Balloon-Expandable TAVR in Inoperable Patients With Severe Symptomatic Native Aortic Valve Stenosis: The PARTNER Trial Cohort B 2-Year Results

The information in this slide deck is intended for educational purposes only,

and should be read and used in its entirety.

3

Background

September 22, 2010 on NEJM.org

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Objectives

• To evaluate the clinical outcomes of the Edwards SAPIEN transcatheter heart valve (THV) compared to standard therapy at 2 years in “inoperable” patients with severe symptomatic native aortic valve stenosis

• To assess valve hemodynamic performance using echocardiography

• To perform analyses to better define the impact of comorbidities on outcomes

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Aortic Stenosis Is Life-Threatening and Progresses Rapidly1

• Survival after onset of symptoms is 50% at 2 years and 20% at 5 years2

• Surgical intervention for severe aortic stenosis should be performed promptly once even minor symptoms occur2

Undertreatment Is Profound

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A New Era Begins

• There has been tremendous interest in transcatheter aortic valve replacement (TAVR) since the first procedure in 2002

• Since then, patient selection, operator skills, and technology have improved

• There was a requirement for clinical data to evaluate TAVR compared with current standard therapies

Study Design

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Definitive Results Through Rigorous Design

The PARTNER Trial represents a paradigm shift in clinical trial design and execution for patients with severe symptomatic native aortic valve stenosis:

• Interdisciplinary in all aspects

• Strict site selection

• Rigorous study protocols and management

• Careful patient selection

Interdisciplinary in All Aspects

Co-Principal Investigators• Martin B. Leon, Craig R. Smith

Columbia University Medical Center

Executive Committee• Martin B. Leon, Michael Mack, D. Craig Miller,

Jeffrey W. Moses, Craig R. Smith, Lars G. Svensson, E. Murat Tuzcu, John G. Webb

Data and Safety Monitoring Board• Chairman: Joseph P. Carrozza

Tufts University School of Medicine

Clinical Events Committee• Chairman: John L. Petersen

Duke University Medical Center

Echo Core Laboratory• Chairman: Pamela C. Douglas

Duke University Medical Center

Quality of Life and Cost-Effectiveness

• Assessments Chairman: David J. CohenMid America Heart Institute, Kansas City

Independent Biostatistical Core Laboratory

• Stuart Pocock, Duolao WangLondon School of Hygiene and Tropical Medicine

• William N. Anderson

Publications Committee

• Co-chairman: Jeffrey W. Moses

• Co-chairman: Lars G. Svensson

Sponsor

• Jodi J. AkinEdwards Lifesciences

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Executive Committee Members

Rigorous Study Design

11TA, transapical; TF, transfemoral.

Rigorous Study Protocols and Management

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Strict Site Selection

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Emory UniversityAtlanta, GA

Univ. of MiamiMiami, FL

St. Luke’s Hospital Kansas City, MO

Barnes-Jewish HospitalSt. Louis, MO

Medical City DallasDallas, TX

St. Paul's HospitalVancouver, Canada

Univ. of WashingtonSeattle, WA

Mayo ClinicRochester, MN

Stanford UniversityStanford, CA

Hospital LavalQuebec City,

Canada

Cleveland ClinicCleveland, OH

Columbia University New York, NY

Washington Hosp. CenterWash., DC

Univ. of Penn Phila., PA

Mass. GeneralBoston, MA

Northwestern Univ.Chicago, IL

Toronto Gen. Hospital

Toronto, Canada

Evanston HospitalChicago, IL

Leipzig Heart Center Leipzig, Germany

n = 358 Cohort B patients22 Cohort B investigator sites18 USA, 3 Canada, 1 Germany

Scripps ClinicLa Jolla, CA

Cedars-Sinai Medical CenterLos Angeles, CA

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RetroFlex 3 Introducer Sheath Set

RetroFlex 3Delivery System

AtrionInflation Devices

RetroFlexBalloon Catheter

Edwards SAPIEN Transcatheter Heart Valve

The PARTNER Trial Cohort B Study Devices

RetroFlex Dilator KitCrimper

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Cohort B Endpoints

• Primary: All-cause mortality over the duration of the study

– Superiority test (two-sided), 85% power to detect a difference, α = .05, sample size = 350 total patients

• Co-primary: Hierarchical composite of all-cause mortality and repeat hospitalization

– Nonparametric method described by Finkelstein and Schoenfeld (multiple pairwise comparisons)

– > 95% power to detect a difference, α = .05

• Positive study if both endpoints P < .05, or if either endpoint is < .025

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Stringent Patient Screening

Screening Methodology

• Screening including clinical evaluation, echocardiography(+ TEE as needed), full catheterization and angiography (including coronaries), and vascular access assessment

• Case screening logs (screen failure rate > 70% at most sites)

• Case review webcast presentations (twice per week when necessary for expedited reviews) for cohort assignment and treatment strategy discussions (every patient enrolled)

• Treatment goal: within 2 weeks of randomization

TEE, transesophageal echocardiogram.

