From SYMPLICITY HTN-3 to the Renal Denervation Global Registry: Where do we stand and where should we go?

Atul Pathak1*, MD; Sebastian Ewen2, MD; Jean Fajadet3, MD; Benjamin Honton3, MD; Felix Mahfoud2, MD; Jean Marco4, MD; Markus Schlaich5, MD; Roland Schmieder6, MD; Konstantinos Tsioufis7, MD; Christian Ukena2, MD; Thomas Zeller8, MD

1. Université de Toulouse Paul Sabatier, CHU de Toulouse, Service de Pharmacologie Clinique, Unité de Pharmacologie Cardiovasculaire et Autonome, INSERM 1048, Toulouse, France; 2. Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany; 3. Cardiovascular Unit of the Clinique Pasteur, Toulouse, France; 4. PCR, Toulouse, France; 5. Neurovascular Hypertension & Kidney Disease and Human Neurotransmitters Laboratories, Baker IDI Heart & Diabetes Institute and Faculty of Medicine, Nursing & Health Sciences, Monash University, Melbourne, Victoria, Australia; 6. University Hospital Erlangen, Nephrology and Hypertension, Erlangen, Germany; 7. First Cardiology Clinic, University of Athens, Hippokration Hospital, Athens, Greece; 8. Universitaets-Herzzentrum Freiburg – Bad Krozingen, Klinik für Kardiologie und Angiologie II, Bad Krozingen, Germany

We read with interest the paper by Bhatt et al1 published in the New  England Journal of Medicine. In summary, the blinded SYMPLICITY HTN-3 trial did not show a significant difference in the reduction of systolic blood pressure (BP) in patients with resistant hypertension six months after renal denervation (RDN) as compared with a sham control. The primary safety endpoint of the trial was met. Herein, we are aiming not  to discuss  the potential weaknesses of  the  trial and how these may have impacted on the results, but rather to address the question as to whether this trial is informative and what it can teach us, whether  it  should  impact on clinical decision making, how  the trial may help clinicians or investigators to enhance their knowledge about appropriate patient selection for RDN, and whether it may provide a glimpse into the future development of RDN.

What have we learned from patients phenotypes in this trial?

As  in  many  other  studies,  in  SYMPLICITY  HTN-3  one  has  to recognise  that  patients  with  true  resistant  hypertension  represent a  challenging  population. According  to  epidemiological  data,  the prevalence of resistant hypertension among patients with hypertension in industrialised countries is approximately 10%2,3. However, proper selection of patients with true resistant hypertension in RDN trials  has shown that  the  prevalence  might  be  even  lower  if  anatomical feasibility for RDN is taken into account4. Accordingly, the high  screening  failure  in SYMPLICITY HTN-3 is  not  surprising and indicates the strict inclusion and exclusion criteria, with strict protocols for up-titration of medication. Whether the investigated patient  population  represents  a  real-world  situation  or  whether  it is  rather  artificial  needs  to  be  discussed.  The  systematic  use  of 24-hour  ambulatory  BP  monitoring  (ABPM)  was  an  important design feature overcoming known limitations of office BP measurements alone. Unfortunately, thus far only the mean 24-hour ABPM data  have  been  presented  and  it  would  be  interesting  to  analyse other parameters of 24-hour ABPM. For example, almost 44% of patients were diabetic. These patients, when suffering from autonomic neuropathy, are known to display both orthostatic hypotension and also supine hypertension. Patients with obstructive sleep apnoea (OSA) syndrome usually present with nocturnal hypertension or non-dipper/reverse dipper phenotype and the prevalence of OSA amongst patients with resistant hypertension may be as high as 70%. Further, BP  variability  in  this  study  could be used as  an indirect measure to assess autonomic modulation and as a potential biomarker  predicting  response  to  RDN5. The  authors  should  be encouraged to  use  their ABPM data  to perform extensive  assessment of BP phenotype, which may have an impact on RDN results.

What have we learned about RDN and sympathetic modulation?

