Renal denervation and radial approach: Hope or hype

1. Renal Denervation and Radial:
Hope or Hype?
Samir B. Pancholy, MD
Scranton, PA

2. Renal Denervation
• Promising physiologic basis
• Encouraging initial data
• Negative large RCT
– ? Sham/Hawthorne effect
– ? Inadequate denervation (operators/catheter)

3. Renal arterial anatomy
• Inferiorly pointed in majority of patients
• Suitable for access from above

4. HTN a risk factor for femoral access site complications
• Need reference

5. Consistent and Significant Reductions in Blood Pressure Among Early
Phase RDN Trials for Refractory Stage II HTN
Blood pressure (BP) reduction in mmHg
Symplicity HTN-22
0
-10
-20
-30
REDUCE-HTN4
Systolic BP
Diastolic BP
0
-10
-20
-30
-19
-22
0
-10
-20
-30
-10 -10 -10 -11 -10
0
-10
-20
-30
1 As per 09/10/2013 2 As per 05/23/2013 3 As per 10/31/2013 4 As per 10/31/2013
5 MAE’s: a) One renal artery dissection from injection of contrast into renal artery wall during dye angiography. Lesion was stented without further consequence. b) One hospitalization prolonged in a crossover patient due to hypotension following RDN. IV fluids
administered, anti-hypertensive medication decreased and patient discharged without further incident.
6 No serious peri-procedural events; 4 MAE’s through 18M: a) Worsening of pre-existing proteinuria b) Symptomatic hypotension c) Worsening of pre-existing renal artery stenosis d) New stenotic lesion
7 MAE: a) Bilateral flank pain: Extended hospital stay for observation, add. testing was negative b) Renal artery stenosis: Baseline stenosis was 17% based on core lab assessment of angiogram; stenosis of 60% noted by angiography
at 6M FU; patient received PTA/stent; continues to be monitored c) Access site infection (2 pts.) d) Vomiting e) Hematoma f) Pseudoaneurysm at access site g) Femoral artery thrombus
Source: Clinicaltrials.gov; Press releases; Congress presentations; Medical papers
-20
-32 -28 -32 -34
-7
-12 -10
-13 -13
-40
18M
[n=44]
12M
[n=47]
6M
[n=49]
1M
[n=49]
-25
-30
-10
-14
-21
-23
-10 -8
-40
3M
[n=144]
1M
[n=142]
Symplicity HTN-11
EnligHTN-I3
-27 -29
-32
-9 -10
-14 -14 -14
-40
1M
[n=141]
36M
[n=88]
24M
[n=105]
6M
[n=144]
12M
[n=132]
6M
[n=45]
3M
[n=46]
1M
[n=46]
Study details
Start: 04/2008
Patient group:
Refractory stage II
hypertension
# of pts (target
enrollment): 45
[expanded: 153]
Main endpoint:
Safety of RSD
treatment
MAE: None1
Study details
Start: 06/2009
Patient group:
Refractory stage II
hypertension
# of pts (target
enrollment): 106
[randomized1:1]
Main endpoint:
Blood pressure
reduction
MAE: 25
Study details
Start: 10/2011
Patient group:
Refractory stage II
hypertension
# of pts (target
enrollment): 47
Main endpoint:
Office blood pressure
MAE: [0/4]6
Study details
Start: 02/2012
Patient group:
Refractory stage II
hypertension
# of pts (target
enrollment): 18
[expanded: 146]
Main endpoint:
Change in SBP and
DBP
MAE: 87
12M
[n=41]
6M
[n=139]
12M
[n=45]
30M
[n=44]
-24
-28 -27 -26 -27
-40
18M
[n=44]

6. Annualized Increase in Number and Size of RDN Clinical Trials
1 study 1 study 16 studies 35 studies 49 studies
New RSD
studies
26
106
* Includes MDT Global Symplicity RSD study with 5,000 planned patients
2,470
Source: Clinicaltrials.gov (search terms: “Renal denervation”, “Renal sympathetic denervation”, “RDN”, “RSD”)
6,875
2013
9,272*
5,000
4,272
2012
2010 2011
2009
Planned
patient
numbers

