1. Renal Denervation Rises From the Ashes
Moderator
David E. Kandzari, MD
Chief Scientific Officer
Director of Interventional Cardiology
Piedmont Heart Institute
Atlanta, Georgia

2. Panelists Michael Böhm, MD, PhD Franz Messerli, MD
Cardiologist in Chief
Director
Department of Internal Medicine 3
Saarland University
Homburg, Germany
Franz Messerli, MD
Department of Cardiology
Bern University Hospital
Bern, Switzerland
Mount Sinai Health Medical Center
New York, New York
Jagiellonian University
Krakow, Poland
Roland E. Schmieder, MD
Professor
University Hospital
Friedrich-Alexander-University Erlangen-Nürnberg
Erlangen, Germany
Panelists Layout (Title slide layout)

3. Program Goals Renal denervation:
Where we have been and where we are heading?
Important clinical trial data presented At ESC
ESC = European Society of Cardiology

4. Hypertension
HTN is a leading contributor to morbidity and mortality worldwide
The prevalence has remained steady over time
It is essential to lower BP however it may be achieved
Typically, that BP was controlled with pharmacology
Role of device therapy needs to be established
BP = blood pressure
HTN = hypertension
Image similar to this one

5. SYMPLICITY HTN-3: Design
Patient and research staff performing 1-, 3-, and 6-month follow-ups are blinded to treatment status
No change in medications for 6 mo
30 days or maximum 6 wk in exceptional circumstances
2 wk
Confirming Screening
Office SBP ≥ 160 mm Hg
Documented medication compliance
Lab work
24-hr ABPM SBP ≥ 135
Home BP & Medication Confirmation
Renal Angiogram
If eligible anatomy, randomize "on the table"
3 mo
1 mo
6 mo
Control
Treatment
Primary End Point mo
Initial Screening
Full tolerated doses of ≥ 3 meds
No HTN med changes in past 2 weeks
No plan to change meds for 6 mo
Medical history
Patients with severe drug-resistant HTN (office SBP ≥ 160 mm Hg)
2:1 randomization
Sham procedure in control patients included renal angiogram
N = 535 (63% screen failure rate)
Primary efficacy end point:
Change in office SBP
Primary safety end point:
MAE through 1 mo, including renal artery stenosis within 6 mo
ABMP = ambulatory blood pressure monitoring
HTN = hypertension
MAE = major adverse event
SBP = systolic blood pressure
MAE defined as all-cause mortality, ESRD, embolic event resulting in end-organ damage, renal artery or other vascular complication, hypertensive crisis through 30 days including new renal artery stenosis within six months
2 wk
Bhatt DL, et al. N Engl J Med 2014;370:

6. SYMPLICITY HTN-3: 6-Month Results
Mean change in SBP ± mm Hg in RDN group vs ± mm Hg in sham-procedure group
P <.001 for both comparisons of the change from baseline
Difference mm Hg (95% CI: -6.89, 2.12; P =.26) for superiority with a margin of 5 mm Hg
Bhatt DL, et al. N Engl J Med 2014;370:

7. SPYRAL HTN-OFF MED: Design
Randomized, sham-controlled, single-blinded trial*
The SPYRAL HTN-OFF MED trial is evaluating renal denervation in the absence of any antihypertensive medications compared to a sham-controlled population.
Prior to randomization, patients will undergo an antihypertensive medication washout period of three to four weeks.
Patients in both groups will be systematically titrated back into anti-hypertensive medical therapy as appropriate three months following randomization. The off-medication trial will help isolate the effect of renal denervation on blood pressure reduction, and was requested by both the FDA and many clinicians.
* Only for patients discontinuing anti-hypertensive medications.
Kandzari D, et al. Am Heart J. 2016;171:82-91.

8. SPYRAL HTN-OFF MED Content no longer available
Key Patient Eligibility Criteria
Inclusion[a]
Patient is either:
Not on antihypertensive medications, OR
Permitting discontinuation of drug therapy
2. Office SBP ≥ 150 and < 180 mm Hg
3. Office DBP ≥ 90 mm Hg
4. Systolic 24-hour mean ABPM ≥ 140 and < 170 mm Hg
Content no longer available
eGFR = estimated glomerular filtration rate
HbA1c = glycated hemoglobin
Exclusion[a,b]
Ineligible renal artery anatomy (accessory arteries allowed)
eGFR < 45 mL/min/1.73m2
Type 1 diabetes mellitus or type 2 diabetes mellitus with HbA1C > 8.0%
Secondary causes of HTN
a. Kandzari D, et al. Am Heart J. 2016;171:82-91; b. Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain.

