such patients, as well. Based on the European guidelines, spironolactone is recommended as the fourth-line drug option, followed by amiloride, other diuretics, doxazosin, bisoprolol or clonidine. Among several device-based approaches, renal sympathetic denervation had fallen into hibernation after the disappointing results of the Renal Denervation in Patients With Uncontrolled Hypertension (SYMPLICITY HTN) 3 trial. However, the technique re-emerged at the epicenter of the clinical and research interest after the favorable results of three sham-controlled studies, which facilitated novel catheters and techniques to perform the denervation. Significant results of iliac anastomosis on blood pressure levels have also been demonstrated. Nevertheless, the technique-related adverse events resulted in withdrawal of this interventional approach. Last, the sympatholytic properties of the carotid baroreceptor activation therapy were associated with significant blood pressure reductions in patients with resistant hypertension, which need to be verified in larger controlled trials. Currently device-based approaches are recommended only in the setting of clinical trials until more safety and efficacy data become available.