7. SYMPLICITY HTN 3
Primary Efficacy Endpoint
200
150
100
50
0
Δ = -2.39 (95% CI, -6.89 to 2.12)
Denervation Sham
Baseline
6 Months
Δ = -14.1±23.9
P<0.001
Δ = -11.7±25.9
P<0.001
P=0.26*
(N=364) (N=171)
Office SBP (mm Hg)
(N=353) (N=171)
180 mm Hg
166 mm Hg
180 mm Hg
168 mm Hg
*P value for superiority with a 5 mm Hg margin; bars denote standard deviations
Bhatt et al. NEJM 2014

8. SYMPLICITY HTN 3
Powered Secondary Efficacy Endpoint
180
150
120
90
60
30
0
Δ = -1.96 (95% CI, -4.97 to 1.06)
Denervation Sham
Baseline
6 Months
Δ = -6.8±15.1
P<0.001
Δ = -4.8±17.3
P<0.001
P=0.98*
(N=360) (N=167)
24-hour mean systolic
ABPM (mm Hg)
(N=329) (N=162)
159 mm Hg
152 mm Hg
160 mm Hg
154 mm Hg
*P value for superiority with a 2 mm Hg margin; bars denote standard deviations
Bhatt et al. NEJM 2014

9. 1.4%
10%
8%
6%
4%
2%
0%
SYMPLICITY HTN 3
Primary Safety Endpoint
Performance Goal = 9.8%
P < 0.001
Major
Adverse
Event Rate
(MAE)
Renal Denervation
(N=364)
Sham Procedure
(N=171) Difference [95% CI] P*
MAE 1.4% (5/361) 0.6% (1/171) 0.8% [-0.9%, 2.5%] 0.67
*comparison of MAE to control group
Bhatt et al. NEJM 2014

10. SYMPLICITY HTN 3
Adverse Safety Events
Safety Measures (%) Renal
Denervation
(N=364)
Sham
Procedure
(N=171)
Difference
(95% CI)
P
Major Adverse Events 1.4 0.6 0.8 (-0.9, 2.5) 0.67
To 6 Months
6-Month Composite Safety 4.0 5.8 -1.9 (-6.0, 2.2) 0.37
Death 0.6 0.6 0.0 (-1.4, 1.4) 1.00
Myocardial infarction 1.7 1.8 0.0 (-2.4, 2.3) 1.00
New onset ESRD 0 0 - -
Serum creatinine elevation >50% 1.4 0.6 0.8 (-0.8, 2.5) 0.67
Embolic event resulting in end-organ damage 0.3 0 0.3 (-0.3, 0.8) 1.00
Renal artery intervention 0 0 - -
Vascular complication requiring treatment 0.3 0 0.3 (-0.3, 0.8) 1.00
Hypertensive crisis/emergency 2.6 5.3 -2.7 (-6.4, 1.0) 0.13
Stroke 1.1 1.2 0.0 (-2.0, 1.9) 1.00
Hospitalization for new onset heart failure 2.6 1.8 0.8 (-1.8, 3.4) 0.76
Hospitalization for atrial fibrillation 1.4 0.6 0.8 (-0.8, 2.5) 0.67
New renal artery stenosis >70% 0.3 0 0.3 (-0.3, 0.9) 1.00
Bhatt et al. NEJM 2014

12. SYMPLICITY HTN 3: Change in Office Blood Pressure through 12-
Months Post-Procedure
-15.3
-18.9
-17.7
-6.6
-7.8 -7.1
0
-10
-20
-30
RDN 6 Months RDN 12 Months Crossover 6 Months*
Change In Blood Pressure (mm Hg)
SBP
DBP
n=350 n=320 n=92
SBP
DBP
P<0.001 at all time points
Error Bars= 1.96 SE
*Baseline = time of RDN procedure
Baseline SBP (mm Hg) 180 179 184*
Baseline DBP (mm Hg) 97 95 102*
Note: BP changes are vs. patient baseline, not RDN - Control

13. SYMPLICITY HTN 3: Change in Office Blood Pressure through 12-
Months Post-Procedure
-32.9
-21.4
Subjects unblinded
-13.3
-8.2
0
-10
-20
-30
-40
-50
Non-Crossover 6 Months Non-Crossover 12 Months
Change In Blood Pressure (mm Hg)
SBP
DBP
n=48 n=48
P<0.001 at all time points
Error Bars=1.96 SE
Δ 6 to 12 months =
+11.5/+5 mmHg
Baseline SBP (mm Hg) 176 176
Baseline DBP (mm Hg) 94 94
Note: BP changes are vs. patient baseline, not RDN - Control

