Severe Aortic Stenosis and TAVR Joseph N. Wight, Jr, MD MaineHealth Cardiology Maine Medical Center Clinical Assistant Professor Department of Medicine Tufts University School of Medicine September 12, 2014

Disclosures I will not discuss off label use or investigational use in my presentation. I have no financial relationships to disclose. Employee of MaineHealth Cardiology

Prevalence of Aortic Stenosis 16.5 Million People in US Over the Age of 652 Aortic stenosis is estimated to be prevalent in up to 7% of the population over the age of 651 It is more likely to affect men than women; 80% of adults with symptomatic aortic stenosis are male3 Percentage Diagnosed with Aortic Stenosis Aortic stenosis is a common public health problem affecting millions of people in the United States. It is estimated to be prevalent in up to 7% of the population over the age of 65. It is also more likely to affect men than women; 80% of adults with symptomatic aortic stenosis are male.

Aortic Stenosis Demographics Aortic stenosis 2% US population >65yrs old Aortic sclerosis 29% US population> 65 yrs old Aortic sclerosis 50% greater risk of mortality and myocardial infarction. Aortic sclerosis progresses to aortic stenosis in 9% over 5 years

What Causes Aortic Stenosis in Adults? More Common Age-Related Calcific Aortic Stenosis Aortic stenosis in patients over the age of 65 is usually caused by calcific (calcium) deposits associated with aging Rheumatic Fever There are various causes of aortic stenosis. Aortic stenosis in patients over the age of 65 is usually caused by calcific (calcium) deposits associated with aging. It can also be caused by infection, rheumatic fever, or a congenital abnormality. Adults who have had rheumatic fever may also be at risk for aortic stenosis Congenital Abnormality In some cases adults may develop aortic stenosis resulting from a congenital abnormality Less Common

3 Major Etiologies for aortic stenosis

Major Risk Factors Independent clinical factors associated with degenerative aortic valve disease include the following:4 Increasing age Male gender Hypertension Smoking Elevated lipoprotein A Elevated LDL cholesterol Independent clinical factors associated with degenerative aortic valve disease include the following increasing age, male gender, hypertension, smoking, elevated lipoprotein A, elevated LDL cholesterol

Signs and Symptoms Heart Failure Carotid Parvus et Tardus Angina Syncope Carotid Parvus et Tardus Laterally displaced PMI Soft A2 Crescendo-Decrescendo systolic murmur Timing of peak murmur and NOT intensity predicts severity

Aortic Stenosis Is Life Threatening and Progresses Rapidly Literature shows - Survival after onset of symptoms is 50% at 2 years and 20% at 5 years - Surgical intervention for severe aortic stenosis should be performed promptly once even minor symptoms occur Survival after onset of symptoms is 50% at 2 years and 20% at 5 years1 Surgical intervention for severe aortic stenosis should be performed promptly once even minor symptoms occur1

Sobering Perspective 5-Year Survival8 Survival, % Data shows a sobering perspective for inoperable patients: 5 year survival of breast cancer, lung cancer, prostate cancer, ovarian cancer and severe inoperable aortic stenosis Breast Cancer Lung Cancer Colorectal Cancer Prostate Cancer Ovarian Cancer Severe Inoperable AS* *Using constant hazard ratio. Data on file, Edwards Lifesciences LLC. Analysis courtesy of Murat Tuczu, MD, Cleveland Clinic 5 year survival of breast cancer, lung cancer, prostate cancer, ovarian cancer and severe inoperable aortic stenosis

Echocardiographic Guidelines are the Gold Standard in Assessing Severe Aortic Stenosis6 * Echocardiographic guidelines are the gold standard in diagnosing a patient with severe aortic stenosis. According to the 2008 ACC/AHA guidelines, severe aortic stenosis is defined as aortic valve area (AVA) less than 1.0 cm2, mean gradient greater than 40 mmHg or jet velocity greater than 4.0 m/s. *Doppler-Echocardiographic measurements According to the 2014 ACC/AHA guidelines, severe aortic stenosis is defined as: Aortic valve area (AVA) less than 1.0 cm2 Mean gradient greater than 40 mmHg or jet velocity greater than 4.0 m/s

Multiple Modalities May Be Used to Diagnose Severe Aortic Stenosis6 Trans-thoracic Echo (TTE) Chest X-ray Electro-cardiogram Cardiac Cath. Auscultation Multiple modalities may be used to diagnose severe aortic stenosis including review of a patient’s electrocardiogram, chest x-ray, cardiac catheterization, auscultation and transthoracic echocardiography (TTE).

