TAVI Education

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Learning Objectives

1. Provide information on pathophysiology, etiology, prevalence, symptoms, and prognosis for severe aortic stenosis (AS)

2. Describe methods used to diagnose AS

3. Identify treatments for severe AS and associated clinical outcomes

4. Provide information on transcatheter aortic valve implantation (TAVI)

5. Identify potential patients for surgical aortic valve implantation (SAVR) or TAVI procedures

6. Describe the potential future for TAVI

Agenda

• Aortic Stenosis Overview

• Aortic Stenosis Diagnosis

• Aortic Stenosis Treatment Options and Outcomes

• TAVI:– Description– Surgical Procedure– CE-Mark Approved Products– Patient Selection– Clinical Outcomes – Future – Patient Case Example– Conclusions

Aortic Stenosis Overview

Healthy Aortic ValveHealthy Aortic Valve Stenosed Aortic ValveStenosed Aortic Valve

Pathophysiology and Prevalence

• Pathophysiology:– Progressive, degenerative disease of the native leaflets

– Mechanism of stenosis is similar to atherosclerosis1

• Prevalence2:– 2% of people over 65

– 3% of people over 75

– 4% of people over 85

– Most prevalent native valve disease

Aortic Sclerosis Aortic Stenosis

1 Otto CM. Circulation 1994;90:844-853.2 Steward BF. J Am Coll Cardiol 1997;29:630-634.

• Mild calcification• No obstruction of

blood flow

• Severe calcification• Obstruction of

blood flow

Disease Etiology

Predominantly a Degenerative Disease

Etiology of Single Native Left-sided Valve Disease

0%

20%

40%

60%

80%

100%

Aortic Stenosis AorticRegurgitation

Mitral Stenosis MitralRegurgitation

% o

f T

ota

l

Other

Ischemic

Congenital

Inflammatory

Endocarditis

Rheumatic

Degenerative

Messika-Zeitoun D.. Eur Heart J 2003;24:1244-1253.

Aortic Stenosis Severity

Indicator Mild Moderate Severe

Jet Velocity(m/s)

< 3.0 3.0 – 4.0 > 4.0

Mean Gradient(mmHg)

< 25 25 – 40 > 40

Valve Area(cm2)

> 1.5 1.0 – 1.5 < 1.0

Valve Area Index(cm2/m2)

– – < 0.6

Bonow RO. ACC/AHA 2006 Guidelines for the Management of Patients with Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association on Practice Guidelines. Circulation 2006;114:e84-e231.

Onset of Severe Symptoms

Onset of dyspnea and other heart failure symptoms foretell the worst outlook for aortic stenosis patients

Carabello BA. Lancet 2009;373:956-966.

Ross J, Braunwald E. Circulation 1968; 38: 61-67.

Classic symptoms of aortic stenosis:

• Heart Failure

• Syncope

• Angina

Symptoms & Mortality if Valve Not Replaced

• Mortality for untreated severe AS: 38%, 68%, and 82% at 1, 5, and 10 years, respectively. 1,2,3,4

• Aortic Stenosis combined with:

– Heart Failure has a 50% 2 yr mortality rate2

– Syncope has a 50% 3 yr mortality rate2

– Angina has a 50% 5 yr mortality rate2

1 Vahanian A. Eur Heart J. 2008;29:1463-1470.2 Ross J. Circulation 1968;38:61-67.3 Bonow RO J Heart Valve Dis. 1998;7:672-707.4 Varadarajan P. Ann Thorac Surg. 2006;82:2111-2115.

Aortic Stenosis Diagnosis

Physical Examination

• Slow rate of rise of the carotid pulse

• Mid to late peak intensity of murmur

• Decreased intensity of the second heart sound

• Peripheral signs include:– Slow-rising, small volume carotid pulse

– Narrowed pulse pressure

– Sustained, heaving apex beat that is not displaced unless systolic dysfunction of the left ventricular has developed

Echocardiography and Cardiac Catheterization

• EchocardiographyPurpose: Evaluate certain heart murmurs

Helps:

• Define primary lesion, cause and severity

• Evaluate hemodynamics, secondary lesions

• Evaluate chamber size and function

• Re-evaluate patient after intervention

• Cardiac CatheterizationPurpose: Provide additional information beyond initial

echocardiographic and clinical findings

Helps:

• Provide more information about severity and regurgitation

• Confirm non-invasive disease suspicions

Diagnosis: Evaluating Murmurs

Cardiac MurmurCardiac Murmur

Systolic MurmurSystolic Murmur Diastolic MurmurDiastolic Murmur Continuous Murmur

