What s New In Interventional Cardiology

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1 What s New In Interventional Cardiology Yerem Yeghiazarians, MD Yerem Yeghiazarians, M.D. Leone-Perkins Family Endowed Chair in Cardiology University of California, San Francisco June 24, 2013 Yerem Yeghiazarians, MD Disclosures: 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? 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 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 3: What to do with non-operable or high-risk patients with severe aortic stenosis? 1

2 Case 1 Mr. C.N. 78 y.o. man very active male with reported cardiac risk factors of HTN, HL, and prediabetes 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 Stress Myocardial Perfusion 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 2

3 How would you manage him next? 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 S t a r t a s p i r i n,... 3% 3% 3% S t a r t a s p i r i n,... S t a r t a s p i r i n,... 92% S t a r t a s p i r i n,... 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? 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) This is a good example Boden et al NEJM

4 COURAGE TRIAL 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 anatomy 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 anatomy Boden et al NEJM 2007 Boden et al NEJM 2007 COURAGE - Results SURVIVAL FREE of DEATH and MI OVERALL SURVIVAL COURAGE - Results % Patients with angina 90 p=ns SURVIVAL FREE of ACS SURVIVAL FREE of MI p<0.001 p=0.02 p=ns OMT PCI Baseline 1 year 3 year 5 year Boden et al NEJM 2007 Boden et al NEJM

5 COURAGE Issues to keep in mind COURAGE Nuclear Substudy 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 Findings suggest a treatment target of 5% ischemia reduction Ischemia Reduction and Outcome Drug eluting stents in only ~3% All patients had a cardiac cath to define the anatomy first Shaw, L. J. et al. Circulation 2008;117: Cumulative Event-Free Survival Pre-test Probability of CAD When to get concerned about stress test findings? Typical angina Atypical angina Non-anginal chest pain AGE Men Women Men Women Men Women Diamond, Forrester et al JCI

6 High Risk Features on Stress Testing 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 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 Moderate Risk -10 to +4 Low Risk >+5 79% 4-year survival 95% 4-year survival 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 Our patient: mm ST deviation - (minus) 4x treadmill angina index 6 5 (0.75) 4 (2) = Angina score: 0 if no angina. 1 if non-limiting angina. 2 if limiting angina. High Risk < -10 Moderate Risk -10 to +4 Low Risk >+5 79% 4-year survival 95% 4-year survival 99% 4-year survival Mark et al, Ann Int Med 1987 High Risk Features on Stress Testing 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 6

7 Reminder: our patient s stress test Stress Myocardial Perfusion 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 High Risk Features on Stress Testing Our patient Large defect Multiple moderate defects LV dilation or increased lung thalium uptake indicating low cardiac output or elevated LVEDP Drop in LVEF This patient would have been excluded from the Courage Trial he has very high risk features and you need to define his anatomy How would you manage him next? 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 7

8 Revascularization to Improve Survival Anatomy Revasc COR LOE Method 3 VD +/- Proximal LAD CABG I B Disease *# PCI IIb Of uncertain benefit B 2 VD With Proximal CABG I B LAD Disease # PCI IIb Of uncertain benefit B 2 VD Without CABG IIa With extensive ischemia B Proximal LAD Disease Left Main # disease IIb Of uncertain benefit without extensive C ischemia PCI IIb Of uncertain benefit B Survivors of sudden cardiac death with presumed ischemia-mediated VT 1 VD With Proximal LAD disease 1 VD Without Proximal LAD disease CABG IIa With LIMA for long-term benefit B PCI IIb Of uncertain benefit B 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) GNL 2011 GNL 2011 Anatomy Revasc COR LOE Method 3 VD +/- Proximal LAD CABG I B Disease *# PCI IIb Of uncertain benefit B 2 VD With Proximal CABG I B LAD Disease # PCI IIb Of uncertain benefit B 2 VD Without CABG IIa With extensive ischemia B Proximal LAD Disease Left Main # disease IIb Of uncertain benefit without extensive C ischemia PCI IIb Of uncertain benefit B 1 VD With Proximal LAD disease Revascularization to Improve Survival Survivors of sudden cardiac death with presumed ischemia-mediated VT 1 VD Without Proximal LAD disease CABG IIa With LIMA for long-term benefit B PCI IIb Of uncertain benefit B 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) GNL 2011 Revascularization to Improve Symptoms Clinical Setting COR LOE 1 significant stenoses amenable to revascularization and unacceptable angina despite GDMT 1 significant stenoses and unacceptable angina in whom GDMT cannot be implemented because of medication contraindications, adverse effects, or patient preferences Previous CABG with 1 significant stenoses associated with ischemia and unacceptable angina despite GDMT Complex 3 VD (e.g., SYNTAX score >22) +/- involvement of the proximal LAD and a good candidate for CABG No anatomic or physiologic criteria for revascularization I CABG I PCI IIa CABG IIa PCI IIb-CABG IIa PCI IIa CABG preferred over PCI III: Harm CABG III: Harm PCI A C C C B C GNL

