SYMPLICITY HTN-3 Research Articles

Renal Denervation: Past, Present, and Future

Hypertension remains a leading cause of cardiovascular morbidity and mortality worldwide. It is estimated that 12.8% of hypertensive adults have resistant hypertension. The sympathetic nervous system is a well-known contributor to the pathophysiology of resistant hypertension. Renal denervation has emerged as an effective procedure to treat resistant hypertension by blocking the sympathetic nervous system. The medical device industry has developed various catheters in an effort to achieve better denervation in the absence of available testing to document adequate denervation. By adding a sham control group to the study design, researchers found that the results of the Renal Denervation in Patients With Uncontrolled Hypertension study (SYMPLICITY HTN-3) showed that renal denervation was not superior to placebo in decreasing systolic blood pressure. Although SYMPLICITY HTN-3 successfully addressed many issues that might have biased the previously published data, incomplete denervation caused by limited operator experience, catheter design, and the radiofrequency ablation technology may have accounted for the discrepancy of the results. This, along with differences in the study design and population, should direct future renal denervation studies. This article reviews the available literature and proposes future directions for renal denervation studies. It also provides a detailed comparison of the available catheters and their respective clinical data.

4A.10

Objective:To study the impact of catheter-based renal artery denervation (RDN) on change in morning and night systolic BP (SBP) defined by ambulatory BP measurements (ABPM) 6 months post-randomization.Design and method:SYMPLICITY HTN-3 and SYMPLICITY HTN-Japan are prospective, randomized, controlled

PP.26.28

Objective: Treatment resistant hypertension is a challenge for the physician and represents a substantial cardiovascular risk for patients. While many patients are referred to specialists for resistant hypertension, the true resistant subjects are hard to find. We aimed to report the reasons for noneligibility in the Oslo Renal Denervation (RDN)Study following directly observed therapy (DOT) of antihypertensive drugs prior to ambulatory blood pressure monitoring (ABPM). Design and method: Patients with apparent resistant hypertension (n = 83), supposed to fulfill the inclusion/exclusion criteria, which were similar, but not identical with the SYMPLICITY HTN-2 criteria, were referred for renal denervation. All patients went through a throrough clinical and laboratory work-up including screening for renovascular hypertension, renal disease, primary hyperaldosteronism, Cushing's syndrome and pheochromocytoma. Nonadherence to antihypertensive drugs and white coat hypertension were controlled for by directly observed therapy followed by ABPM. Results: The proportion of patients being noneligible for renal denervation according to our inclusion/exclusion criteria was 69.9 %. The main reasons for noneligibility were normalization of blood pressure following witnessed intake of antihypertensive drugs (DOT) (43.0 %). Those with high office blood pressure in our clinic, but without prior ABPM from their referring physician, who had normal ABPM after DOT, were labeled white coat hypertensives. However, the possibility of nonadherence even among these subjects cannot be ruled out.Conclusions: True treatment resistant hypertension is rare. Secondary and spurious hypertension can be revealed and treated when medical evaluation of the patients is done thoroughly and according to guidelines by hypertension specialists. Nonadherence seems to be the most common reason for uncontrolled hypertension and may be revealed by directly observed therapy (DOT) followed by ambulatory blood pressure.

