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2/7/2018
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David E. Kandzari, MD, FACC, FSCAI
Chief Scientific OfficerDirector, Interventional Cardiology
Piedmont Heart Institute Atlanta, Georgia [email protected]
Renal Denervation Next Steps:Evolution of Evidence and Future Directions
• Most commonly diagnosed condition in the US
• Astonishing prevalence
– 1 Billion people worldwide - growing to 1.6 Billion by 2025
– 74 Million Americans (1 in 3-4 adults)
– Shared prevalence among men and women
• Single largest contributor to death worldwide
• Single largest contributor to death and disability worldwide
• Dramatically increases the risk of heart attack, stroke, heart failure & kidney failure
• CV mortality doubles for every 20 SBP/10 DBP increase
• Estimated cost this year in US = $73.4B
Sources: American Heart Association; World Health Organization;
A Major Public Health Burden
Kearney et al. Lancet. 2005;365(9455):217-223; Global Burden of Disease Study 2010, Lancet 2012
SPRINT: Systolic Blood Pressure Intervention TrialBlood Pressure, the Mystery Number*
National Heart Lung and Blood Institute, September 11, 2015; *New York Times, June 22, 2015
9361 Patients with HTNExclusions: DM, Prior Stroke
Inclusion: Age >50 and CAD, CKD, 75 (25%) or Framingham Risk 15% over 10 yrs
SBP Goal <120Chlorthalidone, Amlodipine, Lisinopril
SBP Goal <140
Primary Endpoint: MI, CV death, ACS, Heart Failure, Stroke
Secondary Endpoint: All-Cause Mortality 25%
30%
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Xie X, et al. Lancet. 2015 Nov 7. pii: S0140-6736(15)00805-3. doi: 10.1016/S0140-6736(15)00805-3.
Blood Pressure Lowering for Prevention of CV Disease and DeathSystematic Review of 19 Trials, 44,989 Patients, 3.8 Years Follow-Up
133/76 140/81
MI risk reduced 14%, Stroke reduced 22%
Ettehad, Rahimi. Lancet 2015
Blood Pressure Lowering for Prevention of CV Disease and DeathSystematic Review of 123 Trials, 613,815 Patients
• 20% for major CV events: 0.80 (95% CI 0.77–0.83)
• 17% for coronary heart disease: 0.83 (95% CI 0.78–0.88)
• 27% for stroke: 0.73 (95% CI 0.68–0.77)
• 28% for heart failure: 0.72 (95% CI 0.67–0.78)
• 13% for all-cause mortality: 0.87 (95% CI 0.84–0.91)
For every 10 mm Hg reduction in systolic blood pressure,
Reductions in major CV events proportionately greater among those with diabetes or chronic kidney disease
Lowering SBP had no effect on renal failure
ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/ NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults JACC 2017, Hypertension 2017
BP Thresholds for and Goals of Pharmacological Therapy in Patients With Hypertension According to Clinical Conditions
Clinical Condition(s)BP
Threshold, mm Hg
BP Goal, mm Hg
GeneralClinical CVD or 10-year ASCVD risk ≥10% ≥130/80 <130/80No clinical CVD and 10-year ASCVD risk <10% ≥140/90 <130/80Older persons (≥65 years of age; noninstitutionalized, ambulatory, community-living adults)
≥130 (SBP) <130 (SBP)
Specific comorbiditiesDiabetes mellitus ≥130/80 <130/80Chronic kidney disease ≥130/80 <130/80Chronic kidney disease after renal transplantation ≥130/80 <130/80Heart failure ≥130/80 <130/80Stable ischemic heart disease ≥130/80 <130/80Secondary stroke prevention ≥140/90 <130/80Secondary stroke prevention (lacunar) ≥130/80 <130/80Peripheral arterial disease ≥130/80 <130/80
ASCVD indicates atherosclerotic cardiovascular disease; BP, blood pressure; CVD, cardiovascular disease; and SBP, systolic bloodpressure.