While the vast majority of patients considered for RDN will have high sympathetic activity, this may not be the case in all. Despite the use of sophisticated non-invasive or invasive techniques (norepinephrine  spillover,  muscle  sympathetic  nerve  activity,  heart rate  variability  [HRV],  plasmatic  or  urinary  metabolites  of  sympathetic  pathway),  no  definitive  study  has  yet  been  able  to  identify the right biomarker to detect and predict elevated sympathetic activity  or  the  optimal  candidate  for  RDN.  However,  two  recent studies  have  assessed  potential  biomarkers  for RDN. Zuern  et  al suggested that cardiac baroreflex sensitivity (BRS) may be a predictor  of  response  to RDN6. Dörr et  al found that RDN responders had significantly higher serum levels of sFLT-1, ICAM-1, and VCAM-1 compared to the non responders group7. In the subgroup analyses  of  SYMPLICITY  HTN-3,  Afro-Americans  (AA)  were shown to have low renin levels and one out of two had genetic polymorphisms in the beta-1 adrenergic receptor gene, which provides evidence for  the  differences in pathophysiology of hypertension8. From antihypertensive drug trials, it is well known that AA respond differently to antihypertensive drugs, e.g., ACE inhibitors and angiotensin  receptor  blockers  are  less  effective,  whereas  vasodilators are  quite  potent  in  lowering BP  in  this  population8.  Interestingly, in SYMPLICITY HTN-3 one quarter of the recruited patients were AA. A subgroup analysis revealed that AA had a substantially more pronounced  sham  response  compared  to  non-AA  (–17.8  mmHg versus –8.6 mmHg). In the RDN groups, AA and non-AA response was  almost  exactly  the  same.  Further  investigations  are  clearly needed to understand these results.

Are there some technical issues, or was renal denervation effective in this trial?

One reason why the trial could be neutral is that although the interventionists were experienced operators, the majority were unfamiliar with the specific RDN procedure. Looking at site experience, among 88 centres, 364 procedures have been performed by 111 operators, with 31% having performed only one procedure. As with any procedure, a  learning curve can be postulated and  the question arises as to whether this may have impacted on the degree of denervation achieved and, thereby, on BP results. The overall number of complete ablations was lower compared to other trials and the rate of notches following RDN was very low (60% had 0-1 notches). Additionally, further analysis of the results of different proctors would be interest-ing, to investigate whether there was a difference between operators who performed one or more than five procedures. Furthermore, there is no intraprocedural marker to confirm that RDN was successfully achieved in SYMPLICITY HTN-3. In SYMPLICITY HTN-19, a significant reduction in kidney norepinephrine spillover was measured in the first 10 patients to confirm a successful treatment; however, these patients were treated with a different catheter system and clearly the denervation achieved, on average a 47% reduction in renal noradrenaline spillover, is far from being complete. In most published RDN studies and even in those with limited BP lowering effects, heart rate significantly decreased after the procedure, partly BP independent. In SYMPLICITY HTN-3, heart rate remained unchanged in patients undergoing RDN, which might be a sign of unsuccessful RDN. The study underlines the need to develop biomarkers predicting response of effectiveness of the procedure. Finally, new technological developments and refinements (multi-electrode approach, stability of the device, other energy source such as ultrasound ablation or cryoablation) could help to improve the reproducibility with which substantial renal denervation can be achieved and thereby outcomes.

Is there a difference in effectiveness and safety when renal denervation is performed in realworld settings?

The Global SYMPLICITY Registry10  is  the  first and  largest dataset of patients treated with RDN. This open-label, multicentre study aimed to examine the safety and effectiveness of the procedure, and outcomes  presented  are  for  the  first  1,000  consecutively  enrolled patients  at  six months. There were  five  adverse  events  attributed to the procedure, including four vascular access-site complications (0.34%) and one renal artery dissection that was treated. There were also nine hospitalisations for hypertensive emergency (1.0%), eight for  atrial  fibrillation  (0.9%),  eight  strokes  (0.9%),  six hospitalisations for new onset heart failure (0.7%), five heart attacks (0.6%), four  deaths  (0.4%)  and  two  cases  of  new  onset  end-stage  kidney disease (0.2%) that were considered unrelated to the procedure. In addition to the favourable safety profile, office systolic BP showed a significant drop at six months of 11.9 mmHg for all patients and of 19.8 mmHg for patients with baseline office pressure values greater than or equal to 160 mmHg. Ambulatory systolic BP dropped significantly at six months (–7.9 mmHg for all patients with pressures 140 or higher compared to –9.2 mmHg for the subset of patients with BP greater than or equal to 160 mmHg). This data set confirms previously published data about the safety of the procedure and indicated that RDN lowers BP in that open-label real-world registry.

Is a sham procedure a clinically meaningful control arm?