8B.05

Objective: Actual procedure of renal denervation (RD) in Symplicity HTN-3 study - 4–6 point ablations equally distributed along the length and circumference of main trunk of renal artery (RA) - may only be effective if renal nerves are likewise equally distributed along and around the RA strictly following its course. However, a number of surgical studies demonstrated that renal nerves form a fan-shaped triangle plexus converging toward hilum, i.e. proximally the nerves go at a distance from RA obliquely to its course and join it in the middle/distal portion so that number of fibers available for endovascular ablation is small in proximal portion of RA but rises to maximum in its distal part. To evaluate whether ablation of sympathetic nerves in distal part of RA is more effective than conventional RD treatment equally distributed in its main trunk. Design and method: We initiated randomized (1:1) controlled study in which we compare the modified operative technique (ablations performed in distal part and major branches of RA) with conventional RD in patients with resistant hypertension using Symplicity device. Results: At the time of this analysis 26 patients (13 treated by modified technique and 13 – by conventional RD) completed 6 months follow up. The only complication was 1 post-punctional pseudoaneurysm. Ambulatory BP decreased significantly in the group of modified technique: -21.3/-11.5 (SD 20.5/11.2) mmHg (mean 24-hr BP, systolic/diastolic respectively), p = 0.003/0.003 and only slightly in the group of standard RD: -6.2/-4.5 (SD 16.4/8.3) p = 0.19/0.07. The difference in the effects was statistically significant for mean 24-h systolic BP (p = 0.049) and close to significance for mean 24-h diastolic BP (p = 0.085). Office BP lowering did not differ significantly between groups: -25.3/-10.8 vs -22.1/-12.1 respectively. Conclusions: Radiofrequency denervation of distal part and segmental branches of renal artery based on the surgical findings of distal convergence of renal nerves seems to be significantly more effective than existed mode of RD presuming equal nerve availability along the artery. This may indicate anatomical inadequacy of the existed mode of RD explaining its failure in Symplicity HTN-3 trial.

Influence of pseudo-resistance on the effect of renal denervation on 24-hour ambulatory blood pressure levels.

Renal denervation (RDN) is a promising treatment option in addition to medical antihypertensive treatment in patients suffering from resistant hypertension. Despite the growing interest in RDN, the negative result of the Symplicity HTN-3 trial led to a debate on the efficacy of RDN. We systematically investigated the effects of RDN, evaluated by 24-hr ambulatory blood pressure measurements (ABPM), in a consecutive series of patients with resistant hypertension, which was defined by a mean office systolic blood pressure (SBP) >160 mm Hg (>150 mm Hg in patients with diabetes). Patients with a mean 24-hr SBP of less than 130 mm Hg at baseline were classified as pseudo-resistant, while all other patients were classified as true-resistant. After six months, we analyzed the response rates in true-resistant and in pseudo-resistant patients, respectively, by the means of 24-hr ABPM. Thereby, patients with a reduction of more than 5 mm Hg in 24-hr SBP were classified as responders. RDN was performed in 106 patients. By 24-hr ABPM, 20 patients (18.9%) were classified as pseudo-resistant patients. In this cohort, we only found two responders (response rate 10%) six months after RDN. By contrast, in true-resistant patients, the response rate was almost 60% and the mean BP reduction was -18.6/-9 mm Hg in 24-hr ABPM. We found a significant BP reduction in almost 60% of patients with true-resistant hypertension, but only in 10% in patients with pseudo-resistant hypertension. According to our results, patient selection seems to be crucial for acceptable response rates after RDN.

Renal denervation--hypes and hopes.

Catheter-based renal denervation (RDN) is a novel invasive approach in the treatment of resistant hypertension. It is considered a minimally invasive and safe procedure which, as shown by initial experimental and clinical trials, is able not only to reduce blood pressure but also to modify its risk factors by modulation of autonomic nervous system. Recently published results of a randomized Symplicity HTN-3 trial, which failed to demonstrate RDN-induced reduction of blood pressure at six months, decreased the initial enthusiasm regarding RDN and raised a question about real efficacy of this procedure. Nevertheless, still there are some other conditions characterized by increased sympathetic tone such as heart failure, atrial fibrillation, or ventricular arrhythmias that may benefit from RDN. Furthermore, novel therapeutical approach toward RDN using adapted electrophysiological or new specially designed electrodes may improve effectiveness of RDN procedure.