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Hypertension: Historical Perspective
Traube (Berlin, 1856)
“High Blood Pressure Is Essential”
— Postulated that arterial pressure was elevated to overcome mechanical resistance against blood flow through thickened arteries
— Believed that increased blood pressure was necessary for excretory efficiency of the kidney
— Promoted these concepts which were unchallenged for almost 80 years
Traube L. Ueber den zusammenhang von herz und nierenkrankeiten. Berlin: Hisrchwald, 1856.
Hypertension: Historical Perspective
Osler W. British Medical Journal, 1912.
Osler (Glasgow, 1912) “Life is a gift of one’s blood pressure as Egypt is a gift of the Nile”
— Small vessel obstruction (hypertrophy) analogous to weeds obscuring the tributaries of the Nile– ‘weeding the irrigation channels and keeping free the drainage’
— Case presentations from asymptomatic to cardio- and cerebrovascularcompromise
— Likened the variability and unpredictability of blood pressure manifestations to variability of products like Gillette razors and cars
— Described failure of contemporary therapies– nitrates and potassium iodide
Alpha blockers
Thiazide diuretics
Directvasodilators
Peripheralsympatholytics
Ganglion blockers
Veratrumalkaloids
1940s 1950 1957 1960s 1970s 1980s 1990s 2007
Chronology of Antihypertensive Drug Development
Effectiveness
Tolerability
Central alpha2
agonists
Non-DHPCCBs
Beta blockers
DHP CCBs
ACE inhibitors
ARBs DRIs
Over the past 20 years “46 trials and more than 230,000 patients have probably been too many to end up with the current conclusion that what really matters is lowering blood pressure whatever the agents administered”
Alberto ZanchettiEditor, Journal of Hypertension, J Hypertension 2011;29:1-3
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Renal Sympathetic Efferent Nerve ActivityKidney as Recipient of Sympathetic Signals
Renal EfferentNerves
↑ Renin Release RAAS activation↑ Sodium Retention↓ Renal Blood Flow
10DiBona, Gerald F. Am. J Physiol Regul Integr Comp Physiol. 289: R633-R641, 2005
HypertrophyArrhythmiaOxygen Consumption
VasoconstrictionAtherosclerosis
InsulinResistance
Renal Sympathetic Afferent NervesKidney as Origin of Central Sympathetic Drive
Renal AfferentNerves
↑ Renin Release RAAS activation↑ Sodium Retention↓ Renal Blood Flow
Sleep Disturbances
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1930-1960s: Dr. Reginald H. Smithwick and others develop open surgical sympathectomy for malignant hypertension
Dr. Reginald H. Smithwick
Role of Sympathetic System on Resistant HypertensionEarly Surgical Precedent
1952
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• Group 1: Patients with persistently elevated BP, minimal/no eyeground changes nor abnormalities in cerebral, cardiac, or renal nerves
• Groups 2-4:Patients with increasing amounts of cardiovascular disease
100
90
80
70
60
50
40
30
20
10
00 2 3 4 5 6 7 8 9 101
Time in Years
% S
urv
iva
ls
Surgical n=1266
Medical n=467
Group 3
Group 3
Group 1
Group 2
Group 4
Group 1
Group 2
Group 4
Survival rate of normal population
Age 43
1. Adapted and reproduced with permission from Smithwick RH, Thompson JE. JAMA. 1953;152:1501-1504.2. Gewirtz JR, et al. Cardiol J. 2011;18:97-102.
However, surgical sympathectomy was associated with significant morbidity2However, surgical sympathectomy was associated with significant morbidity2
Sympathectomy in Hypertension Effects on Survival with Collateral Morbidity
• Arise from ~ T10-L2• Follow the renal artery to the kidney• Primarily lie within the adventitia
Vessel Lumen
Media
Adventitia
Renal Nerves
Renal Nerves as a Therapeutic Target
Renin-Angiotensin-Aldosterone System (RAAS) in Hypertension
Angiotensinogen Angiotensin I Angiotensin II
Renin
ACE
Pulmonary andrenal epithelium:
Decrease in renal
perfusion
Increased sympathetic activity
Tubular Na+
reabsorption, K+ excretion and water retention
Aldosteronesecretion
Vasoconstriction and increased BP
Schrier RW. Renal and Electrolyte Disorders. 5th ed. 1997.
