Renal denervation: Is it still promising?

Renal Denervation: Is it Still 
Promising? 
A/Prof Michael Nguyen 
Fiona Stanley Hospital 
Australia 
For distribution only in markets where the Symplicity™ renal denervation system has been approved. Not for distribution in the USA, Japan or 
France. © 2014 Medtronic, Inc. All rights reserved. UC201502039bML 8/14 
Medtronic SYMPLICITY HTN-3 Announcement 
January 9th Announcement 
• Primary efficacy endpoint was not met 
• Powered safety endpoint was met 
The Symplicity™ renal denervation system is not approved for sale in the US. 
For distribution only in markets where the Symplicity™ renal denervation system has been approved. Not for distribution in the USA, Japan or 
France. © 2014 Medtronic, Inc. All rights reserved. UC201502039bML 8/14 
SYMPLICITY HTN-3 Primary Efficacy Endpoint 
Office Systolic Blood Pressure at 6 Months, 5 mm Superiority Margin 
• Did not meet primary efficacy endpoint 
-2.39 (-6.89, 2.12), P=0.255 
(Primary analysis with 5 mm Hg superiority margin) 
RDN Control P value 
Baseline SBP 179.7 180.2 0.765 
6 mo SBP 165.6 168.4 0.260 
Change 
-14.1 
P<0.001 
-11.7 
P<0.001 
0.255 
Bhatt DL et al. N Engl J Med. 2014;370:1393-401 
n=353 n=171 
∆
S
B
P
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t 
6
 M
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 0 
-4 
-8 
-12 
-14.1 
-11.7 
-16 
RDN Control 
For distribution only in markets where the Symplicity™ renal denervation system has been approved. Not for distribution in the USA, Japan or 
France. © 2014 Medtronic, Inc. All rights reserved. UC201502039bML 8/14 
Medication Changes During SYMPLICITY HTN-3 Put 
Into Question Resistant Hypertension Concept 
• ~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 
HTN-3 showed how difficult it is to study this patient 
population and put into question this concept of resistant hypertension 
Kandzari, EuroPCR 2014 
For distribution only in markets where the Symplicity™ renal denervation system has been approved. Not for distribution in the USA, Japan or 
France. © 2014 Medtronic, Inc. All rights reserved. UC201502039bML 8/14 
SYMPLICITY HTN-3 Showed Different Outcomes in 
African American Sham Population 
Kandzari, EuroPCR 2014 
For distribution only in markets where the Symplicity™ renal denervation system has been approved. Not for distribution in the USA, Japan or 
France. © 2014 Medtronic, Inc. All rights reserved. UC201502039bML 8/14 
*P value change in SBP for RDN compared with sham 
Data presented are mean (SD) 
SYMPLICITY HTN-3: Impact of Number of Ablation 
Attempts on Change in Ambulatory Blood Pressure: 
Matched Cohort Analysis 
Kandzari, EuroPCR 2014 
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For distribution only in markets where the Symplicity™ renal denervation system has been approved. Not for distribution in the USA, Japan or 
France. © 2014 Medtronic, Inc. All rights reserved. UC201502039bML 8/14 
SYMPLICITY HTN-3: Procedural Experience 
HTN-1 HTN-3 
No. of operators 20 112 
No. of procedures per operator 6.0 3.3 
No. of procedures per site 8.6 4.7 
40 
35 
30 
25 
20 
15 
10 
5 
0 
1 2 3 4 5 6 7 8 9 10 11 13 14 
N
u
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b
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r 
o
f 
 P
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lis
ts
>50% of interventionalists performed ≤2 RDN 
procedures in SYMPLICITY HTN-3 
RDN Procedures Performed 
For distribution only in markets where the Symplicity™ renal denervation system has been approved. Not for distribution in the USA, Japan or 
France. © 2014 Medtronic, Inc. All rights reserved. UC201502039bML 8/14 
SYMPLICITY HTN-3: Change in Systolic Blood Pressure 
in Patients Taking an Aldosterone Antagonist at Baseline 
Kandzari, EuroPCR 2014 
For distribution only in markets where the Symplicity™ renal denervation system has been approved. Not for distribution in the USA, Japan or 
France. © 2014 Medtronic, Inc. All rights reserved. UC201502039bML 8/14 
SYMPLICITY HTN-3: Systolic Blood Pressure Change at 
6 Months According to Ablation Pattern 
Four quadrants = 1 superior, 1 inferior, and 2 posterior/anterior 
Bhatt, TCT 2014 
For distribution only in markets where the Symplicity™ renal denervation system has been approved. Not for distribution in the USA, Japan or 
France. © 2014 Medtronic, Inc. All rights reserved. UC201502039bML 8/14 
New Insights on Renal Nerve Anatomy 
Sakakura et al. J Am Coll Cardiol 2014;64:635–643. 