Continuity Equation-Conservation of Mass Echocardiography: Continuity Equation-Conservation of Mass

Echocardiography: 3D Planimetry

Not so classic aortic stenosis

1. Low Flow, Low Gradient Severe AS 2 1. Low Flow, Low Gradient Severe AS 2. Paradoxical Low Flow, Low Gradient Severe AS

Low Flow, Low Gradient AS Low gradient with a small calculated valve area in the setting of poor systolic function. This may result in lack of referral for AVR because of the low gradient. Dobutamine Stress Echo: By increasing cardiac output, we can determine if the AS is severe by reassessing the gradient across the aortic valve (increases) AND the aortic valve area (decreases). Assess myocardial contractile reserve Does the cardiac output improve by 20% or more. Critical for decision making regarding aortic valve replacement.

Paradoxical Low Flow and/or Low Gradient Severe Aortic Stenosis1 Some patients with severe aortic stenosis based on valve area have a lower than expected gradient (e.g. mean gradient < 30 mmHg) despite preserved LV ejection fraction (e.g. EF > 50%) Up to 35% of patients with severe aortic stenosis present with low flow, low gradient These low gradients often lead to an underestimation of the severity of the disease, so many of these patients do not undergo surgical aortic valve replacement According to the 2008 ACC/AHA guidelines, severe aortic stenosis is defined as aortic valve area (AVA) less than 1.0 cm2, mean gradient greater than 40 mmHg or jet velocity greater than 4.0 m/s. In patients with low cardiac output, a low gradient (< 40 mmHg) may be present. In this case, accurate differentiation between true and pseudo severe aortic stenosis is necessary. Dobutamine stress echocardiography should be used to better define the severity of the aortic stenosis in this circumstance.   Dobutamine stress in low gradient, low ejection fraction AS Chambers, Heart. 2006 April; 92(4): 554–558

Stages of Valvular AS. ACC/AHA 2104 Valve Guidelines Nishimura R A et al. Circulation. 2014;129:e521-e643 Copyright © American Heart Association, Inc. All rights reserved.

Summary of Recommendations for AS: Timing of Intervention. Nishimura R A et al. Circulation. 2014;129:e521-e643 Copyright © American Heart Association, Inc. All rights reserved.

Aortic Valve Replacement Greatly Improves Survival Patient Survival16 AVR, No Symptoms AVR, Symptoms No AVR, No Symptoms No AVR, Symptoms Study data demonstrate that early and late outcomes were similarly good in both symptomatic and asymptomatic patients It is important to note that among asymptomatic patients with SAS, omission of surgical treatment was the most important risk factor for late mortality Years Study data demonstrate that early and late outcomes were similarly good in both symptomatic and asymptomatic patients It is important to note that among asymptomatic patients with SAS, omission of surgical treatment was the most important risk factor for late mortality

Options for Aortic Valve Replacement Inoperable OR High Risk Patients Suitable for Open Chest Surgery Transcatheter Aortic Valve Replacement (TAVR) Surgical Aortic Valve Replacement (sAVR) Minimal Incision Valve Surgery (MIVS) Transfemoral Approach

Prosthetic Heart Valves

Tilting Disc Valve

Bio-prosthetic Valve

Low Percentage of Aortic Valve Surgery Aortic Valve Replacement No Aortic Valve Replacement Studies show at least 40% of SAS patients are not treated with an AVR9-15 Studies show at least 40% of patients with severe AS are not treated with an AVR9-15

Summary of Recommendations for AS: Choice of Surgical or Transcatheter Intervention. Nishimura R A et al. Circulation. 2014;129:e521-e643 Copyright © American Heart Association, Inc. All rights reserved.