A sham procedure controlled study is the purest scientific approach to evaluate a new invasive therapy. In drug studies, placebo is an established control arm which could even be used in daily practice to  replace  active  agents  if  being  found  equally  effective  to  true drugs. However, a sham procedure, as used in the SYMPLICITY HTN-3 study, cannot be used in  clinical  daily  practice because it would  be  unethical  to  expose  a  patient  to  general  anaesthesia  or sedation for simply performing a diagnostic renal angiogram. Even if RDN was not superior as compared to the sham procedure it did lower BP  significantly  in  resistant  hypertensive  patients  with  no treatment  alternative  left. Thus,  considering  the  potential  risks  of persistent resistant hypertension, one could argue that it would be unethical  to  withhold from a  patient  a proven BP-lowering treatment option which might prevent life-threatening complications of resistant hypertension, even if this treatment modality is not more effective than a sham procedure. Perhaps not dissimilar to the experience  with  baroreflex  activation  therapy,  it  will  be  important  to assess the longer-term BP effects of RDN vs. sham control with the possibility that any effect  in the sham arm may gradually vanish, whereas the BP-lowering effect of RDN may be sustained, as demonstrated in both SYMPLICITY HTN-1 and HTN-2.

Involvement of patients in future research projects?

RDN might represent a possibility for non-compliant patients or for patients  who  do  not  take  pills  (non-adherent,  non-persistent). Indeed,  Jung  et  al11  recently  reported  that  non-adherence  to  drug treatment  affects  up  to  50%  of  patients  with  difficult  to  control hypertension. Before we give the patient the choice, further studies in that interesting area are needed.

Renal denervation effects beyond blood pressure reduction?

There is growing evidence which is derived from animal and human studies  that  RDN might  exert multiple  pleiotropic  effects  beyond a pure reduction of BP and heart rate. Positive effects after renal sympathetic denervation have been described in glucose metabolism12,13, obstructive sleep apnoea14,15, reduction of left ventricular mass index, improvements of left ventricular ejection fraction and parameters of diastolic dysfunction in echo16 and MRI17 substudies, antiarrhythmic effect  including  atrial  fibrillation18,19  and  ventricular  arrhythmias20, and chronic heart failure21. These small, preliminary studies are interesting but require further investigations to assess the potential utility of RDN in these disease states with increased sympathetic activity.

Conflict of interest statement

A. Pathak has received research grants, speaker honoraria and consultancy fees from Medtronic, St. Jude Medical, Covidien, ReCor Medical. F. Mahfoud was investigator of the Symplicity HTN-1 and HTN-2  trials  and  is  supported  by  Deutsche  Hochdruckliga  and Deutsche  Gesellschaft  für  Kardiologie  and  has  received  research grants,  speaker  honoraria  and  consultancy  fees  from  Medtronic/Ardian, St. Jude Medical, Boston Scientific, and Cordis. M. Schlaich is supported by an NHMRC Research Fellowship and has received consulting fees, and/or travel and research support from Medtronic, Abbott,  Novartis,  Servier,  Pfizer  and  Boehringer-Ingelheim. R. Schmieder is a member of the speakers’ bureau or has received honoraria  from  AstraZeneca,  Berlin  Chemie  AG,  Boehringer Ingelheim,  Bristol  Myers  Squibb,  Daiichi  Sankyo,  Medtronic, Novartis,  Servier,  Takeda  Pharmaceuticals  and  Terumo.  He  has acted  as  a  consultant  for  AstraZeneca,  Boehringer  Ingelheim, Bristol  Myers  Squibb,  Daiichi  Sankyo,  Medtronic,  Novartis  and Servier, and has received grant or research support (awarded to the University  Hospital,  University  Erlangen/Nürnberg)  from AstraZeneca,  Boehringer  Ingelheim,  Bristol  Myers  Squibb, Bundesminesterium  für  Bildung  und  Forschung,  Daiichi  Sankyo, Novartis and Medtronic. K. Tsioufis has received travel expenses from  Medtronic  and  a  research  grant  and  honoraria  fees  from St. Jude Medical and is co-principal investigator of the ENLIGHTN I study. C. Ukena has received scientific support and speakers honoraria from Medtronic, St. Jude Medical, and Covidien. T. Zeller is an  advisor  for  Medtronic,  ReCor,  Boston  Scientific  and  receives study  grants  from  St.  Jude  Medical,  Medtronic,  ReCor,  Boston Scientific. The other authors have no conflict of interest to declare.

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References

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