The Future of Renal Denervation

The Future of Renal Denervation Ron Waksman, MD, FACC, FSCAI Professor of Medicine, (Cardiology) Georgetown University Director, Cardiovascular Research Advanced Education MedStar Heart Institute, Washington DC

Disclosure Statement of Financial Interest Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationship Grant/Research Support Consulting Fees/Honoraria Company Boston Scientific Biotronik Biosensors Astra Zeneca Medtronic Vascular Abbott Vascular

Renal Denervation state of the field

The Symplicity HTN Clinical Trial Program Symplicity HTN-1 First-in-Man, and Expanded Cohort (N=153) 1,2 Symplicity HTN-2 Randomized, Controlled Trial (N=106) 3 = Primary endpoint = Planned follow up = Partial cohort reports Symplicity HTN-3 Randomized, Blinded, Controlled Trial (N~530) 4 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 1. Krum H, et al. Lancet. 2009;373:1275-1281. 2. Symplicity HTN-1 Investigators. Hypertension. 2011;57:911-917. 3. Esler et al. Lancet. 2010;376:1903-1909. 4. Data on file, Medtronic. Shading on bars indicates clinical trial enrollment periods. Enrollment period for HTN-3 is estimated.

Explosion of technology development for RENAL DENERVATION >20 DEVICES RF ablation Baroreceptor stimulation Baroreceptors stents Local drug delivery Brachytherapy Cryotherapy Ultrasound therapy Internal External Ultrasound AV fistulas Imaging technology to detect the sympathetic nerve

Is Renal Denervation Efficacious?

Is Renal Denervation Efficacious?

SYMPLICITY HTN-3 Trial Design 2 weeks Home BP & HTN med confirmation 1 M Sham Procedure 2 weeks 3 M Home BP & 6 M HTN med confirmation Screening Visit 1 Screening Visit 2 Office SBP 160 mm Hg Full doses 3 meds No med changes in past 2 weeks No planned med changes for 6 M Office SBP 160 mm Hg 24-h ABPM SBP 135 mm Hg Documented med adherence Renal angiogram; Eligible subjects randomized Renal Denervation 1 M 3 M Home BP & HTN med confirmation 2 weeks Primary endpoint 6 M 12-60 M Patients, BP assessors, and study personnel all blinded to treatment status No changes in medications for 6 M Bhatt DL, Kandzari DE, O Neill WW, et al. Bakris GL. N Engl J Med 2014

SYMPLICITY HTN-3 Announcement January 9, 2014 And overnight, the future of RDN was in turmoil

Office SBP (mm Hg) Symplicity HTN-3: Efficacy Endpoint Δ = -2.39 (95% CI, -6.89 to 2.12) P=0.26* 200 Δ = -14.1±23.9 P<0.001 Δ = -11.7±25.9 P<0.001 150 180 mm Hg 180 mm Hg 166 mm Hg 168 mm Hg 100 Baseline 6 Months 50 (N=364) (N=353) (N=171) (N=171) 0 Denervation Sham * P value for superiority with a 5 mm Hg margin; bars denote standard deviations Bhatt DL, Kandzari DE, O Neill WW, et al. Bakris GL. N Engl J Med 2014

Ambulatory 24-hour BP (mm Hg) Symplicity HTN-3: Mean 24-hour ABPM 180 160 140 120 100 80 60 40 20 0 Δ = -1.96 (95% CI, -5.12 to 1.20) P=0.22 Δ = -6.75 (95% CI, -8.40, -5.10) P<0.001 (N=360) Bakris GL et al. JACC 2014 (N=329) Δ = -4.79 (95% CI, -7.50, -2.09) P<0.001 (N=167) (N=162) Δ = -4.10 (95% CI, -5.10, -3.09) P<0.001 Baseline 6 Months Δ = -1.00 (95% CI, -2.81 to 0.81) P=0.28 Δ = -3.10 (95% CI, -4.68, -1.52) P<0.001 (N=360) (N=329) (N=167) (N=162) Denervation Sham Denervation Sham SBP DBP

So if We Think that RDN is Efficacious, Why Did SYMPLICITY HTN-3 Fail?

Symplicity Complexity

Areas of Speculation on the Causes of the SYMPLICITY HTN-3 Efficacy Results.. Heterogeneity of U.S. Operator Experience Patient Demographics Catheter Design Medication Changes or Adherence? Trial Design/ Conduct Hawthorne Effect Placebo Effect Ablation Missed Target S. Salmon, CRT 2014

Do We Really Know What We Are Doing?