Water andsalt retention
Effective circulating volume increases
Perfusion of the juxtaglomerular apparatus increases
ACEInhibitors
ReninInhibitors
AngiotensinInhibitors
AldosteroneInhibitors
Diuretics
✗ ✗✗
✗✗
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Stressed kidneys signal central SNS via afferent sensory nerves
Renal distress initiates afferent signal
Efferent sympathetic signals from brain initiate RAAS
RAAS stimulation; salt and water retention; increased BP
Renal Nerves and the Sympathetic Nervous System
Renal denervation therapy destroys both efferent and afferent
nerve fibers
Adapted from Schlaich MP et al. Hypertension. 2009;54:1195–1201.
✗ ✗
Proof of Principle: Therapeutic Renal Denervation and Reduction of Central Sympathetic Nerve Activity
Chart Window
MSN
A (V
)
-0.10
-0.05
-0.00
0.05
0.10
0.15
20:45 20:50 20:55 21:00
Chart Window
MSN
A (V
)
-0.10
-0.05
-0.00
0.05
0.10
0.15
8:20 8:25 8:30 8:35 8:40
baseline MSNA: 46 burst/min
3 Months FU MSNA: 33 burst/min
Chart Window
MSN
A (V)
-0.10
-0.05
-0.00
0.05
0.10
18:20 18:25 18:30 18:35 18:40 18:45
12 Months FU MSNA: 21 burst/min
Baseline
MSNA: 46 burst/minBP: 155/95 mmHg
3 Month Follow-up
MSNA: 33 burst/min (~30%)BP: 133/78 mmHg (22/17 mmHg)
12 Month Follow-up
MSNA: 21 burst/min (~54%)BP: 132/75 mmHg (23/20 mmHg)
Schlaich et al. J Htn. 2009; 27 (suppl 4):s437.
No impact on flight/fight “epinephrine” response
No blunting of baroreceptor function
Preserve central sympathetic homeostatic mechanisms
Reductions in Blood Pressure Among Early Phase RDN Trials for Refractory Stage II HTN
Blood pressure (BP) reduction in mmHg
REDUCE-HTN4
Symplicity HTN-22
Systolic BP
Diastolic BP
1 As per 09/10/2013 2 As per 05/23/2013 3 As per 10/31/2013 4 As per 10/31/20135 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 lesion7 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 thrombusSource: Clinicaltrials.gov; Press releases; Congress presentations; Medical papers
-20
-32 -28 -32 -34
-7-12 -10
-13 -13
-40
-30
-20
-10
0
18M[n=44]
12M[n=47]
6M[n=49]
1M[n=49]
3M[n=144]
1M[n=142]
Symplicity HTN-11
EnligHTN-I3
-19-22
-27 -29 -32
-9 -10-14 -14 -14
-40
-30
-20
-10
0
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]
18M[n=44]
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SYMPLICITY HTN-3: Trial Design
2:1 randomization, blinded and sham controlled
Sham procedure in control patients that included renal angiogram
535 subjects randomized out of 1441 enrolled at 88 sites in the USA (63% screen failure rate)
2-week screening process, including maximum tolerated doses of antihypertensive medications
Bhatt DL et al. N Engl J Med. 2014;370:1393–1401.
Home BP and HTN med confirmation
• Office SBP ≥160 mm Hg
• Full doses ≥3 meds
• No med changes in past 2 weeks
• No planned med changes for 6 mo
Screening visit 1
Home BP andHTN med
confirmation
Home BP andHTN med
confirmation
Primaryendpoint
2 weeks
1 Mo
1 Mo 3 Mo
3 Mo 6 Mo
6 Mo 12–60 Mo
• Patients, BP assessors and study personnel all blinded to treatment status
• No changes in medications for 6 months
2 weeks
Renal angiogram;eligible subjects
randomized
Sham procedure
Renal denervation
• Office SBP ≥160 mm Hg
• 24-hr ABPM SBP ≥135 mm Hg
• Documented med adherence
Screening visit 2 Crossover
SYMPLICITY HTN-3 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-Month SBP 165.6 168.4 0.260
Change-14.1
p<0.001-11.7
p<0.0010.255
-8
-16
n = 353 n = 171
∆S
BP
at
6 M
on
ths
0
-14.1-11.7
RDN Control
Bhatt DL et al. N Engl J Med. 2014;370:1393–1401.
