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5/28/2013
1
Updates in Cardiology Yerem Yeghiazarians, MD
Yerem Yeghiazarians, M.D.Associate Professor of Medicine
Leone‐Perkins Family Endowed Chair in Cardiology
University of California, San FranciscoMay 27, 2013
Yerem Yeghiazarians, MD
Disclosures:
No conflicts of interest
5/28/2013
2
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?
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).
5/28/2013
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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/c/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
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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
Stress Myocardial Perfusion
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?
5/28/2013
5
• 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
5/28/2013
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COURAGE TRIAL
• 2287 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
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
5/28/2013
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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 - Results
Boden et al NEJM 2007
SURVIVAL FREE of DEATH and MI OVERALL SURVIVAL
SURVIVAL FREE of ACS SURVIVAL FREE of MI
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COURAGE - Results
0
10
20
30
40
50
60
70
80
90
Baseline 1 year 3 year 5 year
OMT
PCI
p<0.001p=0.02
p=ns
p=ns
% Patients with angina
Boden et al NEJM 2007
COURAGE –Issues to keep in mind
• Of the >35,000 patients screened, only ~2,287 were eligible and randomized – 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 first
5/28/2013
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Shaw, 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?
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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
• 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
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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
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• Large defect
• Multiple moderate defects
• LV dilation or increased lung thalium uptake 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
• 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
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• Large defect
• Multiple moderate defects
• LV dilation or increased lung thalium uptake 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
5/28/2013
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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?
GNL 2011GNL 2011
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GNL 2011
Anatomy Revasc
Method
COR LOE
3 VD +/‐ Proximal LAD
Disease*#CABG I B
PCI IIbOf uncertain benefit B
2 VD With Proximal
LAD Disease#CABG I B
PCI IIbOf uncertain benefit B
2 VD Without
Proximal LAD Disease#CABG IIaWith extensive ischemia B
IIbOf uncertain benefit without extensive
ischemia
C
PCI IIbOf uncertain benefit B
1 VD With Proximal
LAD disease
CABG IIaWith LIMA for long‐term benefit B
PCI IIbOf uncertain benefit B
1 VD Without
Proximal LAD disease
CABG III: Harm B
PCI 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 Revasc
Method
COR LOE
3 VD +/‐ Proximal LAD
Disease*#CABG I B
PCI IIbOf uncertain benefit B
2 VD With Proximal
LAD Disease#CABG I B
PCI IIbOf uncertain benefit B
2 VD Without
Proximal LAD Disease#CABG IIaWith extensive ischemia B
IIbOf uncertain benefit without extensive
ischemia
C
PCI IIbOf uncertain benefit B
1 VD With Proximal
LAD disease
CABG IIaWith LIMA for long‐term benefit B
PCI IIbOf uncertain benefit B
1 VD Without
Proximal LAD disease
CABG III: Harm B
PCI 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
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GNL 2011
Revascularization to Improve SymptomsClinical Setting COR LOE
≥1 significant stenoses amenable to revascularization and unacceptable angina despite GDMT
I−CABG A
I−PCI
≥1 significant stenoses and unacceptable angina in whom GDMT cannot be implemented because of medication contraindications, adverse effects, or patient preferences
IIa−CABG C
IIa−PCI
Previous CABG with ≥1 significant stenoses associated with ischemia and unacceptable angina despite GDMT
IIb‐CABG C
IIa−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 C
III: Harm−PCI
GNL 2011
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
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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.
TIMI Risk Score For UA/NSTEMI7 Independent Predictors
1. Age > 65 years
2. > 3 CAD risk factors (high cholesterol, family history, hypertension, diabetes, smoking)
3. Prior coronary artery disease (stenosis > 50 %)
4. ST-segment deviation on the ECG
5. > 2 anginal events < 24 hours
6. ASA in last 7 days
7. Elevated cardiac biomarkers (troponin or CK-MB)
Antman et al, JAMA 2000; 284 : 835-842.
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TIMI Risk Score For UA/NSTEMIUFH Group TIMI 11B (N= 1957)
4.78.3
13.219.9
26.2
40.9
0
10
20
30
40
50
0-1 2 3 4 5 6-7
D/M
I/Urg
Rev
asc
(%)
Number of Risk Factors
% Pts: 4.3 17.3 32.0 29.3 13.0 3.4
2 trend P <0.001
Antman et al, JAMA 2000; 284 : 835-842.
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
5/28/2013
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Right Coronary Artery
Left Coronary System
5/28/2013
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Left Coronary System
Long-term Rx: ACS
1. Aspirin (lifelong)
2. Clopidogrel, Prasugrel or Ticagrelor (at least one year)
3. -Blocker
4. Lipid-lowering agent goal 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
5/28/2013
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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?
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
5/28/2013
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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/c/r
• Abd: soft, NTND, no abdominal bruit
• Ext: no edema, warm ext
Labs
4.1
14.1
41.3
252
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)
5/28/2013
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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
Renal angiogram12/4/12
5/28/2013
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Renal Angiogram
Renal Angiogram
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Renal Angiogram
Labs
Date 9/27/12
11/20/12 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=8
Patient placed on KCL supplement
TTKG=9.8
On KCL 60meq daily
BP normal off meds
Off KCL
BP normal off meds
Renal Artery Angioplasty Performed
5/28/2013
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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
5/28/2013
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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
ACC/AHA Practice Guidelines 2005; White CJ 2007
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
ACC/AHA Practice Guidelines 2005; White CJ 2007
5/28/2013
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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
Medical management
Risk factor modification (smoking cessation, blood pressure control, lipid lowering therapy and diabetes control)
Class I recommendations (if unilateral RAS is present):– ACE-inhibitors– ARBs– Calcium-channel blockers– Beta-blockers
5/28/2013
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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 angina
ACC/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
5/28/2013
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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.