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Careful Patient Selection

• Select inclusion criteria– Severe symptomatic native aortic valve stenosis (aortic valve area < 0.8

cm2, mean gradient > 40 mm Hg, or peak aortic jet velocity > 4.0 m/s)

– NYHA functional class II or higher

– Predicted risk of mortality or irreversible morbidity > 50% as determined by 2 cardiothoracic surgeons and a cardiologist

• Select exclusion criteria – Left ventricular ejection fraction (LVEF) < 20%

– Severe (> 3+) mitral regurgitation (MR) or aortic regurgitation (AR)

– Untreated coronary disease (CAD) requiring revascularization

– Serum creatinine > 3.0 mg/dL or hemodialysis

– Recent myocardial infarction (1 month), stroke, or transient ischemic attack (6 months)

– Life expectancy < 12 months

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Study Flow Inoperable Cohort

• No patients were lost to follow-up

• 3 patients in the Edwards SAPIEN THV group were followed outside of the protocol window at 2 years

• 5 patients in the standard therapy group withdrew in the first year

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An Elderly and Highly Symptomatic Population

BAV, balloon aortic valvuloplasty; CABG, coronary artery bypass graft; CAD, coronary artery disease; CVD, cardiovascular disease;MI, myocardial infarction; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; STS, Society of Thoracic Surgeons.

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25% of Patients Had an STS Score ≥ 15 and 37% of Patients Had an STS Score < 10

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Patients Had Multiple Severe Comorbidities

Cohort B Outcomes

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Key Insights for Cohort B

• Standard therapy is failing these patients with severe symptomatic native aortic valve stenosis

• TAVR with Edwards SAPIEN THV delivers:– Superior survival rate– Reduction in symptoms and restoration of quality of life– Improvement in hemodynamics– Sustained valve performance

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Standard Therapy Is Failing These Patients

Standard therapy, including balloon aortic valvuloplasty (BAV), did not alter the dismal natural history of patients with severe symptomatic native aortic valve stenosis

• All-cause and cardiovascular mortality at 2 years were 68.0% and 62.4%, respectively

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Procedural OutcomesStandard Therapy (179 Patients)

• BAV performed in 141 patients (78.8%)

• In addition:– 11 (6.1%) patients received AVR– 5 (2.8%) received AVR plus left ventricular to descending aortic

valve conduit– 4 (2.2%) received TAVR outside the US

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TAVR Was Superior to Standard Therapy in All Measurements of Survival at 2 Years

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Absolute Reduction in Mortality Continues to Diverge at 2 Years

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> 30% Absolute Reduction in Cardiovascular Mortality

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25% Absolute Reduction in Mortality

> 30% Absolute Reduction in Cardiovascular Mortality

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> 30% Absolute Reduction in Mortality orRepeat Hospitalization

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> 35% Reduction in Repeat Hospitalization

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Improvement in Hemodynamics and Sustained Valve Performance

Serial echocardiograms in TAVR patients revealed:

• Reduced mean gradients and improved aortic valve area (AVA), which were unchanged during 1-year and 2-year follow-up

• Frequent paravalvular aortic regurgitation (AR), which was usually mild (~90%), remained stable during 1-year follow-up, slightly improved at 2 years, and rarely required further treatment

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Mea

n G

radi

ent,

mm

Hg

Reduced Mean Gradient

Error bars = ± 1 Std Dev

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Increased Valve Area

Error bars = ± 1 Std Dev

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Paravalvular Regurgitation Slightly Improved Over Time

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Reduction in Symptoms and Restoration ofQuality of Life

At 1 year, patients that underwent TAVR with the Edwards SAPIEN THV showed significant improvements in:

• NYHA functional class

• Kansas City Cardiomyopathy Questionnaire (KCCQ)

• SF-12

• 6-minute walk test

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Sustained Improvement in NYHA Functional Class

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Significant Improvement in 6-Minute Walk Test

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Significant Improvement in 6-Minute Walk Test

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Robust Evaluation of Quality of Life

• Assessments performed by self-administered questionnaires at baseline, 1 month, 6 months, and 12 months

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Statistical Analysis

• Primary QOL endpoint: KCCQ Overall Summary Score

• Secondary QOL endpoints: All other QOL scales

• Scores at each follow-up time point compared between groups by ANCOVA, adjusting for baseline

• Longitudinal analyses performed using random-effect growth curve models, adjusting for treatment group(TAVR vs control), time (linear, quadratic, cubic effects), and all potential 2-way and 3-way interactions

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Baseline QOL Data

P = NS for all comparisons.

