A randomized controlled trial of distal renal denervation vs conventional mode of the intervention for treatment of resistant hypertension Stanislav Pekarskiy Cardiology Research Institute, Tomsk NRMC, Russian Academy Of Sciences

INTRODUCTION Hypertension remains a main health problem in the world despite a highly developed drug treatment. Antihypertensive pharmacotherapy is ineffective in patients with resistant hypertension (~10%) and in patients with persisting non- compliance (~ 30%). A conceptually new treatment of hypertension - endovascular renal denervation (RDN) – potentially may help to improve blood pressure control in both above areas of ineffective drug treatment. Regrettably, RDN failed in large Symplicity HTN-3 trial

WRONG ANATOMICAL MODE OF CONVENTIONAL RDN In our opinion, RDN failed because it was done in anatomically wrong way Specifically, 4-6 point ablations were done equally distributed within main trunk of renal artery This mode may only be effective if all renal nerves closely follow the course of renal artery from aorta to the kidney with equal circumferential density and within 2 mm from its lumen (depth of the RF treatment)  

REAL ANATOMY OF RENAL PLEXUS In contrast, the surgical studies show that renal plexus has a triangular form with wide base directed toward aorta and apex converging to the kidney   i.e. proximally, the majority of the nerves proceed obliquely at a distance from renal artery and join mainly its distal part [Page, 1935. Oldham, 1950].

DISTAL MODE OF RDN We developed a distal mode of RDN in segmental branches of renal artery:   Ablation catheter is advanced sequentially into segmental branches, and 2 or 4 separate point treatments are performed in each branch depending on its diameter: 4 - if the diameter is 4 mm or greater 2 - if the diameter is less than 4 mm   Plus 2 additional treatments in the distal trunk to guarantee sufficient completeness of neural damage when at least one branch was treated with 2 ablations

Our trial of distal RDN vs conventional mode for treatment of resistant hypertension (NCT02667912) A Double Blind Randomized Controlled Study With 2 Parallel Groups Inclusion Criteria: 1. Men and women 18-80 years 2. BP >= 160/100 mmHg despite at least 3 drugs including a diuretic 3. Given written informed consent Exclusion Criteria: 1. Secondary hypertension 2. 24 h mean systolic BP <135 mmHg (ABPM) 3. eGFR < 30 mL/min/1.73 m2 4. Severe renal artery stenosis 5. Any other clinically important disorders preventing study participation (investigator's assessment) The primary study outcome: The between-group difference in the changes of 24h mean systolic BP (ABPM) from baseline to 6 m Secondary outcomes: The changes of office BP, daytime, and nighttime BPs, serum creatinine, eGFR and resistant index (RI) of renal blood flow assessed by Doppler flowmetry 6 months FU AE, office BP, ABPM, DFM, serum creatinine, eGFR randomization 1:1 Intervention Baseline evaluation office BP, ABPM, DFM, serum creatinine, eGFR Patients with resistant hypertension Conventional RDN Distal RDN Then we compare our distal mode of renal denervation with conventional form of the intervention in double blind randomized controlled study. We used the same eligibility criteria as in the Symplicity trial.

Assessed for eligibility (n=65) THE STUDY PROFILE Enrollment Assessed for eligibility (n=65) Excluded (n=10) ¨  Not meeting inclusion criteria (n=4) ¨  Declined to participate (n=6) Randomized (n=55) Allocation Allocated to distal RDN(n=28) ¨ Received allocated intervention (n=28) Allocated to conventional RDN(n=27) ¨ Received allocated intervention (n=27) Follow-Up Fifty five patients were randomized. Twenty eight – in the group of distal therapy, twenty seven – in the group of conventional denervation. Fifty one patient completed 6 months follow up. Twenty seven patients after distal treatment and twenty four – after conventional intervention. Lost to follow-up (n=1) ¨ Inability to get to the study site (n=1) Lost to follow-up (n=3) ¨ Inability to get to the study site (n=1) ¨ Consent withdrawal (n=2) Analysis Analysed (n=27) Analysed (n=24)

Treatment of segmental branches SAFETY OF DISTAL RDN Treatment of segmental branches Control angiography Technical success was 100% in both groups Intraoperational angiography did not show any significant damage of segmental branches of renal artery after distal treatment There was only one complication - a post-punctional pseudoaneurysm in patient treated by distal technique.

PRIMARY STUDY OUTCOME (final results) Technical success was 100% in both groups A magnitude of the decrease in 24h mean BP was significantly (2 times) greater after distal therapy then after conventional RDN No major safety issue was observed P<0,05

SECONDARY OUTCOMES P<0,05 Daytime, nighttime, and office BPs also decreased more in the group of distal therapy. then in the group of conventional renal denervation. The difference reached statistical significance for daytime systolic BP

CONCLUSIONS Renal denervation treatment is significantly less effective in the trunk of renal artery than in segmental branches The failure of Symplicity HTN-3 trial may be fully explained by anatomically wrong mode of the intervention in the trunk of renal artery Future development of RDN needs to be re-directed to producing devices for use in segmental branches of renal artery