Office Systolic Blood Pressure at 6 Months, 5-mm Superiority Margin
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‘We are all born ignorant, but one must work hard to remain stupid’
Next Steps in RDN TrialsHow Current Evidence Informs Challenges of Patients and Protocols
Benjamin Franklin
Renal Denervation Therapy for HypertensionWhat is Known, Needed to Know, Nice to Know
Interest Measure
SafetyPerformance
Goal
EfficacyOffice SystolicBlood Pressure
Design
Sham Blinded, Randomized,
Controlled Medicine
PopulationSevere,
Treatment-Resistant HTN
Interest Challenge
SafetyNew TechniquesNovel Devices
Efficacy ABPM
DesignRandomized
ShamWashout
Patient Population
GeneralizabilityHeterogeneity
Medication Adherence
OtherPredictors of Effect
Influence of Home BP
Before SYMPLICITY HTN 3 After SYMPLICITY HTN 3
Renal DenervationLessons Learned
• Association of increasing number of ablation attempts and circumferential ablation with greater magnitude of BP reduction1
• Combined branch and main artery treatment associated with greater and more consistent effect in preclinical models2,3
1Kandzari. Eur Heart J 2015; 2Melder. JACC 2015; 3Henegar. Am J Hypertension 2015
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Mompeo et al., Clin Anat, 2016 doi: 10.1002/ca.22720
Imndaze et al. J Interv Cardiol. 2016 Sep 29. doi: 10.1111/joic.12343
Evolving Perspective on Renal Nerve Distribution: Anatomic Data Regarding Extent of Innervation
Combined Branch and Main Artery Treatment Resulted in Greater and More Consistent Pre-Clinical Effect
Mahfoud et al. J Am Coll Cardiol. 2015;66:1766-75.
%NE Change ± SD
-71 ± 27% -83 ± 21% -92 ± 9%
Pre-clinical data show significantly greater reductions in renal sympathetic activity with combined proximal and distal therapy application.
Greater Decreases in ABPM with Distal vs. Proximal RDN Therapy Application in Treatment Resistant Hypertensive Patients
Pekarskiy EuroPCR, 2016
N=516 month change in BP with Symplicity Flex
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Renal Denervation Lessons Learned and Next Steps
• Association of increasing number of ablation attempts and circumferential ablation with greater magnitude of BP reduction1
• Combined branch and main artery treatment associated with greater and more consistent effect in preclinical models2,3
• Evolution of new technologies to permit circumferential treatment, expansion into branches, greater depth of ablation
1Kandzari. Eur Heart J 2015; 2Melder. JACC 2015; 3Henegar. Am J Hypertension 2015
Renal DenervationEnergy Sources and Access
Ablation Sources
– Radio Frequency (RF)– Ultrasound
• Internal• External
– Chemical• EtOH• Neurotoxin
– Microwave– Radioactivity
Access
• Femoral Artery
• Radial/Brachial Artery
• Renal Plexus (Urethra)
Symplicity Spyral™ Multi-Electrode Renal Denervation Catheter
• 4Fr catheter profile
• 6Fr guide catheter compatible
• 0.014” over-the-wire rapid exchange delivery
• 60-second simultaneous energy delivery
• Vessel diameter range: 3–8 mm
• Multi-sensor feedback to control energy delivery
*Performance data on file at Medtronic, Inc.