Different responses of arterial blood pressure to electrical stimulation of the renal artery in patients with resistant hypertension

SIMPLICITY-HTN 3 revealed several limitations of renal denervation (RDN) for the treatment of resistant hypertension [ [1] Bhatt D.L. Kandzari D.E. O'Neill W.W. D'Agostino R. Flack J.M. Katzen B.T. Leon M.B. Liu M. Mauri L. Negoita M. Cohen S.A. Oparil S. Rocha-Singh K. Townsend R.R. Bakris G.L. SYMPLICITY HTN-3 Investigators: a controlled trial of renal denervation for resistant hypertension. N. Engl. J. Med. 2014; 370: 1393-1401 Crossref PubMed Scopus (1566) Google Scholar ]. One of the main limitations is that the current RDN technique lacks a measurable endpoint. Recently, electrical stimulation of the renal nerves through the ablation catheter introduced in the renal artery before and after RDN was proposed as a promising method in this journal [ 2 Hilbert S. Kosiuk J. Hindricks G. Bollmann A. Blood pressure and autonomic responses to electrical stimulation of the renal arterial nerves before and after ablation of the renal artery. Int. J. Cardiol. 2014; 177: 669-671 Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar , 3 Hao Y. Lu Z. Renal denervation: should we still hang in there?. Int. J. Cardiol. 2014; 176: 1255-1256 Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar ]. These reports showed that the effect of intra-renal artery electrical stimulation on renal nerves, especially the afferent sensory nerve, before and after ablation, was useful as RDN endpoint. However, the afferent sensory nerve on the lateral side of renal artery might include not only afferent excitatory sympathetic nerve fibers but also inhibitory sympathetic nerve fibers [ [4] Stella A. Weaver L. Golin R. Genovesi S. Zanchetti A. Cardiovascular effects of afferent renal nerve stimulation. Clin. Exp. Hypertens. A. 1987; 9: 97-111 Crossref PubMed Scopus (12) Google Scholar ]. In this report, we present two patients with resistant hypertension who showed opposite arterial blood pressure responses to electrical stimulation before and after RDN.

12-Month Blood Pressure Results of Catheter-Based Renal Artery Denervation for Resistant Hypertension: The SYMPLICITY HTN-3 Trial

BackgroundResults of the SYMPLICITY HTN-3 (Renal Denervation in Patients With Uncontrolled Hypertension) trial confirmed the safety but not the efficacy of renal denervation for treatment-resistant hypertension at 6 months post procedure. ObjectivesThis study sought to analyze the 12-month SYMPLICITY HTN-3 results for the original denervation group, the sham subjects who underwent denervation after the 6-month endpoint (crossover group), and the sham subjects who did not undergo denervation after 6 months (non-crossover group). MethodsEligible subjects were randomized 2:1 to denervation or sham procedure. Subjects were unblinded to their treatment group after the 6-month primary endpoint was ascertained; subjects in the sham group meeting eligibility requirements could undergo denervation. Change in blood pressure (BP) at 12 months post randomization (6 months for crossover subjects) was analyzed. ResultsThe 12-month follow-up was available for 319 of 361 denervation subjects and 48 of 101 non-crossover subjects; 6-month denervation follow-up was available for 93 of 101 crossover subjects. In denervation subjects, the 12-month office systolic BP (SBP) change was greater than that observed at 6 months (−15.5 ± 24.1 mm Hg vs. −18.9 ± 25.4 mm Hg, respectively; p = 0.025), but the 24-h SBP change was not significantly different at 12 months (p = 0.229). The non-crossover group office SBP decreased by −32.9 ± 28.1 mm Hg at 6 months, but this response regressed to −21.4 ± 19.9 mm Hg (p = 0.01) at 12 months, increasing to 11.5 ± 29.8 mm Hg. ConclusionsThese data support no further reduction in office or ambulatory BP after 1-year follow-up. Loss of BP reduction in the non-crossover group may reflect decreased medication adherence or other related factors. (Renal Denervation in Patients With Uncontrolled Hypertension [SYMPLICITY HTN-3]; NCT01418261)

Hypertension: Renal denervation-promising data from the DENERHTN trial.

In patients with resistant hypertension, renal denervation plus standardized stepped-care antihypertensive treatment (SSAHT) resulted in significant blood-pressure lowering compared with SSAHT alone. These new data from the DENERHTN trial may indicate that despite the failure of SYMPLICITY HTN-3, there is light at the end of the tunnel for renal denervation.

