what’s new in interventional cardiology

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What’s New In Interventional Cardiology

Yerem Yeghiazarians, MD

Yerem Yeghiazarians, M.D.Leone-Perkins Family Endowed Chair in Cardiology

University of California, San FranciscoJune 24, 2013

Yerem Yeghiazarians, MDDisclosures:

No conflicts of interest

Today’s Topics

Case 1: When to worry about a stress test result and how best to manage high risk patients with CAD?

Case 2: When to look for and treat secondary hypertension due to renal artery disease?

Case 3: What to do with non-operable or high-risk patients with severe aortic stenosis?

Today’s Topics




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Case 1 – Mr. C.N.

• 78 y.o. man very active male with reported cardiac risk factors of HTN, HL, and pre-diabetes who presented with progressive exertional chest pain x 1 month. Saw his PCP and referred to a referring cardiologist (4/2013).

Physical Exam

• BP 115/75; HR 64; RR 12; O2sat 98% on RA

• Gen: NAD, AAOx3

• Neck: JVP flat

• Chest: CTAB

• CV: RRR, normal S1/S2, no m/g/r

• Abd: soft, NTND, no abdominal bruit

• Ext: no edema, warm ext

Mr. C. N.

• No cardiac meds

• EKG with RBBB

• CXR normal

• Labs at baseline normal

• Lipids –TC 217, LDL 132, HDL 43, TG 208

• Bruce protocol, 6’05”, 7.1 METS, 8-9/10 chest pain at peak exercise, ST depression 0.75 mm V2-6

– Ischemia entire septum as well as mid-distal anterior wall to apex

– EF dropped from 50% to 20%

– LV cavity enlarged with stress compared with rest

Stress Myocardial Perfusion

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How would you manage him next?

S t ar t a

s p ir i n ,

. . . S t a

r t as p i

r i n ,. . .

S t ar t a

s p ir i n ,

. . . S t a

r t as p i

r i n ,. . .

3% 3%

92%

3%

A. Start aspirin, beta-blocker and treat symptoms with nitrates

B. Start aspirin, beta-blocker, statin and see how he does

C. Start aspirin, beta-blocker, statin and refer for cardiac cath

D. Start aspirin, beta-blocker and get a stress echocardiogram

• Decision was made by his PCP and referring Cardiologist, presumably based on the Courage Trial, to treat medically

• Aspirin, Metoprolol 25mg BID, Imdur 30mg QD

When not to say you are following the

COURAGE Trial?

This is a good example

COURAGE TRIAL

• 2,287 patients in US and Canada

• Coronary artery disease documented by coronary angiography + ischemia

• Randomized to optimal medical therapy (OMT) or PCI +OMT (PCI)

Boden et al NEJM 2007

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COURAGE TRIAL

Inclusion criteria:• ≥ one 70% stenosis +

abnormal ECG /positive stress test

OR• ≥ one 80% stenosis +

angina

Exclusion criteria• CCS class IV angina• Markedly positive stress

test• Refractory heart failure• LVEF < 30%• Revascularization w/in

6 months• Cardiogenic shock• Unsuitable coronary

anatomyBoden et al NEJM 2007

COURAGE TRIAL

Inclusion criteria:• ≥ one 70% stenosis +

abnormal ECG /positive stress test

OR• ≥ one 80% stenosis +

angina

Exclusion criteria• CCS class IV angina• Markedly positive stress

test• Refractory heart failure• LVEF < 30%• Revascularization w/in

6 months• Cardiogenic shock• Unsuitable coronary

anatomyBoden et al NEJM 2007

COURAGE - Results


SURVIVAL FREE of DEATH and MI OVERALL SURVIVAL

SURVIVAL FREE of ACS SURVIVAL FREE of MI

COURAGE - Results

0

10

20

30

40

50

60

70

80

90

Baseline 1 year 3 year 5 year

OMTPCI

p<0.001p=0.02

p=ns

p=ns

% Patients with angina


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COURAGE –Issues to keep in mind

• Of the >35,000 patients screened, only ~2,287 were eligible and randomized (~6%)– Not your “real world practice”

• 42% of patients had class 0 or 1 angina at baseline

• 33% of OMT group had PCI or CABG

• Drug eluting stents in only ~3% • All patients had a cardiac cath to define the

anatomy firstShaw, L. J. et al. Circulation 2008;117:1283-1291

COURAGE Nuclear Substudy

Ischemia Reduction and Outcome

Cum

ulat

ive

Eve

nt-F

ree

Sur

viva

l

Findings suggest a treatment target of ≥5% ischemia reduction

When to get concerned about stress test

findings?

