From the Ashes Moderator David E Kandzari MD Chief Scientific Officer Director of Interventional Cardiology Piedmont Heart Institute Atlanta Georgia Panelists Roland E Schmieder MD Professor ID: 747603
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Slide1
Renal Denervation Rises From the Ashes
Moderator
David E. Kandzari, MD
Chief Scientific Officer
Director of Interventional Cardiology
Piedmont Heart Institute
Atlanta, GeorgiaSlide2
Panelists
Roland E. Schmieder, MD
Professor
University Hospital
Friedrich-Alexander-University Erlangen-Nürnberg
Erlangen, Germany
Michael Böhm,
MD, PhDCardiologist in ChiefDirectorDepartment of Internal Medicine 3Saarland UniversityHomburg, Germany
Franz Messerli, MDDepartment of CardiologyBern University HospitalBern, SwitzerlandDepartment of CardiologyMount Sinai Health Medical CenterNew York, New YorkJagiellonian UniversityKrakow, PolandSlide3
Program GoalsRenal denervation:Where we have been and where we are heading?Important clinical trial data presented At ESCSlide4
HypertensionHTN is a leading contributor to morbidity and mortality worldwideThe prevalence has remained steady over time
It is essential to lower BP however it may be achievedTypically, that BP was controlled with pharmacologyRole of device therapy
needs to be establishedSlide5
SYMPLICITY HTN-3: Design Bhatt DL, et al. N Engl J Med
2014;370:1393-1401.
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 e
fficacy end p
oint:Change in office SBPPrimary safety
e
nd
p
oint
:
MAE through 1 mo, including
renal
artery stenosis within
6
mo
Patient and
research
staff performing
1-, 3-, and 6-month
follow-ups are blinded to treatment statusNo change in medications for 6 mo
30 days or maximum 6 wk in exceptional circumstances
2
wk
Confirming Screening
Office SBP ≥ 160
mm HgDocumented medication complianceLab work24-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
3 mo
1 mo
6 mo
Primary
End Point
12 - 60 mo
Home BP & Medication Confirmation
2
wk
Initial Screening
Office SBP ≥ 160
mm Hg
Full
tolerated
doses
of ≥
3 meds
No HTN med changes
in
past 2 weeksNo plan to change meds for 6 moMedical history
Home BP & Medication Confirmation
2
wk Slide6
Bhatt DL, et al. N Engl J Med 2014;370:1393-1401.SYMPLICITY HTN-3:
6-Month ResultsN = 535
Mean change in SBP -14.13 ± 23.93 mm Hg in RDN group vs -11.74 ± 25.94 mm Hg in sham-procedure group
P
<.001 for both comparisons of the change from baseline
Difference -2.39 mm Hg (95% CI:
-6.89, 2.12; P =.26) for superiority with a margin of 5 mm HgSlide7
* Only for patients discontinuing anti-hypertensive medications.
Kandzari D, et al. Am Heart J. 2016;171:82-91.
SPYRAL HTN-OFF MED:
Design
Randomized, sham-controlled, single-blinded
trial*Slide8
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.
SPYRAL
HTN-OFF MED
Key Patient Eligibility
Criteria
Inclusion
[a]
Exclusion
[a,b]
Ineligible renal artery anatomy (accessory arteries allowed)
eGFR < 45 mL/min/1.73m
2
Type 1 diabetes mellitus or type 2 diabetes mellitus with HbA1C > 8.0%
Secondary causes of
HTN
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 availableSlide9
Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain.
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
Study device: Symplicity Spyral
™
catheterSlide10
Medication AdherenceData presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain.
SPYRAL
HTN-OFF MED
Drug
testing of
urine
and serum by tandem HPLC and mass s
pectroscopy
% (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)
.53Patients meeting escape criteria (n)24Slide11
*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.
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 durationAssessed 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)Slide12
Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain.
SPYRAL HTN-OFF MED Results:
24-H ABPM
Δ
-4.4
mm Hg
(-7.2, -1.6)
P
=.
002
n
= 35
n
= 35
Systolic
Diastolic
Δ
-5.0
mm Hg
(-9.9, -0.2)
P
=
.
04
Baseline BP (
mm Hg
)
154
15210099
n = 36
n
= 36BP Change from Baseline to 3 moSlide13
Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain.SPYRAL HTN-OFF
MED Results: Office BP
Systolic
Diastolic
n
= 37
n
= 37
Baseline
BP (mmHg)
162
161
100
101
n
= 41
n
= 41
Δ
-4.9 mmHg
(-8.5, -1.4)
P
=.008
Δ
-7.7 mmHg
(-14.0, -1.5)
P
=.02
BP Change
from Baseline to 3
moSlide14
SPYRAL HTN-OFF MED: ConclusionsBiologic proof of principle for the efficacy of RDNClinically meaningful BP reductions at 3 months
In mild to moderate patients with HTN treated with RDN in the absence of antihypertensive medications vs sham controlNo 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 trialSlide15
Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain.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 technologiesSlide16
SPYRAL HTN-ON MED: Design
Kandzari D, et al.
Am Heart J
. 2016;171:82-91.
Content no longer availableSlide17
a. Bhatt DL, et al. N Engl J Med. 2014;370:1393-13401; 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
.
SPYRAL vs 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: 11.2 ± 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
Advances of SPYRAL HTN Compared to SYMPLICITY
HTN-3Slide18
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?Slide19
Xie X, et al. Lancet
. 2016;387:435-443.
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
RR 14%(95% CI: 4, 22)
RR 13%(95% CI: 0, 24)RR 22%(95% CI: 10, 32)
Intensive BP-Lowering Treatment RR Reductions
Risk Reduction,%Slide20
Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain.
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)24
Drug testing of
urine and serum by tandem HPLC and mass spectroscopySlide21
Antihypertensive MedicationPatients 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 medicationsIt 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 Slide22
Antihypertensive Medication (cont)Patients who may remain normotensive without medication include those with:Young age
Normal body weightLow 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;265:1566-1571.Slide23
a. Kandzari D, et al. Am Heart J. 2016;171:82-91.
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]Slide24
Patients in TrialsPatients who enroll in trials tend to be open-minded and more interested in medical interventionsIn 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 practiceImportantly, patients who are not
adherent to the protocol and took
other medication were equally
distributed in the sham group
and in the treatment groupSlide25
Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain.SPYRAL Program
Procedures were done with a different technology and in a very different wayRDN 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
d
evice: Symplicity Spyral
™
c
atheterSlide26
ConclusionsSPYRAL HTN-OFF Med demonstrated that RDN is effective in reducing BP as measured by 24-hour ABPMConsidered 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 Slide27
Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain.SPYRAL HTN-OFF MED
Safety Results at 3 Months
Adverse Events, %
RDN
(n
= 38)
Sham Control
(n
= 42)
Death
0
0
New
MI
0
0
Major bleeding (
TIMI)
0
0
New onset
ESRD
0
0
Serum creatinine elevation >50%
0
0
Significant embolic event resulting in end-organ damage
0
0
Vascular complications
0
0
Hospitalization for
HTN crisis/emergency
0
0
New stroke
0
0Slide28
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