Continuous Murmur

Midsystolic (grade 2 or less)

Midsystolic (grade 2 or less)

• Early systolic• Midsystolic

(grade 3 or less)• Late systolic• Holosystolic

• Early systolic• Midsystolic

(grade 3 or less)• Late systolic• Holosystolic

AsymptomaticAsymptomaticSymptomatic or other signs of

cardiac disease

Symptomatic or other signs of

cardiac disease

Catheterization and/or

Angiography

Catheterization and/or

Angiography

EchocardiographyEchocardiography

• Venous hum• Mammary soufflé

or pregnancy

• Venous hum• Mammary soufflé

or pregnancy

No further workup Required

No further workup Required

Bonow RO. ACC/AHA 2006 Guidelines for the Management of Patients with Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association on Practice Guidelines. Circulation 2006;114:e84-e231.

Severe AS Treatments and Outcomes

SAVR • In the absence of serious co-morbid conditions, SAVR is indicated in virtually all symptomatic patients with severe AS1

TAVI • High risk or contraindications for SAVR

Aortic Balloon Valvuloplasty

• Bridge to surgery in hemodynamically unstable adult patients with AS who are at high risk for AVR1

• For palliation in adult patients with AS in whom AVR cannot be performed because of serious comorbid conditions1

Medical Management • Serious comorbid conditions, malignancy, short life expectancy or patient preference1

1. Adapted from Bonow RO. J Am Coll Cardiol. 2008;52(13):e1-142.

Treatments

ESC Valvular Heart Disease Guidelines: Class I Indications for SAVR

1. Patients with severe AS and any symptoms

2. Patients with severe AS undergoing CABG or surgery on the ascending aorta or other heart valves

3. Asymptomatic patients with severe AS and systolic left ventricular dysfunction (LVEF < 50%)

4. Asymptomatic patients with severe AS showing symptoms on exercise

Vahanian A. Eur Heart J 2007;28:230-268.

Severe AS Survival Results:With and Without AVR

AS=aortic stenosis; AVR=aortic valve replacement.

1. Varadarajan P, et al. Eur J Cardiothorac Surg. 2006;30:722-727.

Aortic Balloon Valvuloplasty

• High restenosis rate: 50% in six years1,2

• Acute improvements: 26% repeat BAV after 30 days3

• Only 21% of patients were in NYHA II or less at one year3

1Otto CM. Circulation 1994;89:642-650.2Rahmitoola SH. J Am Coll Cardiol 1994;23:1076-1078.3Tuzcu, EM. Clinical Outcomes from “Standard Therapy” in the PARTNER Inoperable Patients. TCT 2010, Washington D.C.

% Severe AS Patients Not Treated with SAVR

Charlson1 Pellikka2 Iung3 Bouma4

U.S. Europe1 Charlson E. J Heart Valve Dis 2006;15:312-321. 3 Iung B. Eur Heart J 2003;24:1231-1243.2 Pellikka PA. Circulation 2005;111:3290-3295. 4 Bouma BJ. Heart 1999;82:143-148.

No SAVR

SAVR

Reasons Severe AS Patients are Not Treated with SAVR

Meet Medical Guidelines – But Not Treated1,2 :

• Age concerns

• Co-morbidity concerns

• Lack of guideline knowledge

• Patient refusal

Contra-indicated for SAVR:

• Surgery risk too high

1 Charlson E. J Heart Valve Dis 2006;15:312-321. 2 Iung B. Eur Heart J 2003;24:1231-1243.

Transcatheter Aortic Valve Implant (TAVI) Background

TAVI Description

• Provides percutaneous orthotopic placement of a prosthetic tissue heart valve

• Replaces native aortic heart valve without open-heart surgery and without concomitant surgical removal of the failed native valve

• Placed within the annulus of the stenotic valve by means of a catheter

• Three components:– Delivery Catheter System– Aortic Valve Prosthesis– Crimping/Loading System

TAVI Implantation Approach Options

1. Transfemoral: Catheter advanced to the stenotic aortic valve via the femoral artery.

2. Subclavian / Axillary: Catheter advanced to the stenotic aortic valve via a small incision exposing the subclavian / axillary artery.

3. Direct Aortic: Catheter advanced to the stenotic aortic valve via minimally invasive thoracotomy (e.g. right anterior mini-thoracotomy) or sternotomy (e.g. upper partial mini-sternotomy)

4. Transapical: Catheter is inserted via a small intercostal incision. The apex of the left ventricle is punctured, and the valve is positioned within the stenotic aortic valve.