Typical angina Atypical angina

Non-anginalchest pain

AGE Men Women Men Women Men Women

30-39 69.7 25.8 21.8 4.2 5.2 0.8

40-49 87.3 55.2 46.1 13.3 14.1 2.8

50-59 92.0 79.4 58.9 32.4 21.5 8.4

60-69 94.3 90.6 90.6 54.6 28.1 18.6

Diamond, Forrester et al JCI 1980

Pre-test Probability of CAD

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• Early positive-stage I: Mortality >5%/year• Strongly positive > 2.5 mm ST depression• ST elevation > 1 mm in leads without Q waves• Fall in SBP >10 mm Hg• Early onset ventricular arrhythmias• Chronotropic incompetence (HR <120/min not

due to drugs)• Prolonged ischemic changes in recovery

> 2mm lasting > 6 minutes in multiple leads

High Risk Features on Stress Testing Prognostic Information -- Stress Testing Duke treadmill score = duration of exercise in minutes on the Bruce protocol- (minus) 5x maximal mm ST deviation- (minus) 4x treadmill angina index

Angina score:0 if no angina.1 if non-limiting angina.2 if limiting angina.

High Risk < -10 79% 4-year survivalModerate Risk -10 to +4 95% 4-year survivalLow Risk >+5 99% 4-year survival

Mark et al, Ann Int Med 1987

Prognostic Information -- Stress Testing Duke treadmill score = duration of exercise in minutes on the Bruce protocol- (minus) 5x maximal mm ST deviation- (minus) 4x treadmill angina index

Angina score:0 if no angina.1 if non-limiting angina.2 if limiting angina.

High Risk < -10 79% 4-year survivalModerate Risk -10 to +4 95% 4-year survivalLow Risk >+5 99% 4-year survival

Mark et al, Ann Int Med 1987

Our patient:

6 – 5 (0.75) – 4 (2) = - 5.75

• Large defect

• Multiple moderate defects

• LV dilation or increased lung thaliumuptake indicating low cardiac output or elevated LVEDP

• Echo abnormal in >2 segments at low dose dobutamine or low heart rate (<120 bpm)

• Drop in LVEF

High Risk Features on Stress Testing

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• Bruce protocol, 6’05”, 7.1 METS, 8-9/10 chest pain at peak exercise, ST depression 0.75 mm V2-6

– Ischemia entire septum as well as mid-distal anterior wall to apex

– EF dropped from 50% to 20%

– LV cavity enlarged with stress compared with rest

Reminder: our patient’s stress testStress Myocardial Perfusion

• Large defect

• Multiple moderate defects

• LV dilation or increased lung thaliumuptake indicating low cardiac output or elevated LVEDP

• Drop in LVEF

High Risk Features on Stress TestingOur patient

This patient would have been excluded from the

Courage Trial – he has very high risk features and you

need to define his anatomy

A) Start aspirin, beta-blocker and treat symptoms with nitrates

B) Start aspirin, beta-blocker, statin and see how he does

C) Start aspirin, beta-blocker, statin and refer for cardiac cath

D) Start aspirin, beta-blocker and get a stress echocardiogram

How would you manage him next?

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GNL 2011GNL 2011 GNL 2011

Anatomy RevascMethod

COR LOE

3 VD +/- Proximal LAD Disease*#

CABG I BPCI IIbOf uncertain benefit B

2 VD With Proximal LAD Disease#


2 VD Without Proximal LAD Disease#

CABG IIaWith extensive ischemia BIIbOf uncertain benefit without extensive

ischemiaC

PCI IIbOf uncertain benefit B1 VD With Proximal LAD disease

CABG IIaWith LIMA for long-term benefit BPCI IIbOf uncertain benefit B

1 VD WithoutProximal LAD disease

CABG III: Harm BPCI III: Harm B

*Reasonable to choose CABG over PCI for good CABG candidates with complex 3-vessel disease (e.g., SYNTAX score >22) (Class IIa; LOE:B)