5/28/2013
31
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
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.
5/28/2013
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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
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 pupils
Inhibits salivation
Relaxes bronchi
Accelerates heart
Inhibits digestive activity
Stimulates glucose release by liver
Relaxes bladder
Contracts rectum
Cer
vica
lTh
orac
icLu
mba
r
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
Dr. Reginald H. Smithwick
Sympathectomy: An Early Surgical Procedure
1952
Photo of Dr. Smithwick reproduced with permission from JAMA.
5/28/2013
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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
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
Adventitia
Renal Nerves
6565
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
• Standard interventional technique• 4-6 two-minute treatments per artery
Renal Nerve Anatomy Allows a Catheter-Based Approach
66
5/28/2013
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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
6767
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 12mm
DeflectableShaft
EnligHTN – St. Jude MedicalOneShot – CovidienSingle 2-minute inflation
Paradise – ReCor MedicalCircumferential catheter-based ultrasound technology
5/28/2013
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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
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.
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
Six Month Post-Procedure Histology (Porcine Model)• An area of medial injury (yellow) is located between the arrows on the left. An
enlargement of the boxed region is shown on the right– Findings: minimal intimal thickening and minimal internal elastic lamina injury
overlying areas of mild full thickness medial fibrosis (yellow [fibrosis] with green [proteoglycan deposition]) and adventitial fibrosis (yellow)
Rippy MK, et. al. Clin Res Cardiol. 2011;doi:101007s00392-011-0346-8.
Movat’s Pentachrome Stain
5/28/2013
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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
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
71
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
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
72
Symplicity HTN-1
Symplicity HTN-1 Investigators. Hypertension. 2011;57:911-917.
Hypertension. 2011;57:911-917.
5/28/2013
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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
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
73
Symplicity HTN-1 Investigators. Hypertension. 2011;57:911-917.
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
• 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)
74
Symplicity HTN-2
Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909.
Lancet. 2010;376:1903-1909.
5/28/2013
38
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
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
75
Systolic
Diastolic
Systolic Diastolic
Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909.
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
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)
76
0
-4
10
-2
0
-30
-20
-10
0
10
20
SystolicDiastolic
Control∆ from
Baseline (mmHg)
††
†
††† †††
Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909.
5/28/2013
39
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
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.
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
7878
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 Screening
2 weeks
ConfirmatoryScreening
Renal Angiogram
Home BP & Med Confirmation
2 weeks
Home BP & Med Confirmation
2 weeks
1M 3M
3M1M
InitialScreening
ABPM
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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?
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?
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~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 patients with aortic stenosis: the decision and its consequences. Heart 1999;82:143-1482. Iung B et al. A prospective survey of patients with valvular heart disease in Europe: The Euro Heart Survey on Valvular Heart Disease. European Heart Journal
2003;24:1231-1243 (*includes both Aortic Stenosis and Mitral Regurgitation patients)3. Pellikka, Sarano et al. Outcome of 622 Adults with Asymptomatic, Hemodynamically Significant Aortic Stenosis During Prolonged Follow-Up. Circulation 20054. Charlson E et al. Decision-making and outcomes in severe symptomatic aortic stenosis. J Heart Valve Dis2006;15:312-321
Transfemoral Transapical
TAVRTransfemoral and Transapical
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Study Devices
Edwards SAPIEN THV23 and 26 mm valves
RetroFlex 22 and 24 F sheaths
Ascendra 24 and 26 F sheaths
N = 699 N = 358High RiskHigh Risk InoperableInoperable
PARTNER Study Design
Symptomatic Severe Aortic Stenosis
ASSESSMENT: High-Risk AVR Candidate3,105 Total Patients Screened
ASSESSMENT: High-Risk AVR Candidate3,105 Total Patients Screened
Total = 1,057 patients
2 Parallel Trials: Individually Powered
StandardTherapy
ASSESSMENT: Transfemoral
Access
ASSESSMENT: Transfemoral
Access
Not In Study
TF TAVR
Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority)
Co-Primary Endpoint: Composite of All-Cause Mortalityand Repeat Hospitalization (Superiority)
1:1 Randomization
VS
Yes No
N = 179 N = 179
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Inoperable PARTNER CohortPrimary Endpoint: All-Cause Mortality
Numbers at Risk
TAVI 179 138 122 67 26Standard Rx 179 121 83 41 12
Standard Rx
TAVIA
ll-ca
use
mor
talit
y (%
)
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 (%)
86
≤ 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).
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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).
87
Conclusions (2)
• There were more neurologic events in TAVR patients vs Standard Rx (16.2% vs 5.5%; p = 0.003) with 5 new events (3 strokes and 2 TIAs) between 1-2 years in TAVR patients.
88
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N = 179
N = 358InoperableInoperable
StandardTherapy
ASSESSMENT: Transfemoral
Access
ASSESSMENT: Transfemoral
Access
Not In Study
TF TAVR
Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority)
Co-Primary Endpoint: Composite of All-Cause Mortalityand 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
ASSESSMENT: High-Risk AVR Candidate3,105 Total Patients Screened
ASSESSMENT: High-Risk AVR Candidate3,105 Total Patients Screened
Total = 1,057 patients
2 Parallel Trials: Individually Powered
N = 699 High RiskHigh Risk
ASSESSMENT: Transfemoral
Access
ASSESSMENT: Transfemoral
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
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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
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
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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-T
reat
ed T
rial 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
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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
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?
5/28/2013
49
THANK YOU