Renal denervation in refractory hypertension: joint statement of the German hypertension league DHL eV and the German societies of cardiology, angiology, nephrology and radiology

Arterial hypertension is a major risk factor for cardiovascular mortality and remains insufficiently controlled in Germany. The sham controlled Symplicity HTN-3 trial did meet its primary safety endpoint but failed to meet its primary efficacy endpoint. Renal denervation can not replace established, well-proven therapies. It can only be used in selected truly resistant hypertensive patients as an additive approach and should be performed by specialized centers only. Randomized controlled trials are needed to further evaluate renal denervation.

Cardiorenal syndrome in chronic kidney disease.

The purpose of this study is to review current perspectives regarding the pathogenesis of cardiorenal syndrome (CRS) in chronic kidney disease (CKD), and current treatment guidelines for this condition. The pathophysiological mechanisms underlying the development of CRS in CKD include neurohumoral, haemodynamic and CKD-related mechanisms. Recent evidence suggests that sympathetic nerve activity plays a role in CRS, but the SYMPLICITY HTN-3 trial failed to show a reduction of blood pressure after catheter-based renal denervation in patients with resistant hypertension. Kidney injury in patients with heart failure was previously considered to result from arterial underfilling due to low cardiac output, but the role of renal venous hypertension in this process has also recently been investigated. It would be useful to develop a reliable treatment option for CRS due to haemodynamic mechanism other than volume control using diuretics. Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone that has recently been identified as a CKD-related factor affecting CRS. FGF23 treatment has both advantages and disadvantages in terms of CRS progression. Multiple disorders underlie the development of CRS. Current treatment options include renin-angiotensin system blockade and volume control, but remain limited. A multidisciplinary approach is required to prevent CRS, including renal sympathetic denervation, treatment of renal venous hypertension and FGF23 treatment.

Renal denervation for severe hypertension: Past, present and future

The seven-year anniversary of the first catheter-based renal denervation procedure for resistant hypertension nears. At the “end of the beginning”, it is timely to reflect on the next phase in the development and clinical application of renal denervation in hypertension treatment. Unresolved procedural and technical questions are central: how much renal denervation is optimal; is unilateral denervation, now commonly used, beneficial; will renal denervation show a “class effect”, with the different energy forms now used for renal nerve ablation producing equivalent blood pressure lowering? The Achilles heel in catheter-based studies of renal denervation for severe hypertension is the almost universal failure to apply a confirmatory test for renal denervation. When I have assessed renal denervation efficacy, using measurements of the spillover of norepinephrine from the renal sympathetic nerves to plasma, the only test validated to this point, denervation was found to be incomplete and non-uniform between patients. It is probable that the degree of denervation has typically been sub-optimal in renal denervation trials. This criticism applies with special force to the Symplicity HTN-3 trial, where the proceduralists, although expert interventional cardiologists, had no prior experience with the renal denervation technique. Their learning curve fell during the trial, a shortcoming accentuated by the fact that one third of operators performed one procedure only. Recently presented results from the Symplicity HTN-3 trialists confirms that renal denervation was not effectively or consistently achieved in the trial.

Position paper on the results of Symplicity HTN-3 trial. Grupo de estudio de la hipertensión arterial resistente

Renal artery denervation has shown to be an effective treatment for resistant hypertension. Symplicity HTN 1 and 2 trials showed in small and uncontrolled groups, significant systolic blood pressure reductions down to 30 mm Hg. Symplicity HTN-3, a double blind, randomized, placebo controlled clinical trial shaded this initial enthusiasm. Surprisingly, their results showed that renal denervation has a similar effect to placebo. Pre-specified subgroup analysis showed that non-black race individuals, younger than 65 years and with normal renal function, had a statistically significant systolic blood pressure decrease. This manuscript critically appraises the Symplicity HTN-3 trial, proposing possible explanations for the results. Also declares our group position and future actions regarding renal denervation.

An update of the expert consensus statement of the Czech Hypertension Society on renal denervation in resistant hypertension

In the spring of 2012, the Czech Society of Cardiology and Czech Hypertension Society issued a joint expert consensus statement on catheter-based renal denervation (RDN) in the Czech Republic. On the basis of new information from the Symplicity HTN-3, PRAGUE-15 and other studies, there is no reason to introduce RDN into clinical practice. New modalities for RDN, such as radiofrequency ablation, are investigated.