What Have We Learned From RDN Trials

What Have We Learned From RDN Trials

What Have We Learned From RDN Trials

Impact of Number of Ablations on Change in Office SBP: Matched Cohort Analysis 0 8 9 10 11 12 13 14 15 16 N=163 166 152 155 131 134 98 100 61 63 45 46 26 27 18 19 9 10-5 -10-15 -20-25 -30-35 Baseline SBP 95% CI P* -7.6-7.6-7.1-9.4-11.5-11.1-13.1-14.1-14.7-14.7-15.9 178.2 180.1 178.6 180.3 178.2 180.5 179.0 179.4 179.1 179.7 178.3 181.3 181.9 182.3 183.2 182.8 185.4 189.4-1.7(-7.1, 3.7) 0.54 P value for trend= 0.01 Denervation Sham Propensity scores using baseline characteristics as covariates were used to match sham control and denervation patients -3.1 (-8.6, 2.4) 0.27-5.4 (-11.3, 0.5) 0.07-7.1 (-13.9,-0.3) 0.04-8.4 (-17.4, 0.7) 0.07-18.6-11.5 (-21.8,-1.2) 0.03-24.3-14.1 (-28.8, 0.7) 0.06 *P value change in SBP for RDN compared with sham Data presented are mean (SD) -10.2-25.4-13.4-12.0 (-30.0, 5.9) 0.18-30.9-18.5-12.4 (-44.6, 19.8) 0.43 D. Kandzari, EuroPCR 2014

Variable Distribution and Density of Renal Sympathetic Nerves Nerves from 20 human autopsy specimens Greater number of nerves prox/mid vs. distal as well as ventral (anterior) vs. dorsal (posterior) Greater distance from lumen to nerves from prox to distal Sakakura et al, JACC 2014

Is there a Threshold Dose Needed in Order for RDN to Work? Treatment of 8 renal arteries from 4 pigs undergoing bilateral multipolar denervation near ostium Efficacy (1/8) requirements: 4 quadrant ablation Significant depth (9.1 mm) >50% of nerves affected Tzafiri et al, JACC 2014

Procedural Variability Correlation with # of ablations Correlation with 4-quadrant ablation pattern Cross-section of artery Inferior Anterior Superior Posterior 4-quadrant ablation pattern

Can we do better with new methodological approaches to denervation with the existing technology? Histological analyses suggest that a more distal approach could increase the frequency of successful ablations Distal ablation strategies can be executed with both existing RDN catheters Human Main Renal Artery 5.18 + 0.71mm Dia. Human Branch Renal Artery 4.05+0.90mm Dia. Superior 3.81+0.80mm Dia. Inferior Nerves more frequently make a close approach in the distal segment Melder R. EuroPCR 2014; Virmani R., Mahfoud F.

Is Renal Denervation Safe?

RDN Safety in HTN-3 and GSR HTN-3 RDN arm GSR All Patients GSR OSBP 160 and ABPM 135* (N=364) (N=1,000) (N=327) MAE 1.4% 0.8% 1.3% At 6 month Death 0.6% 0.4% 0.3% New onset end stage renal disease 0.0% 0.2% 0.3% Significant embolic event resulting in end-organ damage 0.3% 0.0% 0.0% Renal artery re-intervention 0.0% 0.2% 0.0% Vascular complication 0.3% 0.4% 0.7% Hypertensive crisis/emergency 2.6% 1.0% 1.7% New renal artery stenosis > 70% 0.3% 0.0% 0.0% * with 3 antihypertensive medication classes

But what about subgroups (it should work in someone) Renal Sympathetic Denervation and BP Reduction

Can we therefore conclude that RDN perhaps works in the young, non black without renal insufficiency??? Bhatt et al. N Engl J Med 2014;370:1393-401.

There is hope for renal denervation under the following condition Identifying the right target population (patients with moderate hypertension,chf, crf, arrhythmias) Identifying the target nerve for ablation (distal versus proximal, mapping?) Improvement of the catheter design Getting an immediate feedback that ablation was effective Designing the appropriate trial design

Spiral Global HTN Trials

Future of RDN managing Variability

REDUCE - HTN: REINORCE

RDN Beyond Hypertension

Renal Denervation: Is There Hope? Thank you for your Attention