What is TAVR-Transcatheter Aortic Valve Replacement? An aortic valve replacement as an alternative to traditional thoracotomy. Less invasive than traditional thoracotomy for patients considered too high risk for traditional surgery. If a cardiac surgeon determines that you are too sick for open-heart surgery and if medicine is not helping you feel better, TAVR may be an alternative. This less invasive procedure allows your aortic valve to be replaced with a new valve while your heart is still beating.

Two TAVR Options Edwards Sapien Valve Stainless Steel Frame More Aortic Regurg, less AV block/PPM Better for severe bulky calcification. Medtronic CoreValve Nitinol Frame-self expanding Less Aortic Regurg, More heart block/PPM

TAVR Multimodality imaging

PARTNER Study Design Cohort A Cohort B N = 358 Inoperable High Risk Symptomatic Severe Aortic Stenosis Cohort A ASSESSMENT: High-Risk AVR Candidate 3,105 Total Patients Screened Cohort B N = 179 N = 358 Inoperable Standard Therapy 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 Mortality and Repeat Hospitalization (Superiority) 1:1 Randomization VS Yes No Total = 1,057 patients High Risk N = 699 2 Parallel Trials: Individually Powered ASSESSMENT: Transfemoral Access Transapical (TA) Transfemoral (TF) 1:1 Randomization Yes No TF TAVR AVR Primary Endpoint: All-Cause Mortality at 1 yr (Non-inferiority) TA TAVR VS N = 248 N = 104 N = 103 N = 244

PARTNER Trial B Exclusion Criteria: bicuspid or noncalcified aortic valve acute myocardial infarction substantial coronary artery disease requiring revascularization left ventricular ejection fraction of less than 20% a diameter of the aortic annulus of less than 18 mm or more than 25 mm severe (>3+) mitral or aortic regurgitation a transient ischemic attack or stroke within the previous 6 months severe renal insufficiency (creatinine greater than 3 or on dialysis). Iliac-femoral anatomy precluding safe sheath insertion

PARTNER Trial B Primary End-Points: Death from any cause Rate of a hierarchical composite of the time to death from any cause or the time to the first repeat hospitalization from aortic valve disease or procedure related complication

PARTNER Trial B Secondary End-Points: the rate of death from cardiovascular causes NYHA functional class The distance covered during a 6-minute walk test Valve performance (assessed by echocardiography) The rates of myocardial infarction, stroke, acute kidney injury, vascular complications, and bleeding

Characteristics of an Inoperable Patient Cohort B TAVR patients may present with some of the following: Severe, symptomatic native aortic valve stenosis Old age Frailty History of stroke/CVA History of syncope Reduced EF Heavily calcified aorta Prior CABG Prior chest radiation History of AFib History of CAD Prior open chest surgery History of COPD Fatigue, slow gait History of renal insufficiency Peripheral vascular disease Diabetes and hypertension

“Standard Medical Therapy” 179 Patients assigned Balloon Valvuloplasty perfomed in 114 (63.7%) patients in first 30 days and 36 (20.1%) additional patients 30 days after randomization. 12 (6.7%) underwent AVR! 5 (2.8%) LV apex to Aorta conduit

TAVR Group 179 Patients 6 did not undergo TAVR 2 died before implantation 2 unsuccessful transfemoral access 2 aortic valve annulus was to large

Cohort B Survival THE PARTNER TRIAL COHORT B Despite frequent BAV (78.8%), standard therapy failed to alter the dismal natural course of the disease. The Edwards SAPIEN transcatheter heart valve demonstrated an absolute reduction in mortality of 25% at two years. THE PARTNER TRIAL COHORT B

Edwards SAPIEN THV Improved Cardiac Function The dramatic reduction in mean gradient in the Edwards SAPIEN transcatheter heart valve arm of Cohort B was sustained out to two years. The mean gradient worsened over time for the patients in the standard therapy group, with no sustained hemodynamic benefit from BAV. Error bars = ± 1 Std Dev THE PARTNER TRIAL COHORT B