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• Minimizing Patient Variability
— Opportunities for overestimation (‘Big Day Bias’) and underestimation (‘Check Once More’) of blood pressure1
— Regression to mean
— Ambulatory blood pressure monitoring vs office systolic blood pressure
Endpoint Selection and Patient Population
1Howard. Int J Cardiology 2014
• Minimizing Patient Variability
— Opportunities for overestimation (‘Big Day Bias’) and underestimation (‘Check Once More’) of blood pressure1
— Regression to Mean
— Ambulatory blood pressure monitoring vs office systolic blood pressure
• Inclusion Blood Pressure, Indications and Endpoints
— Treatment Resistant vs Moderate Uncontrolled HTN— Isolated vs Combined Systolic HTN2
— Morning and Nighttime HTNsives3
Endpoint Selection and Patient Population
1Howard. Int J Cardiology 2014; 2Mahfoud. ACC 2015; 3Kario. Hypertension 2015
• Randomization, Sham Control and Blinding1
— Feasibility data as substitute for sham procedure— Therapies for which blinding may not be feasible/practical
• Medication Protocols and Timelines
— Drug washout 2-5
— Fixed drug regimen: 1 vs 2 vs 3 medications, classes, max dose— <3 month endpoints— Medication reinstatement
• Patient and Prescriber Behavior
— Placebo/Sham/Hawthorne effect— Drug adherence and monitoring— Influence of home BP measurement
Trial Design and Conduct
1Howard. Circ Cardiovasc Outcomes 2016; 2White. Hypertension 2011; 3DeFelice. J Hum Hypertens 20084White. J Am Soc Hypertension 2015; 5Weber. Cathet Cardiovasc Intervent 2015
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SYMPLICITY HTN-3 Confounding Factors
Drug changes and variable patient
adherence
Study population Procedural experience and variability
Superior Posterior
Kandzari et al. Eur Heart J 2014
Spyral HTN Global Clinical Trial Program
Kandzari et al. Am Heart J 2015
SPYRAL HTN Pivotal• Based on OFF/ON trial results
• Cost effectiveness data/QOL to be measured
Second Phase
SPYRAL HTN–OFF MED• Up to 100 patients
• Sham RCT (1:1)
• Main body and branch ablation
• No specific baseline medication requirement
• Compare ABPM change at 3 months
SPYRAL HTN–ON MED• Up to 100 patients
• Sham RCT (1:1), 3 medication classes
• Main body and branch ablation
• No max tolerated dose
• Compare ABPM change at 3 months
First Phase
3-4 wks
SPYRAL HTN – OFF MEDStudy Design
* Only for patients discontinuing anti-hypertensive medications
Kandzari D, et al. Am Heart J. 2016;171:82-91.
Screen failure
Office BP
Drug naïve or medications D/C
Screening visit 1
6M
12-36M
Renal denervation
Sham control
Office BP (Baseline) 24-hr ABPM Drug testing
Screening visit 2
3M
6M3M
12-36M
ABPM SBP ≥140 to <170
Office SBP ≥150 to <180 Office DBP ≥ 90 mm Hg
2-week safety check*
Follow-up every 2 weeks
Follow-up every 2 weeks
1-2 wk
OSBP≥180
ABPMOffice BP
Drug testing
Randomization /Procedure
Randomized, sham-controlled, single-blinded trial
Unblinding
Drug titrationuntil OSBP<140
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SPYRAL HTN – OFF MED
Mean ± SDRDN Sham Control
Office measurements N = 38 N = 42
Office SBP (mm Hg) 162.0 ± 7.6 161.4 ± 6.4
Office DBP (mm Hg) 99.9 ± 6.8 101.5 ± 7.5
Office heart rate (bpm) 71.1 ± 11.0 73.4 ± 9.8
24-hour measurements N = 37 N = 42
Mean 24-hour SBP (mm Hg) 153.4 ± 9.0 151.6 ± 7.4