#Reasonable to choose CABG over PCI for MVD in patients with DM (Class IIa; LOE:B)

Revascularization to Improve Survival

GNL 2011

• Left Main disease• Survivors of sudden cardiac death with

presumed ischemia-mediated VT

GNL 2011

Anatomy RevascMethod

COR LOE

3 VD +/- Proximal LAD Disease*#


2 VD With Proximal LAD Disease#


2 VD Without Proximal LAD Disease#

CABG IIaWith extensive ischemia BIIbOf uncertain benefit without extensive

ischemiaC

PCI IIbOf uncertain benefit B1 VD With Proximal LAD disease

CABG IIaWith LIMA for long-term benefit BPCI IIbOf uncertain benefit B

1 VD WithoutProximal LAD disease

CABG III: Harm BPCI III: Harm B

*Reasonable to choose CABG over PCI for good CABG candidates with complex 3-vessel disease (e.g., SYNTAX score >22) (Class IIa; LOE:B)

#Reasonable to choose CABG over PCI for MVD in patients with DM (Class IIa; LOE:B)

Revascularization to Improve Survival

GNL 2011

• Left Main disease• Survivors of sudden cardiac death with

presumed ischemia-mediated VT

GNL 2011

Revascularization to Improve SymptomsClinical Setting COR LOE

≥1 significant stenoses amenable to revascularization and unacceptable angina despite GDMT

I−CABG AI−PCI

≥1 significant stenoses and unacceptable angina in whom GDMT cannot be implemented because of medication contraindications, adverse effects, or patient preferences

IIa−CABG CIIa−PCI

Previous CABG with ≥1 significant stenoses associated with ischemia and unacceptable angina despite GDMT

IIb-CABG CIIa−PCI C

Complex 3 VD (e.g., SYNTAX score >22) +/-involvement of the proximal LAD and a good candidate for CABG

IIa−CABG preferred over PCI

B

No anatomic or physiologic criteria for revascularization

III: Harm−CABG CIII: Harm−PCI

GNL 2011

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Case 1: Back to Mr. C. N.

• 4 days later, he continued to have persistent symptoms and comes to UCSF ER

• EKG with RBBB and NSSTT waves

• Troponin 0.72 (nl <0.05 µg/L)

• Treated with aspirin 325 mg, Clopidogrel 600 mg, and started on IV Heparin

• Persistent on/off chest pains

• Cardiology consulted

• Cardiac cath recommended for ACS

New clinical classification of MIClassification Description1 Spontaneous MI related to ischemia due to a

primary coronary event, such as plaque erosion and/or rupture, fissuring, or dissection

2 MI secondary to ischemia due to an imbalance of O2supply and demand, as from coronary spasm or embolism, anemia, arrhythmias, hypertension, or hypotension

3 Sudden unexpected cardiac death, including cardiac arrest, often with symptoms suggesting ischemia with new ST-segment elevation; new left bundle branch block; or pathologic or angiographic evidence of fresh coronary thrombus--in the absence of reliable biomarker findings

4a MI associated with PCI4b MI associated with documented in-stent thrombosis5 MI associated with CABG surgery

Thygesen K et al. Circulation 2007; available at: http://circ.ahajournals.org.

GNL 2011

General Considerations in Deciding Between an Early Invasive Strategy and an Initial Conservative Strategy in UA/NSTEMI

Early Invasive Strategy Generally Preferred

Initial Conservative Strategy Generally Preferred or Reasonable

• Recurrent angina or ischemia at rest or with low level activities despite intensive medical therapy

• Elevated cardiac biomarkers (TnT or TnI)• New or presumably new ST-depression • Signs or symptoms of heart failure• Hemodynamic instability• High risk score (e.g., GRACE, TIMI)• Sustained ventricular tachycardia• PCI within 6 mo• Prior CABG• Diabetes mellitus• Mild to moderate renal dysfunction• Reduced LV function (LVEF <40%)

• Low risk score (e.g., GRACE, TIMI)• Absence of high-risk features• High risk for catheterization-related

complications• Patient not a revascularization candidate

(with either PCI or CABG)• Patient prefers conservative therapy

GNL 2011

Right Coronary Artery

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Left Coronary System Left Coronary System

Long-term Rx: ACS

1. Aspirin 81 mg daily (lifelong)

2. Clopidogrel, Prasugrel or Ticagrelor (at least one year)

3. β-Blocker

4. Lipid-lowering agentgoal LDL < 70

5. ACEI or ARB especially for patients with CHF, LV dysfunction (EF<0.40), hypertension, or diabetes

6. Aldosterone blockers (Eplerenone) for patients with LV EF < 40% and CHF.

7. Smoke cessation and lifestyle modifications as indicated

Today’s Topics




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Case 2 – Ms. Y.