TAVI Implantation Approach Options

Transfemoral

Subclavian

Direct Aortic

Transapical

1. Balloon catheter threaded through sheath and into heart

TAVI Procedure Example:CoreValve® Transfemoral Approach

2. Transcatheter valve placed into position over the diseased aortic valve

3. Transcatheter valve in place, procedure completed

TAVI Procedure and Recovery

• Local or general anesthesia

• No heart-lung bypass machine required

• Catheter is placed transarterially

• 1 to 3 hour procedure (typical)

• 3 to 5 day hospital stay (typical)

• Approximately 1 week recovery

Note: SAVR patients who undergo open-heart surgery typically have a longer hospital stay and 6-8 week recovery period.

EACTS, ESC and EAPCI Position Statement on TAVI Patient Selection

• Calcified pure or predominant AS

• Severe AS with symptoms

• Patients at high-risk or with contraindications for SAVR

• Assessment for TAVI contraindications

Vahanian A. Eur Heart J 2008;29:1463-1470.

EACTS, ESC and EAPCI Position Statement TAVI Patient Selection – Contraindications

• Aortic annulus < 18 or > 25 mm for balloon-expandable and < 20 or > 27 for self-expandable devices

• Bicuspid valves because of the risk of incomplete deployment of the prosthesis

• Presence of asymmetric heavy valvular calcification, which may compress the coronary arteries during TAVI

• Aortic root dimension > 45 mm at the aorto-tubular junction for self-expandable prostheses

• Presence of apical LV thrombus

Vahanian A. Eur Heart J 2008;29:1463-1470. Note: With 31mm valve, CoreValve® annulus ranges is 20-29mm.

CE-Mark Approved TAVI Products for the Treatment of Severe AS

Company Medtronic Edwards Lifesciences

Product CoreValve® SAPIEN™

CE approval 2007 2007

Expansion Self-expandable Balloon-expandable

Frame Nitinol Stainless Steel / Cobalt Chromium

Valve Material Porcine Bovine

Sheath Size 18Fr 22-26Fr and 18-19.5Fr

Aortic Annulus

20 mm–29 mm

(Transfemoral, Subclavian, & Direct Aortic)

Transfemoral: 18 mm–25 mm

Transapical: 18 mm–27 mm

Over 20,000 TAVI procedures have been performed since 2007

TAVI Outcome Results

1. PARTNER (SAPIEN™) Cohort B Clinical Trial Results

2. CoreValve® 18 Fr Safety and Effectiveness (SE) Study; Australian and European Registry Study Results

3. CoreValve® Quality of Life Study

4. CoreValve® Safety and Durability Studies

PARTNER Trial Purpose

• Assess the safety and effectiveness of TAVI (n=179) compared with standard therapy (n=179) in patients with severe AS and cardiac symptoms, who can not undergo surgery (“inoperable”)

Leon MB. N Engl J Med 2010;363:1597-1607.

PARTNER: All Cause Mortality

Numbers at Risk

TAVI 179 138 122 67 26

Standard Rx 179 121 83 41 12

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Months

Standard RxTAVI

P < 0.001Hazard Ratio 0.55

30.7%

50.7%

45% reduction in all cause mortality with TAVI

Leon MB. N Engl J Med 2010;363:1597-1607.

PARTNER: Cardiovascular Mortality

100

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Car

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vasc

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)

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Standard RxTAVI

P < 0.001Hazard Ratio 0.39

20.5%

44.6%

Numbers at Risk

TAVI 179 138 122 67 26

Standard Rx 179 121 83 41 12

61% reduction in all CV mortality with TAVI

Leon MB. N Engl J Med 2010;363:1597-1607.

PARTNER: Mortality or Repeat Hospitalization

100

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(%

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0 6 12 18 24

Months

Standard RxTAVI

P < 0.001Hazard Ratio 0.46

42.5% (22.3% hospitalization

only)

70.4% (44.1% hospitalization only)

Numbers at Risk

TAVI 179 117 102 56 22

Standard Rx 179 86 49 23 4

54% reduction in mortality or repeat hospitalization

with TAVI

Leon MB. N Engl J Med 2010;363:1597-1607.

PARTNER: NYHA Class Over Time

Leon MB. N Engl J Med 2010;363:1597-1607.

