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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

11

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


# of pts (target enrollment): 106 [randomized1:1]

Main endpoint:Blood pressure reduction

MAE: 25

Study details

Start: 10/2011


# of pts (target enrollment): 47

Main endpoint: Office blood pressure

MAE: [0/4]6

Study details

Start: 02/2012


# 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


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


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


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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



% (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


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


< 170/105 mmHg

RADIANCE SOLO Cohort(Essential HTN)

RADIANCE SOLO Cohort(Essential HTN)



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



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

device therapties for hypertension including renal ... · alpha blockers thiazide diuretics direct...

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