Renal sympathetic denervation after Symplicity HTN-3 and therapeutic drug monitoring in severe hypertension.

Renal sympathetic denervation (RDN) has been and is still proposed as a new treatment modality in patients with apparently treatment resistant hypertension (TRH), a condition defined as persistent blood pressure elevation despite prescription of at least 3 antihypertensive drugs including a diuretic. However, the large fall in blood pressure after RDN reported in the first randomized study, Symplicity HTN-2 and multiple observational studies has not been confirmed in five subsequent prospective randomized studies and may be largely explained by non-specific effects such as improvement of drug adherence in initially poorly adherent patients (the Hawthorne effect), placebo effect and regression to the mean. The overall blood-pressure lowering effect of RDN seems rather limited and the characteristics of true responders are largely unknown. Accordingly, RDN is not ready for clinical practice. In most patients with apparently TRH, drug monitoring and improvement of drug adherence may prove more effective and cost-beneficial to achieve blood pressure control. In the meantime, research should aim at identifying characteristics of those patients with truly TRH who may respond to RDN.

Reinnervation following catheter-based radio-frequency renal denervation.

What is the topic of this review? Does catheter-based renal denervation effectively denervate the afferent and efferent renal nerves and does reinnervation occur? What advances does it highlight? Following catheter-based renal denervation, the afferent and efferent responses to electrical stimulation were abolished, renal sympathetic nerve activity was absent, and levels of renal noradrenaline and immunohistochemistry for tyrosine hydroxylase and calcitonin gene-related peptide were significantly reduced. By 11months after renal denervation, both the functional responses and anatomical markers of afferent and efferent renal nerves had returned to normal, indicating reinnervation. Renal denervation reduces blood pressure in animals with experimental hypertension and, recently, catheter-based renal denervation was shown to cause a prolonged decrease in blood pressure in patients with resistant hypertension. The randomized, sham-controlled Symplicity HTN-3 trial failed to meet its primary efficacy end-point, but there is evidence that renal denervation was incomplete in many patients. Currently, there is little information regarding the effectiveness of catheter-based renal denervation and the extent of reinnervation. We assessed the effectiveness of renal nerve denervation with the Symplicity Flex catheter and the functional and anatomical reinnervation at 5.5 and 11months postdenervation. In anaesthetized, non-denervated sheep, there was a high level of renal sympathetic nerve activity, and electrical stimulation of the renal nerve increased blood pressure and reduced heart rate (afferent response) and caused renal vasoconstriction and reduced renal blood flow (efferent response). Immediately after renal denervation, renal sympathetic nerve activity and the responses to electrical stimulation were absent, indicating effective denervation. By 11months after denervation, renal sympathetic nerve activity was present and the responses to electrical stimulation were normal, indicating reinnervation. Anatomical measures of renal innervation by sympathetic efferent nerves (tissue noradrenaline and tyrosine hydroxylase) and afferent sensory nerves (calcitonin gene-related peptide) demonstrated large decreases at 1week postdenervation, but normal levels at 11months postdenervation. In summary, catheter-based renal denervation is effective, but reinnervation occurs. Studies of central and renal changes postdenervation are required to understand the causes of the prolonged hypotensive response to catheter-based renal denervation in human hypertension.

Renal sympathetic denervation after Symplicity HTN-3 and therapeutic drug monitoring in patients with resistant hypertension to improve patients' adherence.

Renal sympathetic denervation (RDN) has been proposed as a new treatment modality in patients with apparent treatment-resistant hypertension (TRH), a condition defined as persistent blood pressure (BP) elevation despite prescription of at least three anti-hypertensive drugs including a diuretic. However, the large fall in BP reported after RDN in Symplicity HTN-2, the first randomized study, and in multiple observational studies has not been confirmed in five subsequent prospective randomized studies. The reduction in BP may be mostly due to non-specific effects, such as improvement of drug adherence in initially poorly adherent patients (the Hawthorne effect), placebo effect and regression to the mean. The overall BP lowering effect of RDN seems rather limited and the characteristics of the true responders remain largely unknown. Accordingly, RDN is not ready for clinical practice. In most patients with TRH, drug monitoring and subsequent improvement of drug adherence may prove more effective and cost-effective to achieve BP control. In the meantime, research should aim at identifying characteristics of those few patients adherent to drug treatment who has TRH and may respond to RDN.