• 26 y.o. woman noted to have HTN in July 2012

• Fam Hx: cousin in her 20’s has HTN

• Meds: Amlodipine 10mg po daily

Physical Exam

• BP 181/123 bilaterally and in the legs ;

HR 75; RR 12; O2sat 98% on RA

• Gen: NAD, AAOx3

• Neck: JVP flat

• Chest: CTAB

• CV: RRR, norm S1/S2, no m/g/r

• Abd: soft, NTND, no abdominal bruit

• Ext: no edema, warm ext

Labs

4.114.1

41.3252

10138

2.7

99

29 0.8

34.2

1.0

Plasma renin activity: 29.87 (norm 0.25-5.82)Serum aldosterone: 130 (norm < 28)

Imaging

• Renal artery vascular study

– Severe proximal right renal artery stenosis

– Left renal artery normal

• CTA brain

– No evidence of aneurysm

• MRA Abdomen

– Narrowing of proximal right renal artery just distal to ostium

– Asymmetric small size of right kidney

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Renal angiogram12/4/12

Renal Angiogram

Renal Angiogram Renal Angiogram

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LabsDate 9/27/1

211/20/12 11/28/12 12/20/12 2/6/13

Serum K 2.7 3.8 4.2 4.1

Aldosterone(ref <21-28)

57 46 130 14 19

Renin(ref 0.25-5.82)

11.7 17.2 29.9 0.84 2.86

Misc TTKG=8Patient placed on KCL supplement

TTKG=9.8On KCL 60meq daily

BP normal off meds

Off KCLBP normal off meds

Renal Artery Angioplasty Performed

Renal Artery Disease -- FMD– Fibromuscular dysplasia (FMD):

� Younger (<50), women, “beads on a string” angio� Progression to complete occlusion of renal artery rare� 80% Medial fibroplasia >> intimal (~10%) or

adventitial� 60% bilateral� In 25%, disease extends into segmental arteries� Other arteries can also be involved (carotid,

vertebral, iliac and mesenteric)� All patients need head imaging to r/o cerebral

aneurysms

Atherosclerotic Renal Artery Disease (RAS)– Prevalence of RAS ~1-6%– As high as 25-50% if atherosclerosis is present in other vascular beds

– 70-80% unilateral– Most common cause of secondary HTN– Probably, 10-15% of patients beginning dialysis have RAS of some severity

ACC/AHA Practice Guidelines 2005; White CJ 2007

Renal Artery Disease (RAS)– Progressive disease:

� 48% of patients with <60% stenosis progress to >60% over 3 years

� 39% patients with >75% stenosis progress to complete occlusion over 1-5 years

– Average progression ~7% per year– Note that progression of RAS and loss of renal function occur independently of blood pressure control


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Clinical Clues to the Diagnosis of RAS

� Onset of HTN before age 30 or severe HTN after age 55� Accelerated, resistant, or malignant HTN� New azotemia or worsening renal fxn after Ace-inhibitor or ARB Rx� Unexplained atrophic kidney or size discrepancy between kidneys > 1.5 cm� Sudden unexplained pulmonary edema� Unexplained renal dysfunction� Multi-vessel CAD


Asymptomatic RAS� No evidence to support benefit for treatment of asymptomatic RAS

� Class IIb (level of evidence C) �treatment of significant bilateral RAS or unilateral RAS in solitary kidney

Cardiac Destabilization Syndromes

� Class I (LOE B)– Revascularization is indicated in patients with hemodynamically significant RAS if recurrent unexplained heart failure or sudden unexplained pulmomary edema

� Class IIa (LOE B)– Revascularization is reasonable for unilateral

significant RAS with unstable anginaACC/AHA Practice Guidelines 2005

Conditions to At Least Consider Revascularization if RAS ≥ ~70% (Controversial)� Medically refractory hypertension (≥3 Rx at max doses) >140/90. But also consider if:

– Malignant HTN on meds: end-organ damage– Accelerated HTN: sudden, persistent worsening of previously controlled HTN

� Significant HTN + FMD� ARF after starting ACE-I� Recurrent flash pulmonary edema in setting of uncontrolled HTN� Severe RAS in solitary kidney� Severe bilateral RAS� Subacute renal failure (<6 mo), esp if creat <3.0, kidney size ≥ 9 cm in length

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Renal Denervation

Caution: The Symplicity® Catheter System™ is an Investigational Device. Limited by U.S. law to investigational use. For OMA distribution only. © 2011 Medtronic, Inc. All rights reserved. 10014487DOC-1B 11/2011

Resistant Hypertension

1. Calhoun DA, et al. Circulation. 2008;117;e510-e526.2. Makris A, et al. Int J Hypertens. 2011;doi: 10.4061/2011/598694.3. Papademetriou V, et al. Int J Hypertens. 2011;doi:10.4061/2011/196518.

Causes of PseudoresistantHypertension1,2

Suboptimal dosing of antihypertensive agents

White coat effect

Suboptimal BP measurement technique

Lifestyle factors

Medications that interfere with BP control

Pseudoresistance caused by poor adherence to prescribed medication

However, a majority of

patients with resistant

hypertension and no identifiable

secondary causes have an activated

sympathetic nervous system and increased sympathetic outflow3

Secondary Causes of Hypertension1,2

Obstructive sleep apnea

Primary aldosteronism

Renal artery stenosis

Caution: The Symplicity® Renal Denervation System™ is an Investigational Device. Limited by U.S. law to investigational use.


Even Small Reductions in BP Reduce Risk of CV Mortality

SBP = systolic blood pressure.Lewington S, et al. Lancet. 2002;360:1903-1913.

2 mm Hg decrease in mean office SBP 10% reduction in risk

of stroke mortality

7% reduction in risk of ischemic heart disease mortality

Caution: The Symplicity® Renal Denervation System™ is an Investigational Device. Limited by U.S. law to investigational use. Caution: The Symplicity® Catheter System™ is an Investigational Device. Limited by U.S. law to investigational

use. For OMA distribution only. © 2011 Medtronic, Inc. All rights reserved. 10014487DOC-1B 11/2011

Afferent Renal Sympathetics

The kidney is a source of central sympathetic activity, sending signals to the CNS

Efferent Sympathetics

Sympathetic signals from the CNS modulate the physiology of

the kidneys

Renal Nerves and the SNS

Adapted from Schlaich MP, et al. Hypertension. 2009;54:1195-1201.

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The Sympathetic Nervous System

• The SNS supplies catabolic signals to the body, acting whenever rapid response to the environment is needed

• Functions include:

– Accelerating the heart

– Dilating coronary vessels

– Increasing arterial BP

– Emptying blood reservoirs

– Dilating bronchi

– Releasing glucose

– Inhibiting GI activityGI=gastrointestinal.Campbell WW. DeJong’s The Neurologic Examination: Incorporating the Fundamentals of Neuroanatomy and Neurophysiology. 6th ed. 2005.

Epinephrine—adrenal glandsNorepinephrine—kidney

Dilates pupilsInhibits salivation

Relaxes bronchi

Accelerates heart

Inhibits digestive activity

Stimulates glucose release by liver

Relaxes bladder

Contracts rectum

Cerv

ical

Thor

acic

Lumba

r


Dr. Reginald H. Smithwick

Sympathectomy: An Early Surgical Procedure

1952

Photo of Dr. Smithwick reproduced with permission from JAMA.