What are the questions we need to 
ask? 
• How much denervation do we need to have a meaningful 
effect on BP? 
• Is there a threshold for renal denervation or a dose 
response? 
• Knowing that a great proportion of fibers are found as far 
as 12 mm from the lumen, how do we get there? 
• How can we monitor success in the lab? 
• Does radiofrequency ablation have a chance to meet the 
above requirements? 
• How can other approaches, e.g. ethanol and HIFUS play a 
role? 
• Can we identify the right population? 
Identification of Responders 
• Complex 
– “why do some respond and others don’t” 
– Resistent HT is multifactorial 
• Physician factors – inertia, drug selection 
• Patient factors – genetics, compliance 
– Need for specific test rather than arbitrary blood pressure range 
• Measure of sympathetic over-activity 
– Muscle sympathetic nerve activity and noradrenaline spillover 
are the gold standards – not readily available 
– heart rate, plasma catecholamines 
– All these tests have not proven to be effective identifying 
responders 
Procedural Advancements 
• A circumferential injury of at least 75% of the sympathetic fibers is needed 
to attain adequate and clinically significant renal sympathetic denervation. 
• Current systems using low-energy radio- frequency ablation achieve injury 
up to 2–3 mm from the lumen 
• Autopsy data: sympathetic nerves are deeper at proximal segments and 
more superficial at distal segments. ? Techniques aimed at circumferential 
ablation in distal segments? 
• Technological advancements that will allow for deeper penetration of 
energy without producing any substantial injury of the endothelium, renal 
artery wall or perivascular tissue. 
Measuring Success 
• Identify the markers of successful sympathetic nerve injury to be used 
during the procedure. 
• Currently “blind procedure” 
• Regional renal noradrenaline spillover could be assumed as an ideal can- 
didate, but cannot be used during the procedure. 
• The identification of a feasible and accurate test that could assess 
sympathetic activity during the procedure is of paramount importance for 
the future of renal sympathetic denervation. 
Long-Term Data 
• Relevant data regarding the long-term safety of the procedure, the 
persistence of BP reduction over time and the effects of renal denervation 
on cardiovascular outcomes are needed. 
• The persistence of BP reduction is another important issue, since 
experimental data suggest the re-innervation of renal sympathetic fibers 
does occur. 
Future Trials 
• Medtronic has initiated the SPYRAL HTN 
Global Clinical Program with SPYRAL HTN-OFF 
MED and SPYRAL HTN- ON MED 
SPYRAL HTN-OFF MED 
• Evaluating renal sympathetic denervation in 
the absence of antihypertensive medications 
compared to a sham- controlled population. 
• This off-medication trial will help isolate the 
effect of renal denervation on BP reduction, 
and it was requested by both the FDA and 
many clinicians. 
SPYRAL HTN-ON MED 
• Evaluating renal denervation compared to a sham-controlled 
population with patients on a standardized treatment 
regimen of 3 antihypertensive medications (thiazide- type 
diuretic, a dihydropyridine calcium-channel-blocker and an 
ACE inhibitor/angiotensin receptor blocker) for at least 6 
weeks prior to randomization and expected to maintain the 
regimen for at least 6 months. 
• By specifying specific medications at the maximum tolerated 
dose, medication variability will be reduced; 
Conclusion 
• The future of renal sympathetic denervation depends on 
– the identification of response predictors 
– technological advances that obtain complete or at least near-complete 
injury of renal sympathetic fibers 
– proof of long-term cardiovascular benefits in patients with resistant 
hypertension and/or other diseases. 
• Given the setback from Symplicity 3, the medical community 
will set even higher standards for this technology and 
therefore large randomized controlled trials with strong 
primary endpoints and long-term follow-up will be needed for 
its acceptance.