9 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 MI Classification Description 1 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 O 2 supply 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 4b MI associated with PCI MI associated with documented in-stent thrombosis 5 MI associated with CABG surgery Thygesen K et al. Circulation 2007; available at: General Considerations in Deciding Between an Early Invasive Strategy and an Initial Conservative Strategy in UA/NSTEMI Early Invasive Strategy Generally Preferred 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%) Initial Conservative Strategy Generally Preferred or Reasonable 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 Right Coronary Artery GNL

10 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 agent goal LDL < 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 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? 10

11 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 Plasma renin activity: (norm ) Serum aldosterone: 130 (norm < 28) 1.0 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 11

12 Renal Angiogram Renal angiogram 12/4/12 Renal Angiogram Renal Angiogram 12

13 Date 9/27/1 2 Labs 11/20/12 11/28/12 12/20/12 2/6/13 Serum K Aldosterone (ref <21-28) Renin (ref ) Misc TTKG=8 Patient placed on KCL supplement TTKG=9.8 On KCL 60meq daily BP normal off meds Renal Artery Angioplasty Performed Off KCL BP normal off meds 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 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 ACC/AHA Practice Guidelines 2005; White CJ

14 Clinical Clues to the Diagnosis of RAS Asymptomatic 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 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 ACC/AHA Practice Guidelines 2005; White CJ 2007 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 14

15 Resistant Hypertension Renal Denervation Causes of Pseudoresistant Hypertension 1,2 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 1. Calhoun DA, et al. Circulation. 2008;117;e510-e Makris A, et al. Int J Hypertens. 2011;doi: /2011/ Papademetriou V, et al. Int J Hypertens. 2011;doi: /2011/ Secondary Causes of Hypertension 1,2 Obstructive sleep apnea Primary aldosteronism Renal artery stenosis However, a majority of patients with resistant hypertension and no identifiable secondary causes have an activated sympathetic nervous system and increased sympathetic outflow 3 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 Renal Nerves and the SNS Efferent Sympathetics Afferent Renal Sympathetics 2 mm Hg decrease in mean office SBP 10% reduction in risk of stroke mortality 7% reduction in risk of ischemic heart disease mortality Sympathetic signals from the CNS modulate the physiology of the kidneys The kidney is a source of central sympathetic activity, sending signals to the CNS SBP = systolic blood pressure. Lewington S, et al. Lancet. 2002;360: Caution: The Symplicity Renal Denervation System is an Investigational Device. Limited by U.S. law to investigational use. Adapted from Schlaich MP, et al. Hypertension. 2009;54:

16 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 activity Dilates pupils Inhibits salivation Relaxes bronchi Accelerates heart Inhibits digestive activity Stimulates glucose release by liver Epinephrine adrenal glands Norepinephrine kidney Relaxes bladder Contracts rectum GI=gastrointestinal. Campbell WW. DeJong s The Neurologic Examination: Incorporating the Fundamentals of Neuroanatomy and Neurophysiology. 6th ed Cervical Thoracic Lumbar Sympathectomy: An Early Surgical Procedure Dr. Reginald H. Smithwick 1952 Photo of Dr. Smithwick reproduced with permission from JAMA. Renal Nerve Anatomy Nerves arise from T10-L2 The nerves arborize around the artery and primarily lie within the adventitia Vessel Lumen Renal Nerve Anatomy Allows a Catheter-Based Approach Media Standard interventional technique 4-6 two-minute treatments per artery Adventitia Renal Nerves CONFIDENTIAL Version Date: 28JUN2011 Caution: The Symplicity Catheter System is an 67 Investigational Device. Limited by U.S. law to investigational

17 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 EnligHTN St. Jude Medical OneShot Covidien Single 2-minute inflation Flexible Tip (self-orienting) 69 5mm 12mm Deflectable Shaft Paradise ReCor Medical Circumferential 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 Data on file. Medtronic, Inc. Renal Tissue NE (pg/mg) P< P=1.0 Staged Clinical Evaluation Symplicity HTN-1 First-in-Man Series of Pilot studies Symplicity HTN-2 EU/AU Randomized Clinical Trial USA Symplicity HTN-3 US Randomized Clinical Trial (ongoing) EU/AU Other Areas of Research: Insulin Resistance, HF/Cardiorenal, Sleep Apnea, More 73 17

18 Symplicity HTN-1 Significant, Sustained BP Reduction 10 Systolic Diastolic Lancet. 2009;373: Hypertension. 2011;57: BP change (mmhg) 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 M (n=138) 3 M (n=135) 6 M (n=86) 12 M (n=64) 18 M (n=36) 24 M (n=18) Symplicity HTN-1 Investigators. Hypertension. 2011;57: Symplicity HTN-1 Investigators. Hypertension. 2011;57: Symplicity HTN-2 Primary Endpoint: 6-Month Office BP Lancet. 2010;376: 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) from Baseline to 6 Months (mmhg) Systolic Diastolic 84% of RDN patients had 10 mmhg reduction in SBP 10% of RDN patients had no reduction in SBP Systolic Diastolic 33/11 mmhg difference between RDN and Control (p<0.0001) Symplicity HTN-2 Investigators. Lancet. 2010;376: Symplicity HTN-2 Investigators. Lancet. 2010;376:

19 Time Course of Office BP Change RDN from Baseline (mmhg) Control from Baseline (mmhg) M 3M 6M Systolic Diastolic Systolic Diastolic Symplicity HTN-2 Investigators. Lancet. 2010;376: p< for between-group comparisons p=0.002 for between-group comparisons p=0.005 for between-group comparisons Two-way repeated measures ANOVA, p= 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. 78 Symplicity HTN-3 Trial: Study Design Office SBP? 160 mmhg Full doses of? 3 meds Initial past 2 wks Screening No plan to change meds for 6 M Initial Screening 2 weeks Home BP & Med Diary Confirmatory Screening ABPM Treatment Renal Angiogram Control 1M 3M 1M 3M 80 2 weeks 6M Home BP & Med Confirmation Primary Endpoint 2 weeks Home BP & Med Confirmation 6M 12-36M Patient and Research staff assessing BP are blinded to treatment status No changes in medications for 6M 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? 19

20 Today s Topics Case 1: When to worry about a stress test result and how best to manage high risk patients with CAD? ~1/3 of patients with severe symptomatic aortic stenosis patients do not undergo 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? 1. Bouma B J et al. To operate or not on elderly patients with aortic stenosis: the decision and its consequences. Heart 1999;82: 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: (*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 Charlson E et al. Decision-making and outcomes in severe symptomatic aortic stenosis. J Heart Valve Dis2006;15: Transfemoral and Transapical Study Devices Transfemoral Transapical Edwards SAPIEN THV 23 and 26 mm valves RetroFlex 22 and 24 F sheaths Ascendra 24 and 26 F sheaths 20

