Potential conflicts of interest Speaker’s name: Pekarskiy  I have the following potential conflicts of interest to report:  Research contracts  Consulting  Employment in industry  Stockholder of a healthcare company  Owner of a healthcare company  Other(s)  I do not have any potential conflict of interest X

Radiofrequency Renal Denervation For Resistant Hypertension: Single Institution Efficacy And Safety Study PEKARSKIY S., VARVARENKO V., VINTIZENKO S., RIPP T., SEMKE G., MORDOVIN V., KRYLOV A., POPOV S. Research Institute of Сardiology, Siberian Branch of the Russian Academy of Medical Sciences TOMSK, RUSSIAN FEDERATION pekarski@cardio.tsu.ru, spekarski@mail.ru

Tomsk Research Institute Of Cardiology is a large governmental research center with 430-bed hospital providing a full spectrum of cardiac services, including emergency care, diagnostic, interventional cardiology, cardiac surgery and rehabilitation to residents of Siberia and Eastern Russia 10 000 patients annually Full array of diagnostic capabilities(CT, MRI, ultrasound, nuclear imaging, biopsy etc) Cath lab with 3 OR providing all kinds of coronary, peripheral, congenital and structural interventions 50-bed dedicated hypertension unit annually provides advanced investigation and treatment to more than 1000 patients with hard- to-control hypertension Largest research institution in the region of Siberia and Eastern Russia with license and expertise to perform all kinds of pre-clinical and clinical research including pre-approval clinical trials of new therapies and devices Insert references here

Our Study Single-center Single-arm Study Of The Efficacy And Safety Of Radiofrequency Sympathetic Renal Denervation For Treatment Of Drug Resistant Hypertension (ClinicalTrials.gov Identifier: NCT01499810). Inclusion Criteria: Age ≥ 18 and ≤ 80 years at the time of randomization Informed consent Treatment with full doses of 3 or more anti-hypertensive medications of different classes, of which one is a diuretic. Office Systolic BP (SBP) ≥ 160 mmHg or Diastolic BP (DBP) ≥ 100 mmHg Exclusion Criteria: An estimated glomerular filtration rate (eGFR) of < 30 mL/min/1.73 m2 (ABPM) 24 hour average SBP < 135 mmHg Symptomatic(secondary) hypertension Severe renal artery stenosis or abnormality Pregnancy, nursing Any other clinically important disorders or dysfunctions preventing study participation (investigator's assessment) Insert references here

Safety endpoints Efficacy endpoints Primary: Number of Serious Adverse Events related to the intervention from baseline to 12 months Secondary: Change in serum creatinine from baseline to 1 week, 6 and 12 months Change of protein concentration in morning urine sample from baseline to 1 week, 6 and 12 months Change in urine specific gravity from baseline to 1 week, 6 and 12 months Change in renal Doppler flowmetry from baseline to 1 week, 6 and 12 months Primary: Change in office BP from baseline to 12 months after the intervention Secondary: Change in mean/variability of 24-h, daytime, nighttime BP, nighttime dip and morning surge of BP from baseline to 6 and 12 months Change in echocardiographic Left Ventricular Mass Index from baseline to 6 and 12 months Change in intima media thickness of carotid artery from baseline to 6 and 12 months Change in cardio-ankle vascular index(CAVI) from baseline to 6 and 12 months Insert references here

How We Do Renal Denervation Preparation and premedication as usual for renal intervention(ballooning/stenting) Standard abdominal aortography 6F guiding sheath (IMA, RDC, MP) is advanced over guidewire into the ostium of renal artery 5F ablation catheter(4 mm tip electrode with thermocouple) is advanced through the guiding sheath into the distal part of renal artery The RF generator is set to temperature control mode with target t=50 C, RF power limit=8 watt, RF timer limit(max duration)=2 min 4-8 point ablations in each artery are performed consecutively from distal part to aorta with 3-4 mm step on the upper, lower, front and back aspects of the artery to get circumferential coverage Control renal angiography to assess acute safety Insert references here

How We Do Renal Denervation Preparation and premedication as usual for renal intervention(ballooning/stenting) Standard abdominal angiography 6F guiding sheath (IMA, RDC, MP) is advanced over guidewire into the ostium of renal artery 5F ablation catheter(4 mm tip electrode with thermocouple) is advanced through the guiding sheath into the distal part of renal artery The RF generator is set to temperature control mode with target t=50 C, RF power limit=8 watt, RF timer limit(max duration)=2 min 4-8 point ablations in each artery are performed consecutively from distal part to aorta with 3-4 mm step on the upper, lower, front and back aspects of the artery to get circumferential coverage Control renal angiography to assess acute safety Insert references here

