Transcatheter Aortic Valve Implantation: Current Use and Future Directions Alan Zajarias Assistant Professor of Medicine Washington University School of Medicine St. Louis

I have no financial conflicts of interest to disclose I will be discussing treatments that are experimental and currently not FDA approved

Question 1 The treatment of a 88 y/o male with severe aortic stenosis, coronary artery disease s/p CABG, mild COPD, insulin dependent diabetes mellitus who complains of worsening lower extremity edema, orthopnea and syncope is: Routine follow up Add digoxin to improve heart failure symptoms Aortic valve replacement Bi-V pacemaker implantation

Question 2 Transcatheter aortic valve implantation: Can be performed in patients with bicuspid aortic valve. Is an experimental treatment that can be utilized in patients with aortic insufficiency. Is commercially available in the US for any patients with severe symptomatic aortic calcific stenosis. Is an experimental treatment that is being evaluated in patients with severe symptomatic aortic stenosis who have an elevated (STS PROM>10%) surgical risk.

Objectives Review the concept of transcatheter aortic valve implantation (TAVI) Describe the evaluation process of patients considered for TAVI Review the short and mid-term results following TAVI Identify future applications of transcatheter valve implantation

Natural History of Aortic Stenosis (AS) 740 pts with severe AS AVA < 0.8 cm2 451 had non surgical treatment Mean age: 75+13yrs LVEF < 40%: 33% CHF: 42% Ann Thorac Surg 2006; 82: 2111-5 6

ACC/AHA recommendations for AVR Class I Symptomatic severe AS Asymptomatic severe AS undergoing CABG Severe AS undergoing surgery of the aorta or other valves Severe AS and LV dysfunction (EF<50%) Class IIa Moderate AS and patients undergoing CABG J Am Coll Cardiol 2008;52:e1-e142

Operative Mortality for AVR AVR in octogenarians 220 pts Op mortality 13% if AVR Op mortality 24% if AVR + CABG Morbidity 60% Survival 85%, 80%, 73% (1,3,5 yrs) Benefits of AVR in octogenarians 81% no/mild disability for daily activities 93% feel less disabled 93% reassured to have access to treatment despite their age STS2001 (%) UKCSR 1999-2001 (%) EHS 2001 AVR 3.7 3.1 2.7 AVR + CABG 6.3 7 4.3 Eur J Cardio Thorac Surg 2007;31:600-606. Eur J Cardio Thorac Surg 2007;31: 1099-1105. Euro J Cardiothorac Surg 2006; 30: 722-727 8

Many patients are not surgically treated! Severe AS* - Percent of Patients Treated J Heart Valve Dis2006;15:312-321; Circulation 2005; European Heart Journal 2003;24:1231-1243; Heart 1999;82:143-148 9

Surgical risk evaluation Operative risk calculators STS risk calculator EuroSCORE Not designed for valvular surgery Do not include many variables that would increase risk of complications (ie: porcelain aorta, cirrhosis, previous mediastinal radiation, history of mediastinits) Reflection of true risk? High risk: >10% risk of operative mortality Preprocedural functional status influences outcomes* *Buellesfeld et al. Euro Heart J 2009 in press

Is there a treatment for patients with severe symptomatic AS whose surgical is prohibitive or who have a frank contraindication to surgical AVR?

Transcatheter Aortic Valve Implantation (TAVI) 1993: Andersen First description of valve sutured in stent Animal model Encountered 2 major limitations Removal of the native valve Obstruction of coronary ostia

First human implantation: Bovine pericardium valve April 16, 2002 (Rouen – France) Bovine pericardium valve 23mm in diameter

Transcatheter Aortic Valve Implantation (TAVI) Placement of a prosthetic valve mounted inside stent/frame in the aortic valve position via a transarterial (retrograde) or transapical (antegrade) approach. CoreValve Revalving system Edwards SAPIEN valve

Differences between the SAPIEN and Surgical Implanted Valves Magna Freestyle EOA (cm2) 1.6 1.2 1.38 Mean Gradient (mmHg) 10 13 14 Absence of AI 12% 62% 66% J Am Coll Cardiol 2009;52:1883-1891 15

Patient Evaluation Multidisciplinary approach Cardiac Surgery Cardiology Valvular Heart Disease Clinic Patients are seen simultaneously by surgeons and cardiologists to assess: Operative candidacy Symptom severity Frailty Patient interest Is aortic valve replacement going to improve their quality of life?