Mean 24-hour DBP (mm Hg) 99.1 ± 7.7 98.7 ± 8.2
Mean 24-hour heart rate (bpm) 72.3 ± 10.9 75.5 ± 11.5
Baseline Blood Pressure
P = NS for differences in all baseline characteristics
Boehm et al. ESC 2017; Townsend et al. Lancet 2017
SPYRAL HTN – OFF MED
Mean ± SDRDN Sham Control
Office measurements N = 38 N = 42
Office SBP (mm Hg) 162.0 ± 7.6 161.4 ± 6.4
Office DBP (mm Hg) 99.9 ± 6.8 101.5 ± 7.5
Office heart rate (bpm) 71.1 ± 11.0 73.4 ± 9.8
24-hour measurements N = 37 N = 42
Mean 24-hour SBP (mm Hg) 153.4 ± 9.0 151.6 ± 7.4
Mean 24-hour DBP (mm Hg) 99.1 ± 7.7 98.7 ± 8.2
Mean 24-hour heart rate (bpm) 72.3 ± 10.9 75.5 ± 11.5
Baseline Blood Pressure
P = NS for differences in all baseline characteristics
Boehm et al. ESC 2017; Townsend et al. Lancet 2017
SPYRAL HTN – OFF MEDBlood Pressure Change from Baseline to 3 Months: 24-Hr ABPM
-5.5(-9.1, -2.0)P=0.003
-4.8(-7.0, -2.6)P<0.001
-0.5(-3.9, 2.9)
P=0.76
-0.4(-2.2, 1.4)
P=0.65
-14
-12
-10
-8
-6
-4
-2
0
BP C
hang
e fro
m b
asel
ine
to 3
mon
ths
(mm
Hg)
Chart Title
RDN Sham
Δ -4.4 mmHg(-7.2, -1.6)
P=0.002
n=35 n=35
Systolic Diastolic
Δ -5.0 mmHg(-9.9, -0.2)
P=0.04
Baseline BP (mmHg) 154 152 100 99n=36 n=36
Boehm et al. ESC 2017; Townsend et al. Lancet 2017
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SPYRAL HTN – OFF MEDBlood Pressure Change from Baseline to 3 Months: Office BP
-10.0(-15.1, -4.9)
P<0.001
-5.3(-7.8, -2.7)P<0.001
-2.3(-6.1, 1.6)
P=0.24
-0.3(-2.9, 2.2)
P=0.81
-14
-12
-10
-8
-6
-4
-2
0
BP C
hang
e fro
m b
asel
ine
to 3
mon
ths
(mm
Hg)
Chart Title
RDN Sham
Systolic Diastolic
n=37 n=37
Baseline BP (mmHg) 162 161 100 101n=41 n=41
Δ -4.9 mmHg(-8.5, -1.4)
P=0.008
Δ -7.7 mmHg(-14.0, -1.5)
P=0.02
Boehm et al. ESC 2017; Townsend et al. Lancet 2017
SPYRAL HTN – OFF MED
% (N) RDN Sham Control P value
No anti-HTN drug identified by drug testing:
At baseline 92.1% (35/38) 88.1% (37/42) 0.72
At 3 months 94.3% (33/35) 92.7% (38/41) 1.00
At baseline and 3 months 88.6% (31/35) 82.9% (34/41) 0.53
Patients meeting escape criteria (n) 2 4
Protocol Adherence
Drug testing of urine and serum by tandem HPLC and mass spectroscopy
Boehm et al. ESC 2017; Townsend et al. Lancet 2017
Key Design Differences Between SYMPLICITY HTN 3 and SPYRAL HTN OFF MED Trials
SYMPLICITY HTN-3 SPYRAL HTN – OFF MED
Geography US US, Europe, Australia, Japan
Office Systolic Blood Pressure Range 180 mmHg 162 mmHg
Baseline Prescribed Antihypertensive Drugs
5.1 0
Radiofrequency Denervation System mono-electrode, sequential 4-electrode, simultaneous
Accessible Vessels Treated main arterymain, branch, accessory
arteries
Number Ablations per Patient 11.2 43.8
Drug Testing No Yes
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Xie X, et al. Lancet. 2016;387:435-443.
Meta-Analysis: Intensive BP Lowering
– Patients in the more intensive BP-lowering treatment group had Mean BP levels of 133/76 mm Hg vs 140/81 mm Hg in the
less intensive treatment group
-25
-20
-15
-10
-5
0
MACE MI Stroke
RR 14%(95% CI: 4,22)
RR 13%(95% CI: 0,24)
RR 22%(95% CI: 10,32)
Intensive BP-Lowering Treatment RR Reductions
Ris
k R
educ
tion,
%
Risk Reduction for a 10 mm Hg Fall in SBP
20
17
2728
13
0
5
10
15
20
25
30
Major CVD CHD Stroke HF Mortality
% risk reduction
Irrespective of baseline BP
or pre-existing conditions
N= 613,815
Ettehad D, Emdin CA, Kiran A, et al. Lancet. 2016; 387: 957-67.