I II III IV Dead

0%

20%

40%

60%

80%

100%

Pat

ien

ts (

%)

TAVI Standard TAVI Standard TAVI Standard TAVI Standard

Baseline 30 Days 6 Months 1 Year

P=0.68 P<0.001 P<0.001 P<0.001

NYHA Class

CoreValve® System Clinical Experience

Med

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Study Study Size Number of Centers Follow-up Status

Italian Registry4 772 14 3 year Enrolling

Belgian Registry5 297 9 3 year Enrolling

Spanish Registry6 108 3 6 months Enrolling

France II Registry7 785 33 6 months Enrolling

UK Registry8 452 25 2 years Enrolling

German Registry9 588 22 30 days Enrolling

Brazilian Registry10 198 12 Procedural Enrolling

Study Study Size Number of Centers Follow-up Status

Australia-New Zealand Registry1 362 10 12 months Enrolling

REDO Study2 18 3 12 months Complete

ADVANCE Study3 1015 44 30 days Enrollment Complete

1. Meredith I.T. 12 Month Results from ANZ CoreValve TAV Study. Presented at: TCT 2011. 2. Müller R. Short- And Long-term Safety & Effectiveness of TAVI in a Failing Surgical Aortic Bioprosthesis. Presented at: TCT 2011. 3. Medtronic CoreValve® ADVANCE Study. http://clinicaltrials.gov/ct2/results?term=NCT01074658. Accessed 7/13/11. 4. Petronio AS. Italian Registry. Presented at: EuroPCR 2010. 5. Bosmans J. Belgian TAVI Registry. Presented at: London Valves 2011. 6. Avanzas P, et al. Rev Esp Cardiol. 2010;63:141-148. 7. Cribier A. FRANCE II Multicenter TAVR Registry. Presented at: TCT 2011. 8. Moat N.E., et al. JACC. 2011; 58. 9. Zahn R., et al. European Heart Journal. 2011; 32:198-204. 10. Brito F.S. Brazilian Registry. Presented at TCT 2011.

Baseline Patient Characteristics

ANZ=Australia-New Zealand; EuroSCORE=European System for Cardiac Operative Risk Evaluation; LVEF=left ventricular ejection fraction; NYHA=New York Heart Association.

1. Meredith I.T. 12 Month Results from ANZ CoreValve TAV Study. Presented at: TCT 2011. 2. Petronio AS. Italian Registry. Presented at: EuroPCR 2010. 3. Moat N.E., et al. JACC. 2011;58. 4. Bosmans J. Belgian TAVI Registry. Presented at: London Valves 2011. 5. Brito F.S. Brazilian Registry. Presented at TCT 2011. 6. Avanzas P, et al. Rev Esp Cardiol. 2010;63:141-148.

ANZ Registry1

ItalianRegistry2

UKRegistry3

BelgianRegistry4

Brazilian Registry5

SpanishRegistry6

N 362 772 452 297 198 108

Age, years 84 ± 6 82 ± 6 81.3 ± 7.4 83 ± 6 82.2 78.6 ± 6.7

Female, % 46 56 48 54 55 54.6

Logistic EuroSCORE, % 18 ± 11 22.9 ± 13.5 18.1 24 ± 15 21.4 16 ± 13.9

NYHA class III and IV, %

78 70.6 73.9 80 83.5 58.4

LVEF, % 58 ± 11 51 ± 13 – 57 ± 15 – –

Mean pressure gradient, mm Hg

51 ± 15 52 ± 17 – 47 ± 16 – 55 ± 14.3

Aortic valve area, cm2 0.7 ± 0.2 – – 0.63 ± 0.14 – 0.63 ± 0.2

Meta-analysis of Patient Characteristics

• N=2156 patients analyzed from 7 national registries– Australia-New Zealand, Belgium, France, Germany, Italy, Spain, and

the United Kingdom

• Mean age of the population: 81.6 years

• Male: 47%

• New York Heart Association class III and IV: 77%

• Mean Logistic EuroSCORE: 21.3% (range, 16.0-24.7)

• Mean aortic valve area: 0.63 cm2

• Mean gradient: 49.7 mm Hg

EuroSCORE=European System for Cardiac Operative Risk Evaluation.

1. Ruiz CE, et al. Weighted meta-analysis of early and late clinical outcomes after CoreValve® – TAVI in seven national registries. Presented at: EuroPCR; May 17-20, 2011; Paris, France. Analysis sponsored by Medtronic, Inc.

Procedural Success* in CoreValve® System Studies

1. Buellesfeld L, et al. J Am Coll Cardiol. 2011;57:1650-1657.

CoreValve® Haemodynamic ImprovementConsistent Improvement Across Studies at 30 Days

1. Meredith I.T. 12 Month Results from ANZ CoreValve TAV Study. Presented at: TCT 2011. 2. Avanzas P, et al. Rev Esp Cardiol. 2010;63:141-148. 3. Petronio AS. Italian Registry. Presented at: EuroPCR 2010.