Catheter-based Renal Denervation for Therapy of Hypertension: Is There a Hope for Its Resurgence?

Hypertension (HTN) is the most common chronic cardiovascular disease with increasing prevalence all over the world. Despite the availability of many effective antihypertensive drugs, blood pressure control to target values remains low. Resis tant hypertension is defined as ‘blood pressure above goal in adherent patients despite a triple antihypertensive therapy in maximum or maximum tolerated doses, inclu ding a diuretic, which is found in approximately 8 to 18% of all hyper tensives’. Treatment requires a multimodal therapy concept, including—polypharmacy, lifestyle modification and a systematic identification of secondary causes of HTN or pseudoresistance. Increased activity of the sympathetic nervous system has been identified as main contributor to the develop ment and maintenance of resistant HTN. Catheterbased renal dener vation has been introduced as a minimal invasive option for patients with resistant HTN. However, the clinical evidence in support of renal denervation as an effective inter ventional technique is conflicting. A number of observa tional studies and four randomized, controlled trials (Symplicity HTN-2, Prague 15, RSD-LEIPZIG and DENERHTN) support both safety and efficacy of this new therapy, but some smaller studies and the large, single-blind, randomized, sham-controlled Symplicity HTN-3 trial failed to show superiority of renal denervation when compared to medical therapy alone. The present review aims at providing an overview about catheter-based renal denervation for treatment of HTN.

Hypertension: The Points of Management of Hypertension for All Physicians--Based on the JSH 2014 Hypertension Guidelines--. Topics: X. Patients eligible for real denervation and PTRA--from the results of SYMPLICITY HTN-3 and CORAL trial

腎交感神経焼灼術（renal denervation：RDN）と経皮的腎血管形成術（percutaneous transluminal angioplasty：PTRA）は高血圧治療のデバイスを使った治療である．RDNについては，ヨーロッパを中心に盛んに行われているが，薬物治療と比較した試験で有用性が示されなかったため，現在，本邦での導入は進んでいない．PTRAも同様に，薬物治療と比較し有用性が示された試験はないが，現在，臨床現場では行われている治療である．重要なのは，両者とも適応をしっかり見極めることであり，究極の個別療法である．

Ealry experience of Renal artery denervation for resistant hypertension using a Multi-Electrode catheter

Introduction: SYMPLICITY HTN-3 trial did not show a significant reduction of BP in patients with resistant hypertension 6 months after renal artery denervation as compared with a sham control. Technical aspects of procedure could explain,in part,the negative findings of study e.g., the number and sites of delivery of energy are left to the operator's choice. Also, arterial wall contact was detectable only indirectly by a decrease in electric impedance, with the consequence that the success of the procedure may be operator-dependent. We present a case of renal denervation using a Multi-electrode catheter that resulted in a significant drop in BP in the1st month post procedure. Case Report: A 62-year-old man was referred with resistant hypertension. Medical history included IHD and T2DM. Treatment: Minoxidil 10mg BD; Amlodipine 10mg; Ramipril 10mg; Sotalol 160mg BD; Moxonidine 400mcg BD and frusemide 40mg. On examination, BP in left and right arm was 142/80 and 143/81mmHg respectively. Serial BP readings in the left arm were 143/87, 147/81 and 146/80mmHg. Secondary causes of HTN were excluded. Renal artery anatomy on CTA was suitable for denervation. Patient underwent renal denervation using the multi-electrode catheter. A total of 32 and 30 ablations were performed in the left and right renal system, respectively, within 25 minutes, as compared with 50-60minutes with 1st generation catheter. At one month, average BP was 135/73mmHg. Conclusion: Multi-electrode catheter provides a safe, effective and time-efficient method for renal artery denervation, which may overcome some of the technical difficulties associated with 1st generation catheter.