SPYRAL HTN OFF MEDPerspective: Extrapolated Risk Reduction
Ettehad D, Emdin CA, Kiran A, et al. Lancet. 2016; 387: 957-67.
Meta analysis of 123 studies
N= 613,815 patients
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Egan et al. Circulation. 130:1692–1699. National Health and Nutrition Examination Survey.
01999–2000 2001–2002 2003–2004 2005–2006 2007–2008 2009–2010 2011–2012
40
60
80
100
(%)
Prevalence
Control
Control/treated
Treatment
Aware
Despite steady prevalence of hypertension, the proportion of patients who achieve “control” has plateaued or decreasing in recent years
Polypharmacy Strategy Is Failing to Achieve Goals for Hypertension Control
Non Adherence to Antihypertensive Medications is Highly Prevalent
1Ritchey O et al. CDC Morbidity and Mortality Weekly Report. September 13, 2016.
2Blaschke T, et al. Annu. Rev. Pharmacol. Toxicol. 2012.52:275-301.
5 millionMedicare beneficiaries (26%) are non-adherent to antihypertensive drugs putting them at risk for severe health complications, including heart disease, stroke, kidney disease, and early death1
• Up to 50% of patients maybecome non-adherent within one year of initiating oral drug therapy.2
• Physicians generally tend to overestimate patient’s adherence.
• Clinicians’ estimates of non-adherence are very poor, with a positive predictive
value of only approximately 30%.
• In fact, detecting non-adherence in clinical practice is almost impossible.
26%
TITRE: average TIme per year spent by newly-identified hypertensive patients at BP care TaRgEt
• Few patients sustained complete, year-round on-target BP over time
• A higher time at target was associated with a lower risk of incident CVDs, independent of widely-used BP control indicators
Chung, S., et al. 2017
Only 5% at target for 9 months or more
>50% at target for 6 months or less
TITRE: Time at Target BP is Associated with Lower CV Risk
PATIENTS ARE RARELY AT BP TARGET FOR SUSTAINED PERIOD OF TIME
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Key Barriers to Drug Adherence: FOCUS Trial Results
RESULTS FROM COUNTRY-ADJUSTED STEPWISE VARIABLE SELECTION MODEL
Degree social support
Insurance coverage (%)
Complexity of therapy
Younger age <50
Depression severity
NONADHERENTADHERENT
0 1 1.5
Castellano M et al. J Am Coll Cardiol. 2014;64:613–621.
Up to 30% of Adults Would Rather Die Early than Submit to Lifelong Polypharmacy
Hutchins et al. Circ Cardiovasc Qual Outcomes. 2015;8:00-00. DOI: 10.1161/CIRCOUTCOMES.114.001240.
69.7
5.53.1 4.1 2.2 2.5 0.5
3.70.5
8.2
0.00 1.00 2.00 4.35 13.04 26.09 39.13 52.18 78.27 104.36
People (%)
Number of Weeks Willing to Trade
N = 1000
0
20
40
60
80
8.2% of adults would give up 2 years of their life to avoid adding 1 daily pillFor every 100 prescriptions written…
National Association of Chain Drug Stores Pharmacies: Improving Health, Reducing Costs. July 2010. Based on IMS Health data.