9. SPYRAL HTN Clinical Program
Multi-electrode catheter with quadrantic vessel contact for simultaneous ablation in up to 4 electrodes
60-second simultaneous energy delivery
Vessel diameter range: 3 mm to 8 mm
Flexible catheter allows branch treatment
6F guiding catheter compatible
We have permission from Medtronic to use these images but they should be referenced as Bohm
Study device: Symplicity Spyral™ catheter
Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain.

10. SPYRAL HTN-OFF MED Medication Adherence % (n) RDN Sham Control P
No anti-HTN drug identified by drug testing:
At baseline
92.1% (35/38)
88.1% (37/42)
.72
At 3 mo
94.3% (33/35)
92.7% (38/41)
1.00
At baseline and 3 mo
88.6% (31/35)
82.9% (34/41)
.53
Patients meeting escape criteria (n) 2 4
HPLC = high-performance liquid chromatography
RDN = renal denervation
Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain
Drug testing of urine and serum by tandem HPLC and mass spectroscopy
Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain.

11. SPYRAL HTN-OFF MED Blinding Procedure and Efficacy
All patients underwent renal angiography
Conscious sedation
Sensory isolation (eg, blindfold and music)
Lack of familiarity with procedural details and expected duration
Assessed by blinding questionnaire at discharge and 3 months:
Time
Blinding Index*
95% CI
Discharge
0.65
(0.56, 0.75)
3 mo
0.59
(0.49, 0.70)
*Blinding Index >0.5 indicates successful blinding.
Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain.

12. SPYRAL HTN-OFF MED Results: 24-H ABPM
BP Change from Baseline to 3 mo
Systolic
Diastolic
Baseline BP (mm Hg)
154
152
100 99
n = 35
n = 36
n = 35
n = 36
Δ -5.0 mm Hg
(-9.9, -0.2)
P =.04
Δ -4.4 mm Hg
(-7.2, -1.6)
P =.002
Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain.

13. SPYRAL HTN-OFF MED Results: Office BP
BP Change from Baseline to 3 mo
Systolic
Diastolic
Baseline BP (mmHg)
162
161
100
101
n = 37
n = 41
n = 37
n = 41
Δ -4.9 mmHg
(-8.5, -1.4)
P =.008
Δ -7.7 mmHg
(-14.0, -1.5)
P =.02
Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain.

14. SPYRAL HTN-OFF MED: Conclusions
Biologic proof of principle for the efficacy of RDN
Clinically meaningful BP reductions at 3 months
In mild to moderate patients with HTN treated with RDN in the absence of antihypertensive medications vs sham control
No major safety events
Despite a more complete RDN procedure that extended into renal artery branch vessels
The results of this feasibility study will inform the design of a larger pivotal trial

15. SPYRAL HTN-OFF MED: Limitations
Proof-of-concept trial, not prospectively powered for statistical significance
Anti-HTN drugs were detected in the blood/urine of some patients despite off-med protocol
Results in the modified ITT and PP populations were consistent
Similar results observed after adjustment for baseline BP (ANCOVA) in all groups
No practical methods to verify nerve destruction
Results may not be generalizable to other RDN technologies
ANCOVA = analysis of covariance
ITT = intention to treat
PP = per protocol
Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain.

16. SPYRAL HTN-ON MED: Design
Content no longer available
Kandzari D, et al. Am Heart J. 2016;171:82-91.

17. Advances of SPYRAL HTN Compared to SYMPLICITY HTN-3
SPYRAL vs HTN-3
Advances of SPYRAL HTN Compared to SYMPLICITY HTN-3
Medications
Patients
Procedure
SYMPLICITY HTN-3[a]
5.1 anti-HTN drugs at time of randomization
No drug adherence testing
Resistant HTN patients (Office SBP 180±16)
No diastolic cutoff
Mono-electrode, sequential ablation system
Mostly inexperienced operators without proctoring
Main artery RDN only
Ablations per pt: ± 2.8
SPYRAL HTN[b,c]
No anti-HTN drugs at time of randomization
Drug adherence testing by plasma and urine
Moderate HTN patients (Office SBP 162±7)
Excluding ISH patients (Office DBP 101±7)
Four-electrode, simultaneous ablation system
Highly experienced operators with proctoring
Main + branches RDN
Ablations/pt: 43.8 ± 13.1
ISH = isolated systolic hypertension
a. Bhatt DL, et al. N Engl J Med. 2014;370: ; b. Kandzari D, et al. Am Heart J. 2016;171:82-91; c. Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain.