14. SYMPLICITY 6-Month Primary Analysis
Number of Patients
RDN 364 350
Sham 171 169

16. Meta Analysis of Controlled RDN Trials
SBP DBP Pulse Pressure
-19.4 (95% C: -32.8,-5.9)mmHg
P<0.00001
-6.4 (95% C: -10.7,-2.0)mmHg
P=0.02
Pancholy, Kandzari et al. Am J Cardiol 2014 http://dx.doi.org/10.1016/j.amjcard.2014.06.018
-12.7 (95% C: -22.3,-3.1) mmHg
P=0.002

17. EnligHTN III
Office Blood Pressure Reduction from Baseline
No serious device or procedure-related adverse events
Worthley. EuroPCR 2014

18. REDUCE HTN
12 and 18 Month Outcomes
Schofer. EuroPCR 2014

19. REDUCE HTN
12 and 18 Month Outcomes
Schofer. EuroPCR 2014

20. Equipment
• Catheter length (how much is needed from
LRA to RA
• Catheter profile (6 french sheath)

21. Feasibility
• Case report from Germany in JIC
• Live case at AIM-Radial 2013 by J. Fajadet
from France using Terumo RDN catheter

22. RDN from radial
• Ideally suited for TR approach
– Renal artery takeoff inferiorly directed
– 6 french capable catheters
– Major reduction in access site complications.
– Ideal for same day discharge.

23. Next Steps in RDN Trials
How Current Evidence Informs Challenges of Patients and Protocols
• Minimizing Patient Variability
— Opportunities for overestimation (‘Big Day Bias’) and
underestimation (‘Check Once More’) of blood pressure
— Predictors of Treatment Effect
• Drug Adherence and Prescription
• Patient Behavior and Population
— Placebo/Sham/Hawthorne Effect
— Treatment Resistant HTN
— Isolated Systolic HTN
• Procedure
• Inclusion BP Indications and Endpoints

24. Enrollment Systolic Office and ABPM Measures
Same or Different Patient Populations?
200
190
180
170
160
150
140
130
Baseline Systolic Blood Pressure (mm Hg)
Office
ABPM

25. Medication Changes During Trial
~40% (n = 211) of trial subjects required
medication changes between baseline and
primary efficacy endpoint assessment:
– 69% of first medication changes were
medically necessary
– 121 patients had a med change due
to an adverse event
– 80 patients had a med change due to
a drug side-effect
– ~69% were changes in drugs at
maximally-tolerated dose
– ~33% had >1 change between
enrollment and 6 months
38%
40%
45
40
35
30
25
20
15
10
5
0
N = 139 N = 72
RDN Control
Patients With Medication Changes (%)

26. Multivariate Predictors of Systolic Blood Pressure
Change at 6 Months
-12.003
Control
RDN
Positive Predictors Negative Predictors
Alpha-1 blocker use
African American race
Baseline Office SBP at ≥180
Aldosterone Antagonist
Total Number of Attempts
-14.311
-8.004
-0.936
-11.975
-9.774
7.551
Baseline Office SBP at ≥180
Vasodilator
P value
-20 -15 -10 -5 0 5 10
Univariate P <0.2 required to enter the model
0.044
0.003
0.064
0.005
0.002
0.04
0.0001

27. Change in 6 Month Office SBP With and Without Vasodilator Use in Non-
African American and African American Subgroups
-10.3
-12.3
-17.6 -18.2
-5.9
-21.9
-10.4
-12.7
0
-5
-10
-15
-20
-25
-30
RDN
-4.4 Sham
p=0.30
9.6
p=0.16
-7.1
p=0.03
-5.6
p=0.42
Non-African American
on Vasodilators
33.7% 40.5%
African American
on Vasodilators*
46.7% 56.0%
African American
Not on Vasodilators
Non-African American
Not on Vasodilators
Systolic blood pressure change, mm Hg
N=86 N=49 N=39 N=27 N=178 N=71 N=46 N=22
Baseline SBP,
mmHg
*P value for interaction= 0.19
178.9 180.9 180.6 187.1 179.8 177.1 180.6 179.9