502515
Rx picked-up
Taken properly
Rx re-filled
Non Adherence to Antihyprtensive Drug Therapy is Widespread, Dynamic and Difficult to Detect
Proportion of pts with resistant HTN
with partial/complete nonadherence
according to drug monitoring
Berra E, et al. Hypertension. 2016;68:297-306
2/7/2018
18
SPYRAL HTN OFF MED
• Proof of principle of renal denervation for hypertension in the absence of drugs
• Clinically meaningful blood pressure reductions at 3 months
– In mild to moderate hypertensive patients treated with RDN
– In the absence of anti-hypertensive medications compared to sham control
• No major safety events
– Despite a more complete denervation procedure that extended into renal artery branch vessels
The results of this study will inform the design of a larger pivotal trial
The impact of reducing medication burden may be more than initially estimated
Conclusions
SPYRAL HTN ON MED
Office SBP
1st screening
1 Mo 6 Mo
12 Mo
Randomisation/Procedure
Sham procedure + meds
Renal denervation + meds
3 Mo
1 Mo 6 Mo3 Mo
N<50
N<50
Office SBP >150 and <180 mm Hg on
1,2 or 3 meds for 6 weeks
Office BPOffice BP
ABPM
Urinalysis
Observed drug intake
Office SBP
ABPM
2nd screening
Drug testing
12–36 Mo
Unblinding
ABPM≥140 to <170
Office ≥150 and <180
DBP ≥ 90
2–4 weeks
Confirmed on meds Thiazide-type diuretic
Calcium channel blocker
ACE/ARB
Beta Blocker
Stable meds
Results expected mid-2018
• Studies that inform design, conduct and patient population of next generation of RDN trials
– Observations and exploratory analyses of predicate trials
– Studies that encourage clinical efficacy of RDN for HTN
• Motivated by increasing awareness of benefits associated with intensive BP lowering against background of challenges and limitations with pharmacology
• Forthcoming evaluation of RDN for HTN require careful trial design that:
– Demonstrates biologic efficacy in context of on and off medications, and
– Differentiates potential confounders of observer and patient bias
– Focus on less variable and more independent endpoints (eg, ABPM)
– Explore opportunities for more effective ablation based on technology and anatomy
Next Steps in RDN TrialsHow Current Evidence Informs Challenges of Patients and Protocols
2/7/2018
19
RDN (n=73)RDN (n=73) Sham (n=73)Sham (n=73)
RADIANCE TRIO Cohort(Resistant HTN)
RADIANCE TRIO Cohort(Resistant HTN)
Stabilize 4 weeksHome BP Monitoring
Stabilize 4 weeksHome BP Monitoring
Washout 4 weeksHome BP Monitoring
Washout 4 weeksHome BP Monitoring
Discontinue HTN meds Discontinue HTN meds
Hypertensive Patient PopulationHypertensive Patient Population
Replace HTN meds with fixed dose, triple HTN combo
Replace HTN meds with fixed dose, triple HTN combo
Elevated Daytime ABP ≥ 135/85 mmHg
< 170/105 mmHg
Elevated Daytime ABP ≥ 135/85 mmHg
< 170/105 mmHg
RADIANCE SOLO Cohort(Essential HTN)
RADIANCE SOLO Cohort(Essential HTN)
Elevated Daytime ABP ≥ 135/85 mmHg
Elevated Daytime ABP ≥ 135/85 mmHg
CTA / MRADuplex
CTA / MRADuplexUrine Analysis,
BiomarkersMMAS-8
Urine Analysis, Biomarkers
MMAS-8
CTA / MRADuplex
CTA / MRADuplex
RDN (n=73)RDN (n=73) Sham (n=73)Sham (n=73)
Primary Efficacy EndpointDifference in Daytime Ambulatory Systolic BP @ 2 months
Primary Efficacy EndpointDifference in Daytime Ambulatory Systolic BP @ 2 months
RADIANCE-HTN Study Design
Clinicaltrials.gov NCT02649426
Marcia P, Age 69
Arteriovenous Anastamosis for Hypertension
2/7/2018
20
Marcia P, Age 69
Arteriovenous Anastamosis for Hypertension
Arteriovenous Anastamosis for Hypertension
Placement between Iliac Artery & Vein
Lobo M et al; Lancet. 2015 Apr 25;385(9978):1634-41.
DBS
Median Nerve
Carotid Body
Endovascular Baroreceptor Stim
A-V Coupler
Baroreceptor Activation
Renal Denervation
The future of other potential device technologies for hypertension therapy may rely on the success of ongoing renal denervation trials