CoreValve® Hemodynamic Performance at 2 Years

1. Buellesfeld L, et al. J Am Coll Cardiol. 2011;57:1650-1657.

CoreValve® Functional Improvement at 2 Years

NYHA=New York Heart Association.

1. Gerckens U. Stable durability and effectiveness at 2 years with CoreValve® transcatheter aortic valve. Presented at: EuroPCR; May 17-20, 2011; Paris, France.

1. Gerckens U. Stable durability and effectiveness at 2 years with CoreValve® transcatheter aortic valve. Presented at: EuroPCR; May 17-20, 2011; Paris, France.

CoreValve® Aortic Regurgitation at 2 Years

Survival rates reported are based on Kaplan-Meier analysis.

CoreValve® 1-Year Survival Rates Across Clinical Trials

1. Meredith I.T. 12 Month Results from ANZ CoreValve TAV Study. Presented at: TCT 2011. 2. Moat N.E., et al. JACC. 2011;58. 3. Petronio AS. Italian Registry. Presented at: EuroPCR 2010. 4. Bosmans J. Belgian TAVI Registry. Presented at: London Valves 2011. 5. Ruiz C.E. Weighted meta-analysis of CoreValve® Outcomes.Presented at: EuroPCR 2011 (analysis sponsored by Medtronic, Inc.).

CoreValve® 2-Year and 3-Year Survival Rates

Survival rates reported are based on Kaplan-Meier analysis.

1. Bosmans J. Belgian TAVI Registry. Presented at: London Valves 2011. 2. Moat N.E., et al. JACC. 2011;58. 3. Tamburino C. Italian CoreValve Registry. Presented at TCT 2011,

• 87 CoreValve® Patients > 80 Years; 80 survived to 6 months follow-up:

– Average scores of all 8 health components significantly improved after TAVI

– Both physical and mental component scores improved significantly

– Brain natriuretic peptide levels also improved significantly

Prospective TAVI Quality of Life Study

Bekeredijian R. Am J Cardiol 2010;106(12):1777-1781.

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

PhysicalFunctioning Role-

Physical

BodilyPain General

Health

VitalitySocial

Functioning

Role-Emotional Mental

Health

Before TAVI

6 Months after TAVI

Short Form 36-Item Health Survey

Potential Complications

Implantation of the transcatheter valve has been associated with complications.

In TAVI clinical studies, patients experienced additional adverse events during or after the procedure which included but were not limited to:– Death including all cause and cardiovascular mortality– Myocardial infarction including coronary occlusion– Stroke including permanent stroke and TIA– Re-intervention including SAVR and repeat valve placement– Aortic regurgitation– Permanent pacemaker placement– Pericardial tamponade (wire perforations)– Vascular and bleeding complications– Valve migration or fracture

Items are listed in order of severity. For complete list of adverse events, warnings and contraindications reference CoreValve® IFU.

TAVI Future

• Continued Clinical Evaluation in Current Patient Population– TAVI will continue to be evaluated in prospective trials for

severe symptomatic AS patients at high or extreme risk for SAVR

• Clinical Evaluations in New Patient Populations– TAVI will be evaluated in a prospective randomized-controlled

trial for severe symptomatic AS patients compared to SAVR

• Product and Surgery Improvements – TAVI outcomes could improve as refinements are made to

devices and implantation techniques, and implantation experience grows

TAVI Patient Selection

Involves multi-disciplinary consultation between cardiologists, surgeons, imaging specialists, anesthesiologists, and others as needed.

Steps:

1. Confirm severity of AS

2. Evaluate symptoms

3. Analyze risk of surgery

4. Assess current life expectancy and quality of life

5. Identify exclusion based on TAVI contraindications

Vahanian A. Eur Heart J 2008;29:1463-1470.

Case Study Slide

Case Study Slide

Outcomes At My Center

• Hospital Length of Stay:

• Procedural Success Rate:

Other Complications or Adverse Events:

• (enter here)

Conclusions or Next Steps – From Physician Presenter

Potential TAVI Patients

Patients to Consider for TAVI Referral– Patient has severe, symptomatic aortic stenosis

– Patient is high risk for surgical aortic valve replacement or is inoperable

– Patient was previously rejected for surgical aortic valve replacement

Patients NOT Recommended for TAVI Referral– Severe ventricular dysfunction (LVEF < 20%)

– End-stage renal disease requiring chronic dialysis

– Life expectancy less than 12 months

– Mitral regurgitation greater than grade 2

* Please refer to product IFUs for more specific details on patient selection

CoreValve® is a registered trademark of Medtronic CV Luxembourg S.a.r.l.

Edwards SAPIEN™ is a registered trademark of Edwards Lifesciences Corporation.