Patient Selection Inclusion Criteria Operable vs. Inoperable Symptomatic patients with severe AS (AVA<0.8 cm2) High risk AVR (STS >10%) NYHA >2 Operable vs. Inoperable Exclusion Criteria AMI < 1 month Bicuspid aortic valve Non-revascularized CAD Existing valvular prosthesis or valvular surgery, > 3+ MR, > 3+ AI HOCM Creatinine > 3 mg/dl Hgb < 9 GI bleed < 3 months Cardiogenic Shock TIA or CVA < 6 months Life expectancy < 12 months AAA Vascular access

Screening Echocardiography Transthoracic Echocardiogram Determine severity of AS Confirm annular dimension Evaluate LVEF Characterize other valvular disease Transesophageal Echocardiogram Annulus confirmation Evaluate severity of MR Controversy in measurements of TTE and TEE* Consider DSE to assess contractile reserve

Screening Angiogram Aortic angiogram Identify ideal projection where all aortic leaflets are in plane with the image intensifier Identify characteristics of the aortic arch and ascending aorta that may complicate the procedure

Screening Angiogram Iliac angiogram Gross marker of peripheral vascular disease Rudimentary assessment of arterial tortuosity, calcification, and diameter to determine patient candidacy for large sheath insertion. EuroIntervention. 2009 Sep;5(4):438-42

Patient Evaluation CT Angiogram Arterial calcification Arterial tortuosity Minimal luminal diameter 22

CT Angiography Contrast vs. non-contrast Intra-arterial contrast decrease contrast volume required Automated vs. manual diameter determination Large arteries determination is similar Smaller, calcified arteries there is a marked difference

Screening CT Distance from coronary artery to aortic annulus Aortic annulus dimension LVOT and sino-tubular dimension

Screening CT Prediction of angle of incidence to limit radiation and contrast Lack of concordance in measurements in the sagital or coronal projections with echocardiography Messika, J Am Coll Cardiol. 2010;55(3):186-94 Kurra JACC Cardiovasc Interv. 2010;3(1):105-13

Transfemoral Approach

CoreValve

Transfemoral Approach Sapien Valve RetroFlex 3 Delivery System Edwards SAPIEN THV RetroFlex Balloon Catheter RetroFlex 3 introducer Sheath Set Atrion Inflation Device Crimper RetroFlex Dilator Kit 28 28

Transfemoral Approach Aortic Angiogram

Transfemoral Approach Balloon Aortic Valvuloplasty

Transfemoral Approach Valve Deployment Aortic Pressure RV pacing: 200/min

Transfemoral Approach Aortic Angiogram

Transfemoral Approach Femoral Angiogram

Transapical Approach

Ascendra™ Transapical Approach Ascendra™ Introducer Sheath Set Edwards SAPIEN™ THV Ascendra™ Delivery System Atrion Inflation Device Ascendra™ Valvuloplasy Catheter 35 Crimper 35

Transapical Approach Direct left ventricular puncture

Transapical Approach Aortic Valvulopalsty

Transapical Approach Placement and valve deployment

Transapical Approach Aortogram

Intra-Procedural Echo Valve placement Early detection of complications Aortic insufficiency Central Peri-valvular Discrepancy with fluoroscopy?