CONFIDENTIALVersion Date: 28JUN2011

• Nerves arise from T10-L2• The nerves arborize around the artery

and primarily lie within the adventitia

Renal Nerve Anatomy

Vessel Lumen

Media

AdventitiaRenal

Nerves

6767


• Standard interventional technique• 4-6 two-minute treatments per artery

Renal Nerve Anatomy Allows a Catheter-Based Approach

68

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6969

Symplicity Investigational Catheter Device• Generator will automatically control RF energy delivery:

– Power automatically ramped and maintained (5-8W)– Continuously monitors temperature and impedance– Automatically shuts off after 2 min or when either impedance or

temperature exceed program limits

Flexible Tip (self-orienting)

5mm 12mmDeflectable

Shaft

EnligHTN – St. Jude Medical OneShot – CovidienSingle 2-minute inflation

Paradise – ReCor MedicalCircumferential catheter-based ultrasound technology


Renal Denervation Preclinical Efficacy and Safety• Extensive research in >300 swine• Effectiveness:

– Significant reduction in renal tissue NE

• Safety:– Verification testing included

angiography, gross pathology, histopathology, & clinical pathology at 7, 30, 60, and 180 days

– Intact endothelium by 7 days– Vascular healing observed at 30

and 60 days; by 180 days, arteries were well healed (no inflammatory cells) – treatment sites were considered sterile and stable

– No stenosis or luminal reduction seen in any treated artery through 180 days

Ren

al T

issu

e N

E (

pg/m

g)

P<0.0001

P=1.0

Data on file. Medtronic, Inc.


Staged Clinical Evaluation

First-in-Man �

Series of Pilot studies �

Symplicity HTN-2 �EU/AU Randomized Clinical Trial

Symplicity HTN-1

USA

Symplicity HTN-3US Randomized Clinical Trial

(ongoing)

EU/AU

Other Areas of Research:Insulin Resistance, HF/Cardiorenal,

Sleep Apnea, More

73

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Initial Cohort – Reported in the Lancet , 2009:-First-in-man, non-randomized-Cohort of 45 patients with resistant HTN (SBP ≥160 mmHg on ≥3 anti-HTN drugs, including a diuretic; eGFR ≥ 45 mL/min) - 12-month data\

Expanded Cohort – This Report (Symplicity HTN-1):-Expanded cohort of patients (n=153)-24-month follow-up

Lancet. 2009;373:1275-1281

74

Symplicity HTN-1

Symplicity HTN-1 Investigators. Hypertension. 2011;57:911-917.

Hypertension. 2011;57:911-917.


Significant, Sustained BP Reduction

BP change(mmHg)

-20 -24 -25 -23 -26 -32-10 -11 -11 -11 -14 -14

-50

-40

-30

-20

-10

0

10

1 M(n=138)

3 M(n=135)

6 M(n=86)

12 M(n=64)

18 M(n=36)

24 M(n=18)

Systolic Diastolic

75

Symplicity HTN-1 Investigators. Hypertension. 2011;57:911-917.


• Purpose: To demonstrate the effectiveness of catheter-based renal denervation for reducing blood pressure in patients with uncontrolled hypertension in a prospective, randomized, controlled, clinical trial

• Patients: 106 patients randomized 1:1 to treatment with renal denervation vs. control

• Clinical Sites: 24 centers in Europe, Australia, & New Zealand (67% were designated hypertension centers of excellence)

76

Symplicity HTN-2

Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909.

Lancet. 2010;376:1903-1909.


Primary Endpoint: 6-Month Office BP

∆ from Baseline

to 6 Months (mmHg)

33/11 mmHg difference between RDN and Control

(p<0.0001)

• 84% of RDN patients had ≥ 10 mmHg reduction in SBP• 10% of RDN patients had no reduction in SBP

77

Systolic

Diastolic

Systolic Diastolic


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Time Course of Office BP Change

-20-24

-32

-7 -8-12

-50

-40

-30

-20

-10

0

1M 3M 6M

SystolicDiastolic

† p<0.0001 for between-group comparisons†† p=0.002 for between-group comparisons††† p=0.005 for between-group comparisonsTwo-way repeated measures ANOVA, p=0.001

RDN∆ from

Baseline (mmHg)

78

0

-4

10

-2

0

-30

-20

-10

0

10

20

SystolicDiastolic

Control∆ from

Baseline (mmHg)

††

†

††† †††



Symplicity HTN-3:Overview

• Design– Multicenter (60 sites in the United States), prospective, randomized,

blinded, controlled study

• Population– 530 patients with treatment-resistant hypertension

• Treatment– Treatment group (endovascular catheter-based RDN with the Symplicity®

Renal Denervation System™ plus baseline antihypertensive medications)

– Control group (sham procedure* plus baseline antihypertensive medications)

• Primary Outcome Measures– Change in office SBP from baseline to 6 months

– Safety*The renal angiogram also acts as the sham procedure for patients in the control group.Data on file, Medtronic.