Interim Results (Latest Data - April 2012) Patients Safety Number of treated pts 40 Age, years 53.8±9.3 Gender, male 18(45%) CAD 8(20%) Diabetes 3(8%) eGFR, mL/min/1.73m2 82.0(±17.4) Office BP, mmHg 182.4/106.2 (±22.2/18.6) 24-h mean BP, mmHg 158.4/93.8 (±15.6/13.7) Number of drugs 4.1±1.2 Use of diuretics 90% No immediate damage of renal arteries from RF ablation in all 40 cases by intraoperational cineangiography. 5 serious adverse events related to the procedure Definitely 1 small subcapsular kidney hematoma due to perforation by hydrophilic guidewire (volume estimated by MRI is 80 m L) treated conservatively 1 contrast nephropathy(asymptomatic transient increase in serum Cr) 2 access site hematomas (false aneurysms) not requiring surgery Probably 1 allergy(skin rash, hypotension, dyspnea) supposedly to contrast media No significant changes in renal blood flow or renal function at 1st week, 6 months(n=30) and 12 months(n=15) of follow-up. Insert references here

Interim Results (Latest Data - April 2012) 12 months follow up Response rate: office BP – 80%, ABP – 71% 6 months follow up Response rate: office BP – 90%, ABP – 55% ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** p<0.05, *p<0.01 ** ** Insert references here

Interpretation Office and ambulatory BP lowering after RD have different time-course: while most of the office BP decrease develops during first months with only slightly further lowering during the rest of the year ambulatory BP lowering after RD is a slow linear decline during a year or more with relatively minor effect at 6 months but finally powerful decrease at 12 months (possibly reflecting long- term structural adaptation of CV system to created defect in renal sympathetic regulation) Insert references here

20% Of Patients Did Not Respond To RD Hypothesis: Methods BP lowering effect of RD depends on a number of ablations and non-response to RD may be explained by “too low dose” of the treatment Non-responders to RD with recommended 4-6 ablations per renal artery may respond to repeated procedure with more ablation points We compared the changes in office and ambulatory BP at 6 months after RD between those with 4-5 ablations per artery(group 1) and those with 6-8 ablations per artery(group 2) We repeated RD in ”higher dose”(more ablation points) in those who remained non-responder (decrease of sBP < 10 mmHg) at 12 months after the primary intervention Insert references here

Baseline Characteristics of Group 1 (4-5 points per artery) vs Group 2 (6-8 points per artery) Number of pts with 4-5 ablations per artery completed 6 mo of FU 14 Age, years 49.8±10.3 Gender, male 8(57%) Office BP, mmHg 190.8/113.9 (±18.2/14.5) 24-h mean BP, mmHg 164.2/100.8 (±17.7/12.8) Number of drugs 4.3±1.5 Number of pts with 6-8 ablations per artery completed 6 mo of FU 14 Age, years 54.5±8.9 Gender, male 9(64%) Office BP, mmHg 181.0/99.7* (±21.9/18.6) 24-h mean BP, mmHg 155.7/90.8 (±14.2/14.4) Number of drugs 3.6±1.1 The patients in group 2(with more extensive ablation) were a bit older and had slightly lower BP at baseline – potential confounding factor Insert references here

6 Months Outcomes In Patients With Different Number Of Ablations Per Artery 6 months after RD with 4-5 points per artery 6 months after RD with 6-8 points per artery Ambulatory BP lowering after RD was as twice as much in he second group with more extensive ablation(6-8 ablations per artery) Insert references here

Repeated Renal Denervation In Non-responders Non-responders At 12 mo After RD Safety of the repeated procedure Number of pts with repeated RD 3 Age, years 45.0±7.5 Gender 1 man/2 women Office BP, mmHg 184.0/104.7 (±27.7/7.6) 24-h mean BP, mmHg 154.6/95.8 (±11.0/10.4) eGFR 98.6±34.3 No of ablations per artery in primary RD 4-5 No of ablations per artery in repeated RD 7-8 No immediate damage of renal arteries from RF ablation by intraoperational cineangiography. The repeated RF procedure was completely uneventful in all 3 cases. No significant changes in renal blood flow or renal function at 1 week and 6 months of follow-up. Insert references here

Repeated More Extensive RD In Non-responders: BP Effect Office BP Insert references here

Repeated More Extensive RD In Non-responders: BP Effect Ambulatory BP Insert references here

Conclusions Transcatheter RD is safe in patients with resistant hypertension. No damage of renal arteries from RF energy. No sustained damage of renal blood flow or renal function Transcatheter RD in patients with resistant hypertension is associated with significant decrease of both office and ambulatory BP Efficacy of RD seems to depend on a number of performed ablations Repeated RD with more ablation points may be effective in non- responders 7-8 ablations per artery is recommended “dose” of RD to avoid non-responding Insert references here

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