Cohort B HF Improvement The vast majority of patients treated with the Edwards SAPIEN THV (who initially presented in NYHA class III or IV) were alive at 12 months. But perhaps as important, they were now mildly symptomatic or asymptomatic in class II or I, respectively. 83% of the Edwards SAPIEN THV patients were classified as NYHA class I or II at two years. Improvement was observed as early as 30 days (P < .0001) The patients in the standard therapy arm didn’t fare as well; the majority who did survive at 1 year still presented with NYHA class III or IV symptoms. THE PARTNER TRIAL COHORT B

Complications THE PARTNER TRIAL COHORT B The Edwards SAPIEN THV was associated with a higher incidence of stroke, major vascular complications and major bleeding at two years. Standard therapy demonstrated higher all-cause mortality as well as death or repeat hospitalization at two years. Stroke was defined as follows: Neurological deficit lasting ≥ 24 hours or lasting less than 24 hours with a brain imaging study showing an infarction. Major vascular complications were defined as any thoracic aortic dissection, access site or access-related vascular injury (dissection, stenosis, perforation, rupture, arterio-venous fistula, pseudoaneurysm, or hematoma) leading to either death, need for significant blood transfusion (> 3 units), or percutaneous or surgical intervention, and/or distal embolization (non-cerebral) from a vascular source requiring surgery or resulting in amputation or irreversible end-organ damage. Bleeding event is defined as ≥ 2 units within the index procedure. THE PARTNER TRIAL COHORT B

PARTNER Study Design Cohort A Cohort B N = 358 Inoperable High Risk Symptomatic Severe Aortic Stenosis Cohort A ASSESSMENT: High-Risk AVR Candidate 3,105 Total Patients Screened Cohort B N = 179 N = 358 Inoperable Standard Therapy 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 Mortality and Repeat Hospitalization (Superiority) 1:1 Randomization VS Yes No Total = 1,057 patients High Risk N = 699 2 Parallel Trials: Individually Powered ASSESSMENT: Transfemoral Access Transapical (TA) Transfemoral (TF) 1:1 Randomization Yes No TF TAVR AVR Primary Endpoint: All-Cause Mortality at 1 yr (Non-inferiority) TA TAVR VS N = 248 N = 104 N = 103 N = 244

Cohort A: All-Cause Mortality HR [95% CI] = 0.93 [0.74, 1.15] p (log rank) = 0.483 44.8% 34.6% 44.2% 26.8% 33.7% 24.3% No. at Risk TAVR 348 298 261 239 222 187 149 AVR 351 252 236 223 202 174 142

Months Post Randomization Cohort A: Strokes 3.2% 6.0% 9.3% 8.2% HR [95% CI] = 1.09 [0.62, 1.91] p (log rank) = 0.763 4.9% 7.7% Months Post Randomization No. at Risk TAVR 348 287 250 228 211 176 139 351 246 230 217 197 169 AVR

CoreValve US Pivotal Trials Iliofemoral Access > 18 Fr Sheath Extreme Risk High Risk CoreValve Iliofemoral Iliofemoral Access > 18 Fr Sheath No Yes Randomization 1:1 Non-Iliofemoral Versus SAVR N=487 N=147 TCT 2013 LBCT Extreme Risk Study | Iliofemoral Pivotal

Extreme Risk Study | Iliofemoral Pivotal Study Purpose Study Purpose: To evaluate the safety and efficacy of the CoreValve THV for the treatment of patients with symptomatic severe aortic stenosis in whom the predicted risk of operative mortality or serious, irreversible morbidity was 50% or greater at 30 days Risk Determined by: Two Clinical Site Cardiac Surgeons and One Interventional Cardiologist Risk Confirmed by: Two Screening Committee Cardiac Surgeons and One Interventional Cardiologist Primary Endpoint: All Cause Mortality or Major Stroke at 12 Months TCT 2013 LBCT Extreme Risk Study | Iliofemoral Pivotal