Results

Results Sapien CoreValve Procedural success: 94% 97% Aortic valve area: 1.56 cm2 NR Mean gradient(mmHg): 11 10 Aortic insufficiency > 2: 4% 0% Coronary obstruction: 0.6% 0% Prosthesis migration: 0.3% NR Surgical conversion: 2.7% 1.4% Malposition: 1.5% NR Valve in valve: NR 2.6% NR: not reported Circulation 2009;119:3009 Eurointervention 2008;4:242-249

Functional Class Sapien CoreValve* European registry (not published) Circulation 2009;119:3009

Complications Sapien CoreValve Procedural Mortality: 1.2-2.4% 1.5-2.8% Mortality (30 d): 6.3-11.3% 8-12% MACE: 14% 9.3% MI: 1% 0.5-1.6% CVA: 2.5-4.2% 1.9-3.2% Pacemaker: 5.4% 10-33% Vascular complications: 6.6% 1.9-3.2% Cardiac tamponade: 2.4% 0.6-2.6% Aortic dissection: 0% 0.6-1.2% Am Heart J 2009;157:860-6; Source Registry Eurointervention 2008;4:242-49 Circulation 2009;119:3009

Pacemaker Incidence of AV block varies between prostheses Occurs in first 7 days Dependent on: Final valve position Pre-existing conduction defects JACC Intervention 2008;1:305-309 Am Heart J 2009;157:860-6

TAVI and CVA Clinical CVA: 1-10% Subclinical CVA due to: CoreValve: 72% CVA due to: Aortic root passage Crossing the valve Valve deployment Is the incidence different with the Sapien valve? J Am Coll Cardiol 2010;55:1427-32

1 Year Survival Circulation 2009;119:3009

Mortality Transapical has a higher mortality rate Higher risk cohort Steep learning curve More invasive arm To date, the transapical approach has only been offered as a alternative to those who are not a transfemoral candidates. Circulation 2009;119:3009 JACC 2010;55:1080-90

Mortality Procedural death 1.7% Post procedural 8.7% 30 day 10.4% Vascular access complications 13% JACC 2010;55:1080-90

Factors Associate with Mortality 30 day GFR<60 Pulmonary HTN Severe MR Hemodynamic support during procedure Late mortality Hemodynamic support Sepsis Pulmonary hypertension COPD Chronic kidney disease JACC 2010;55:1080-90

Porcelain Aorta and Frailty Younger No difference in mortality CVA: 1.6% Frailty Similar mortality rate JACC 2010;55:1080-90

TAVI vs. AVR When compared to partial upper sternotomy, transapical AVR provides: Shorter ICU stay Shorter ventilator time Shorter OR time Similar 30 day morbidity/mortality Thorac Cardiovasc Surg. 2009 Nov;138(5):1067-72

Acute Kidney Injury post TAVI Incidence: 12% Dialysis 1.4% Mortality: 28% vs. 7% TAVI vs. SAVR Acute Kidney Injury: 9.2% vs. 25% Dialysis: 2.5% vs. 8.7% Risk Factors: Hypertension OR= 4.66 COPD OR= 2.64 Transfusion OR= 3.47 E Heart J 2010 in press

TAVI in Degenerated Bioprostheses Aortic Capable with CoreValve and Sapien Bioprosthesis only Annular/Size diameter CoreValve: not in annulus < 21mm Mitral Transapical approach Sapien only Pulmonary Khawaja et al. J Am Coll Cardiol 2010;55:97-101 Wegamer, et al. J Am Coll Cardiol Img 2010;3:222-223

Future Directions FDA approval of TAVI will depend on the results of the PARTNER trial Initiation of the CoreVALVE randomized trial and PARTNER II TAVI modifications Smaller sheaths Repositionable Multi-modality imaging Numerous other valves in development and their introduction will depend on the results and information obtained from the ongoing trials

Unanswered Questions What is the in vivo durability? What is the role of TAVI in low-gradient AS? Which institutions should be qualified to perform TAVI if it is marketed? Should younger patients receive a surgical bioprosthesis in order to avoid long term use of oral anticoagulation, planning that they may receive a TAVI for prosthesis degeneration? Will there be a use of catheter valve implantation in lower risk population?

Conclusion Surgical AVR is the treatment of choice in patients with severe AS. Early detection and treatment of these patients would decrease their surgical risk. TAVI is an exciting new field which opens therapeutic options to patients who were previously not eligible for treatment. The success of any program involved in TAVI will depend on the close interaction of ALL members of the team. Results of the PARTNER trial are eagerly accepted in order to guide the next steps in the development of transcatheter valvular therapy.