8080

Symplicity HTN-3 Trial:Study Design

Treatment

Control

PrimaryEndpoint

6M

6M

12-36M

Home BP & Med Diary

• Patient and Research staff assessing BP are blinded to treatment status

• No changes in medications for 6M

• Office SBP ? 160 mmHg• Full doses of ? 3 meds •

in past 2 wks• No plan to change meds

for 6 M

Initial Screening2 weeks

ConfirmatoryScreening

Renal Angiogram

Home BP & Med Confirmation

2 weeks

Home BP & Med Confirmation

2 weeks

1M 3M

3M1M

InitialScreening ABPM

Possible additional benefits of renal denervation

� Treatment of heart failure? � Improvements in glucose metabolism?

� Sympathetic hyperactivity– Shifts blood from striated skeletal muscle to visceral tissue– Visceral tissue is less insulin sensitive than striated muscle– Sympathetic activity increases glucagon secretion

� Inhibition of the sympathetic nervous system by moxonidine has been shown to improve glucose metabolism

� Reduces atrial fibrillation recurrence when combined with pulmonary vein isolation?

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Today’s Topics




~1/3 of patients with severe symptomatic aortic stenosis patients do not undergo AVR

1. Bouma B J et al. To operate or not on elderly pat ients with aortic stenosis: the decision and its c onsequences. Heart 1999;82:143-1482. Iung B et al. A prospective survey of patients wi th valvular heart disease in Europe: The Euro Heart Survey on Valvular Heart Disease. European Heart J ournal

2003;24:1231-1243 (*includes both Aortic Stenosis a nd Mitral Regurgitation patients)3. Pellikka, Sarano et al. Outcome of 622 Adults wit h Asymptomatic, Hemodynamically Significant Aortic Stenosis During Prolonged Follow-Up. Circulation 20 054. Charlson E et al. Decision-making and outcomes i n severe symptomatic aortic stenosis. J Heart Valv e Dis2006;15:312-321

Transfemoral Transapical

TAVRTransfemoral and Transapical Study Devices

Edwards SAPIEN THV23 and 26 mm valves

RetroFlex 22 and 24 F sheaths

Ascendra 24 and 26 F sheaths

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N = 699 N = 358High RiskHigh Risk InoperableInoperable

PARTNER Study Design

Symptomatic Severe Aortic Stenosis

ASSESSMENT: High-Risk AVR Candidate3,105 Total Patients Screened


Total = 1,057 patients

2 Parallel Trials: Individually Powered

StandardTherapy

ASSESSMENT: Transfemoral

Access


Access

Not In Study

TF TAVR

Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority)

Co-Primary Endpoint: Composite of All-Cause Mortali tyand Repeat Hospitalization (Superiority)

1:1 Randomization

VS

Yes No

N = 179 N = 179

Inoperable PARTNER CohortPrimary Endpoint: All-Cause Mortality

Numbers at Risk

TAVI 179 138 122 67 26Standard Rx 179 121 83 41 12

Standard Rx

TAVI

All-

caus

e m

orta

lity

(%)

Months

∆ at 1 yr = 20.0%NNT = 5.0 pts 50.7%

30.7%

HR [95% CI] =0.54 [0.38, 0.78]

P (log rank) < 0.0001

Leon et al, NEJM 2010; 363:1597-1607

All Cerebrovascular Events (%)

88

≤ 30 Days 31 Days – 1 Year 1 Year – 2 Years

All CVA p = 0.010 p = 0.387 p = 0.028

Ischemic Stroke p = 0.017 p = 0.155 p = 0.083

Hemorrhagic Stroke p = 0.316 p = 0.121 p = 0.415

Eve

nts

0.6 1.11.7

6.7

2.2 1.1

1.7

0.6

0.62.2

0

1

2

3

4

5

6

7

8

StandardRx

TAVR StandardRx

TAVR StandardRx

TAVR

≤ 30 days 31 days- 365 days 366- 730 days

Hemorrhagic CVA

Ischemic CVA

TIA

Note: Percents are of patients in the trial (n/179) .