Inclusion and Exclusion Criteria Inclusion Criteria: Severe aortic stenosis: AVA ≤ 0.8 cm2 or AVAI ≤ 0.5 cm2/m2 AND mean gradient > 40 mm Hg or peak velocity > 4 m/sec at rest or with dobutamine stress (if LVEF < 50%) NYHA functional class II or greater Exclusion Criteria (selected): Recent active GI bleed (3 mos), stroke (6 mos), or MI (30 days) Creatinine clearance < 20 mL/min Significant untreated coronary artery disease LVEF < 20% Life expectancy < 1 year due to co-morbidities TCT 2013 LBCT Extreme Risk Study | Iliofemoral Pivotal

All Cause Mortality or Major Stroke Months Post-Procedure Primary Endpoint All Cause Mortality or Major Stroke P < 0.0001 Performance Goal = 43% All Cause Mortality or Major Stroke 9.3% [6.7,12.0] 25.5% [21.6,29.4] Months Post-Procedure TCT 2013 LBCT Extreme Risk Study | Iliofemoral Pivotal

Percentage of Patients Extreme Risk Study | Iliofemoral Pivotal NYHA Class Survivors 90% of Patients Improved at Least 1 NYHA Class by 1 Year 60% of Patients Improved at Least 2 NYHA Classes by 1 Year Percentage of Patients TCT 2013 LBCT Extreme Risk Study | Iliofemoral Pivotal

Extreme Risk Study | Iliofemoral Pivotal Secondary Endpoints Events* 1 Month 1 Year Any Stroke, % 3.9 6.7 Major, % 2.4 4.1 Minor, % 1.7 3.1 Myocardial Infarction, % 1.3 2.0 Reintervention, % VARC Bleeding, % 35.1 41.4 Life Threatening or Disabling, % 11.7 16.6 24.1 27.6 Major Vascular Complications, % 8.3 8.5 Permanent Pacemaker Implant, % 22.2 27.1 Per ACC Guidelines, % 17.4 19.9 * Percentages obtained from Kaplan Meier estimates TCT 2013 LBCT Extreme Risk Study | Iliofemoral Pivotal

Core Valve Trial 57

Study Disposition

Primary Endpoint: 1 Year All-cause Mortality ACC 2014 19.1% 4.5% Surgical 14.2% P = 0.04 for superiority 3.3% Transcatheter 59

2-Year All-cause Mortality ACC 2014

Major Stroke 62

Other Endpoints Events* 1 Month 1 Year TAVR SAVR P Value Vascular complications (major), % 5.9 1.7 0.003 6.2 2.0 0.004 Pacemaker implant, % 19.8 7.1 <0.001 22.3 11.3 Bleeding (life threatening or disabling),% 13.6 35.0 16.6 38.4 New onset or worsening atrial fibrillation, % 11.7 30.5 15.9 32.7 Acute kidney injury, % 6.0 15.1 * Percentages reported are Kaplan-Meier estimates and log-rank P values 63

MMC Heart Valve Clinic Marco Diaz, MD John Lualdi,MD David Butzell, MD Merle Kellett, MD Reed Quinn, MD Scott Buchanan, MD David Burkey, MD

Evaluate the aortic valvular complex using echocardiography Following Patient Referral, the TAVR Team will Perform Further Evaluation 1 2 3 4 5 Confirm the patient is diagnosed with severe symptomatic native aortic stenosis Confirm the patient has been independently evaluated by two cardiac surgeons and meets the indication for TAVR Evaluate the aortic valvular complex using echocardiography Evaluate the peripheral vasculature and aortic valvular complex using MDCT Evaluate the peripheral vasculature and aortic valvular complex using catheterization Note: Evaluation using CT is typically not done unless the Heart Team confirms that patient is a candidate for TAVR

Key Takeaways Aortic Stenosis is prevalent with a high morbidity and mortality when symptomatic and aortic valve replacement is the only treatment associated with improved outcomes. Asymptomatic low risk patients will benefit from surgical AVR. Low gradient does not necessarily exclude severe aortic stenosis, even when the ejection fraction is normal!! TAVR is an excellent alternative to traditional Aortic Valve Surgery but increased risk of stroke and vascular injury and the need for a permanent pacemaker. MMC Heart Team has performed over 100 TAVR procedures in three years with excellent outcomes.

Thank You!