21 PARTNER Study Design Inoperable PARTNER Cohort Primary Endpoint: All-Cause Mortality Symptomatic Severe Aortic Stenosis ASSESSMENT: High-Risk Candidate 3,105 Total Patients Screened Total = 1,057 patients N = 699 High Risk 2 Parallel Trials: Inoperable N = 358 Individually Powered Yes ASSESSMENT: Transfemoral Access No All-cause mortality (%) Standard Rx TAVI at 1 yr = 20.0% NNT = 5.0 pts HR [95% CI] = 0.54 [0.38, 0.78] P (log rank) < % 30.7% 1:1 Randomization Not In Study N = 179 N = 179 TF VS Standard Therapy Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority) Co-Primary Endpoint: Composite of All-Cause Mortality and Repeat Hospitalization (Superiority) Leon et al, NEJM 2010; 363: Numbers at Risk Months TAVI Standard Rx All Cerebrovascular Events (%) Conclusions (1) Events Standard Rx Standard Rx 30 Days 31 Days 1 Year 1 Year 2 Years All CVA p = p = p = Ischemic Stroke p = p = p = Hemorrhagic Stroke p = p = p = Standard Rx 30 days 31 days- 365 days days Note: Percents are of patients in the trial (n/179). Hemorrhagic CVA Ischemic CVA TIA At 2 years, in patients with symptomatic severe AS who are not suitable candidates for surgery 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 improved NYHA functional status and decreased Class III/IV symptoms compared to standard therapy (17% vs 64%; p < 0.001)

22 Conclusions (2) PARTNER Study Design There were more neurologic events in 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 patients. N = 699 High Risk Symptomatic Severe Aortic Stenosis ASSESSMENT: High-Risk Candidate 3,105 Total Patients Screened Total = 1,057 patients 2 Parallel Trials: Individually Powered Inoperable N = 358 Yes ASSESSMENT: Transfemoral Access No ASSESSMENT: Transfemoral Access Transfemoral (TF) Transapical (TA) Yes No 90 N = 244 TF 1:1 Randomization VS N = 248 N = 104 N = 103 1:1 Randomization TA VS Primary Endpoint: All-Cause Mortality at 1 yr (Non-inferiority) N = 179 TF 1:1 Randomization VS N = 179 Standard Therapy Not In Study Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority) Co-Primary Endpoint: Composite of All-Cause Mortality and Repeat Hospitalization (Superiority) Primary Endpoint: All-Cause Mortality at 1 Year All-Cause Mortality Transfemoral (N=492) HR [95% CI] = 0.93 [0.71, 1.22] P (log rank) = HR [95% CI] = 0.83 [0.60, 1.15] P (log rank) = No. at Risk Months No. at Risk Months

23 All-Cause Mortality Transapical (N=207) Neurological Events at 30 Days and 1 Year All Patients (N=699) HR [95% CI] = 1.22 [0.75, 1.98] P (log rank) = Outcome (N = 348) 30 Days 1 Year (N = 351) p-value (N = 348) (N = 351) p-value 0.3 All Stroke or TIA no. (%) 19 (5.5) 8 (2.4) (8.3) 13 (4.3) TIA no. (%) 3 (0.9) 1 (0.3) (2.3) 4 (1.5) All Stroke no. (%) 16 (4.6) 8 (2.4) (6.0) 10 (3.2) No. at Risk Months Major Stroke no. (%) 13 (3.8) 7 (2.1) (5.1) 8 (2.4) 0.07 Minor Stroke no. (%) 3 (0.9) 1 (0.3) (0.9) 2 (0.7) Death/maj stroke no. (%) 24 (6.9) 28 (8.2) (26.5) 93 (28.0) 0.68 Echo Findings Aortic Valve Gradients Mean and Peak Gradient As-Treated Trial Arms (mmhg) n = 327 Peak Gradient - Peak Gradient - Mean Gradient - Mean Gradient - Baseline 30 Days 6 Months 1 Year n = 301 n = 287 n = 231 n = 246 n = 170 n = 227 n = 159 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 23

24 Today s Topics Case 1: When to worry about a stress test result and how best to manage high risk patients with CAD? THANK YOU 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? 24