Conclusions (1)

At 2 years, in patients with symptomatic severe AS who are not suitable candidates for surgery…

• TAVR remained superior to standard therapy with incremental benefit from 1 to 2 years, markedly reducing the rates of…

� All cause mortality

� Cardiovascular mortality

� Repeat hospitalization

• TAVR improved NYHA functional status and decreased Class III/IV symptoms compared to standard therapy (17% vs 64%; p < 0.001).

89

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Conclusions (2)

• There were more neurologic events in TAVR patients vs Standard Rx (16.2% vs 5.5%; p = 0.003) with 5 ne w events (3 strokes and 2 TIAs) between 1-2 years in TAVR patients.

90

N = 179

N = 358InoperableInoperable

StandardTherapy


Access


Access

Not In Study

TF TAVR

Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority)

Co-Primary Endpoint: Composite of All-Cause Mortali tyand Repeat Hospitalization (Superiority)

1:1 Randomization

VS

Yes No

N = 179

TF TAVR AVR

Primary Endpoint: All-Cause Mortality at 1 yr(Non-inferiority)

TA TAVR AVR

VSVS

N = 248 N = 104 N = 103N = 244

PARTNER Study Design

Symptomatic Severe Aortic Stenosis



Total = 1,057 patients

2 Parallel Trials: Individually Powered

N = 699 High RiskHigh Risk


Access


Access

Transapical (TA)Transfemoral (TF)

1:1 Randomization1:1 Randomization

Yes No

0

0.1

0.2

0.3

0.4

0.5

0 6 12 18 24

TAVR

AVR

Months

348 298 260 147 67

351 252 236 139 65

No. at Risk

TAVR

AVR

26.8

24.2

Primary Endpoint:All-Cause Mortality at 1 Year

HR [95% CI] =0.93 [0.71, 1.22]

P (log rank) = 0.62

All-Cause MortalityTransfemoral (N=492)

Months

244 215 188 119 59

248 180 168 109 56

No. at Risk

TAVR

AVR

26.4

22.2

HR [95% CI] =0.83 [0.60, 1.15]

P (log rank) = 0.25

0

0.1

0.2

0.3

0.4

0.5

0 6 12 18 24

TAVR

AVR

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104 83 72 28 8

103 72 68 30 9

29.0

27.9

TAVR

AVR

MonthsNo. at Risk

All-Cause MortalityTransapical (N=207)

HR [95% CI] =1.22 [0.75, 1.98]

P (log rank) = 0.41

0

0.1

0.2

0.3

0.4

0.5

0 6 12 18 24

TAVR

AVR

30 Days 1 Year

OutcomeTAVR

(N = 348)AVR

(N = 351)TAVR

(N = 348)AVR

(N = 351)

All Stroke or TIA – no. (%) 19 (5.5) 8 (2.4) 0.04 27 (8. 3) 13 (4.3) 0.04

TIA – no. (%) 3 (0.9) 1 (0.3) 0.33 7 (2.3) 4 (1.5) 0.47

All Stroke – no. (%) 16 (4.6) 8 (2.4) 0.12 20 (6.0) 10 (3.2) 0.08

Major Stroke – no. (%) 13 (3.8) 7 (2.1) 0.20 17 (5.1) 8 ( 2.4) 0.07

Minor Stroke – no. (%) 3 (0.9) 1 (0.3) 0.34 3 (0.9) 2 (0. 7) 0.84

Death/maj stroke – no. (%) 24 (6.9) 28 (8.2) 0.52 92 (26. 5) 93 (28.0) 0.68

Neurological Events at 30 Days and 1 Year All Patients (N=699)

p-value p-value

Mean Gradient - AVR

Mean Gradient - TAVR

Peak Gradient - AVR

Peak Gradient - TAVR

Mea

n an

d P

eak

Gra

dien

tA

s-Tr

eate

d Tr

ial A

rms

(mm

Hg)

50

40

30

20

60

70

10

0

80

Baseline 30 Days 6 Months 1 YearTAVR

n = 327AVR

n = 301TAVR

n = 287AVR

n = 231TAVR

n = 246AVR

n = 170TAVR

n = 227AVR

n = 159

Echo FindingsAortic Valve Gradients TAVR

• FDA approved for non-operable or high risk patients with severe aortic stenosis

• UCSF Joint Valve Clinic --Referrals for advanced valve disease evaluation in close collaboration with CT Surgery

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