18. What Do the Results Mean?
Will reduction in BP due to RDN ultimately translate into a reduction of stroke, heart attack, heart failure, and death?

19. Meta-Analysis: Intensive BP Lowering
Patients in the more intensive BP-lowering treatment group had a mean BP level of 133/76 mm Hg vs 140/81 mm Hg in the less intensive treatment group
Intensive BP-Lowering Treatment RR Reductions  
RR 14%
(95% CI: 4, 22)
RR 13%
(95% CI: 0, 24)
RR 22%
(95% CI: 10, 32)
Risk Reduction,%
MACE = major adverse cardiovascular events
MI = myocardial infarction
RR = relative risk
Xie: Intensive blood pressure-lowering treatment achieved RR reductions for major cardiovascular events (14% [95% CI 4-22]), myocardial infarction (13% [0-24]), stroke (22% [10-32]),
Xie X, et al. Lancet. 2016;387:

20. SPYRAL HTN-OFF MED Medication Adherence % (n) RDN Sham Control P
No anti-HTN drug identified by drug testing:
At baseline
92.1% (35/38)
88.1% (37/42)
.72
At 3 mo
94.3% (33/35)
92.7% (38/41)
1.00
At baseline and 3 mo
88.6% (31/35)
82.9% (34/41)
.53
Patients meeting escape criteria (n) 2 4
Drug testing of urine and serum by tandem HPLC and mass spectroscopy
Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain.

21. Antihypertensive Medication
Patients often not willing to take medications, adherence rates in trials is often around 50%
RDN could be a third option to manage HTN beyond lifestyle and medications
It may delay the need for medication
HTN is a progressive disorder and many patients undergoing RDN may eventually need medication
RDN may enable a reduction in the number/dose of medication
Need more data 
Something similar, multiple RXs

22. Antihypertensive Medication (cont)
Patients who may remain normotensive without medication include those with:
Young age
Normal body weight
Low salt intake
No alcohol consumption
Low pretreatment BP
Successful therapy with one drug only
No/minimal signs of target organ damage 
Schmieder RE, et al. JAMA. 1991;265:

23. Device Therapy
Device therapy is complimentary to medical therapy not instead of it
Getting to BP goal, whatever that goal maybe, is important and meaningful for the patient
Patient preference is important, many do not want a pill burden for the rest of their lives
Device therapy may allow reduction, or, in some cases be an alternative to medication
RD vs medication will be investigated in SPYRAL HTN- ON MED[a]
a. Kandzari D, et al. Am Heart J. 2016;171:82-91.

24. Patients in Trials
Patients who enroll in trials tend to be open-minded and more interested in medical interventions
In heart failure trials, patients agreeing to take part in a trial compare to a matched population, who did not take part in the trial, have a better survival
Registry will determine how the procedure is doing in real life practice
Importantly, patients who are not adherent to the protocol and took other medication were equally distributed in the sham group and in the treatment group

25. Study device: Symplicity Spyral™ catheter
SPYRAL Program
Procedures were done with a different technology and in a very different way
RDN was extended into the branch vessels of the renal architecture of the vasculature
May not be a class effect, rather this specific approach is the one that is effective
Study device: Symplicity Spyral™ catheter
Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain.

26. Conclusions
SPYRAL HTN-OFF Med demonstrated that RDN is effective in reducing BP as measured by 24-hour ABPM
Considered to be the gold standard to analyze any anti-HTN efficacy
Next step: more patients, broader inclusion criteria
Which other patients will profit most from RDN?
BP reduction with pharmacological therapy remains a focus of interest

27. SPYRAL HTN-OFF MED Safety Results at 3 Months RDN (n = 38)
Adverse Events, %
RDN
(n = 38)
Sham Control
(n = 42)
Death
New MI
Major bleeding (TIMI)
New onset ESRD
Serum creatinine elevation >50%
Significant embolic event resulting in end-organ damage
Vascular complications
Hospitalization for HTN crisis/emergency
New stroke
TIMI = Thrombolysis In Myocardial Infarction
ESRD = end-stage renal disease
Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain.

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