28. DENER HTN Trial
Primary Endpoint Daytime ABPM
• Prospective, open labelled, randomized, controlled, multi center (n=15 centers)
• N=106 pts (53 vs 53)
• “Stepped-care optimized antihypertensive treatment” (“SOAT”) vs. RDN + SOAT
• Key Inclusion:
– OBP≥ 140 or 90 on 3 drugs including diuretic
– Daytime ABPM > 135 systolic or 85 diastolic mmHg
• All pts switched to fixed dose combination for 4 week run-in
• Baseline Daytime ABPM: 156±16, 151±16 mmHg
• Change in systolic daytime ABPM at 6 months= -5.9 mmHg (95% CI -11.3 to -0.5),
P=0.03
• Change in office and home blood pressure were not significant
• Anti hypertensive drugs increased from 3 to 5 (range 4-7) drugs in both groups
Azizi M, ESH 2014

29. PRAGUE 15
RDN vs Intensified Drug Therapy
• Prospective, multi center, open label, randomized, controlled, non-blinded
• N=106
• RDN vs. “intensified drug therapy” (SOC + addition of aldosterone and or other
drugs)
• Key Inclusion:
– OBP> 140 mmHg on 3 drugs including diuretic
– Mean 24-hr systolic ABPM> 130 mmHg
• Both groups had drops in Office BP and 24 hr mean (-9 mmHg) and daytime (-10
mmHg) and nighttime (-8 mmHg) ABPM at 6 months, but differences were not
significant
• About 25% pts on aldosterone antagonists at baseline in both groups. However,
proportion of patients on aldosterone blockers increased to 60% in control group
(no change in RDN group).
ESH 2014

30. Is the Reduction in Afferent Activity Following RDN Sustained?
Parameter Baseline 3 Months 6 Months 12 Months P value
SBP, mm Hg 166 ± 22 154 ± 24 150 ± 27 144 ± 24 <0.001
DBP, mm HG 88 ± 19 82 ± 17 79 ± 16 77 ± 13 <0.001
HR, bpm 66 ± 14 66 ± 14 65 ± 14 67 ± 13 0.66
MSNA,
bursts/min 51 ± 11 43 ± 14 45 ± 13 45 ± 15 0.001
MSNA,
bursts/100
heartbeats
80 ± 16 69 ± 17 70 ± 16 69 ± 18 <0.001
Hering, Esler, Schlaich et al. Hypertension 2014 In press

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

32. Systolic Blood Pressure Change at 6 Months According to Ablation Pattern
N=253 N=68 N=19 N=236 N=62 N=17 N=248 N=66 N=19
-14.2 (24.1)
-6.3 (15.2)
-7.3 (16.3)
-16.1 (22.6)
-7.7 (13.9)
-8.2 (16.3)
-24.3 (23.3)
-10.3 (20.9) -9.0 (25.5)
2
-3
-8
-13
-18
-23
-28
Office ABPM Home
Change at 6 Months
0 Four-quadrant ablations
1 Four-quadrant ablation (Either Right or Left)
2 Four-quadrant ablations (Both Sides)
Baseline SBP Measurements (mm Hg)
0 four-quadrant tx* 179.6 158.7 168.5
1 Four-quadrant tx 178.8 161.2 171.3
2 four-quadrant tx 186.9 159.9 170.4
*1 superior, 1 inferior and 2 anterior/ posterior
Kandzari D. EuroPCR 2014

33. New insights on
renal nerve
anatomy
Sakkara et al., J Am Coll Cardiol 2014;64:635–43

34. Can we do better with new methodological approaches to
denervation with the existing technology?
Nerves more frequently
make a close approach in the
distal segment
• 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
Melder R. EuroPCR 2014; Virmani R., Mahfoud F.

35. Catheter-Based Renal Denervation
Opportunity, Not an End
• Issue is not whether enough evidence exists for RDN as a routine therapy but
instead is there enough evidence to support further study
– Oversimplification to assume a singular therapy to uniformly treat a heterogeneous
disease condition
– Safety of RDN less equivocal than efficacy, although no ‘class effect’
• There is no singular cause for failure of efficacy in HTN 3
• Need to revisit physiology and identify practical measures of effective sympathetic
interruption
• Forthcoming evaluation of RDN for treatment resistant HTN will require careful
trial design that:
– Demonstrates biologic efficacy, and
– Differentiates potential confounders of observer and patient bias
– Focus on less variable and more independent endpoints (eg, ABPM)
• Studies examining pleitropic effects of reducing sympathetic signature must and
will be held to same standard and ideally be supported independent of BP
lowering