QOL Compliance*

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*Among patients eligible for QOL assessment.

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KCCQ: Development and Validation

• 23 items that measure 5 clinically relevant domains of health status from the patient’s perspective10

– Symptoms – Quality of life– Self-efficacy– Physical limitation– Social limitation

• Individual scales combined into a global summary scale (KCCQ Overall Score)11

– Independently predictive of mortality and cost among patients with heart failure

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KCCQ Interpretation

• The KCCQ, followed by the NYHA and the 6-minute walk test, most accurately reflect clinical change in patients with heart failure

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Primary Endpoint: KCCQ Overall Summary

MCID, minimum clinically important difference.

KCCQ Subscales

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Generic QOL and Utilities

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Subgroup Analysis: KCCQ Improvement at 1 Year13

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*P values from ANCOVA.

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QOL Summary

The extent of benefit was large for both disease-specific and general QOL and was consistent across all pre-specified subgroups

• KCCQ Summary Score 20-25 points (~2-level NHYA class improvement on average)

• SF-12 Physical Component 5 points (~10-year reduction in effective age)

Complications

Higher Incidence of Stroke

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Stroke by Type

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Mortality or Stroke

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Higher Incidence of Major Vascular Complications

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Higher Incidence of Major Bleeding

* Major bleeding is defined as an event that causes death; causes a hospitalization or prolongs hospitalization; requires pericardiocentesis or an open and/or endovascular procedure for repair or hemostasis; causes permanent disability (eg, blindness, paralysis, hearing loss); or requires transfusion of > 3 units of blood within a 24-hour period.

New Pacemaker Implantation

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Conclusions

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Conclusions

At 2 years, in patients with severe symptomatic native aortic valve stenosis who were not suitable candidates for surgery:

• Treatment with the Edwards SAPIEN THV remained superior to standard therapy with incremental benefit from 1 to 2 years, reducing the rates of mortality and repeat hospitalization

• Treatment with Edwards SAPIEN THV improved NYHA functional status and decreased class III/IV symptoms compared to standard therapy

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Conclusions

• There were significantly more strokes in patients treated with the Edwards SAPIEN THV than in patients who received standard therapy

– After 30 days, differences in stroke frequency were largely due to increased hemorrhagic strokes in patients treated with Edwards SAPIEN THV

• Patients treated with the Edwards SAPIEN THV also had a higher incidence of major vascular complications and major bleeding than standard therapy patients

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Conclusions

• Edwards SAPIEN THV hemodynamic performance by echocardiography showed sustainable improvements in mean gradients and aortic valve areas up to 2 years after implantation

• Moderate or severe paravalvular aortic regurgitation in patients treated with the Edwards SAPIEN THV did not influence 2-year survival, and there was a trend towards reduced paravalvular aortic regurgitation between 1 and 2 years

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Clinical Implications

• Two-year data continue to support the role of treatment with Edwards the SAPIEN THV as the standard of care for patients with severe symptomatic native aortic valve stenosis who are not surgical candidates

• The ultimate value of Edwards SAPIEN THV in “inoperable” patients will depend on careful selection of patients who are not surgical candidates, and yet do not have extreme comorbidities that overwhelm the benefits and render the intervention futile

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References

1. Lester SJ, Heilbron B, Gin K, Dodek A, Jue J. The natural history and rate of progression of aortic stenosis. Chest. 1998;113:1109-1114.

2. Otto CM. Timing of aortic valve surgery. Heart. 2000;84:211-218.

3. Bouma BJ, van Den Brink RB, van Der Meulen JH, et al. To operate or not on elderly patients with aortic stenosis: the decision and its consequences. Heart. 1999;82:143-148.

4. Pellikka PA, Sarano ME, Nishimura RA, et al. Outcome of 622 adults with asymptomatic, hemodynamically significant aortic stenosis during prolonged follow-up. Circulation. 2005;111:3290-3295.

5. Charlson E, Legedza AT, Hamel MB. Decision-making and outcomes in severe symptomatic aortic stenosis. J Heart Valve Dis. 2006;15:312-321.

6. Varadarajan P, Kapoor N, Bansal RC, Pai RG. Clinical profile and natural history of 453 nonsurgically managed patients with severe aortic stenosis. Ann Thorac Surg. 2006;82:2111-2115.

7. Jan F, Andreev M, Mori N, Janosik B, Sagar K. Unoperated patients with severe symptomatic aortic stenosis. Circulation. 2009;120;S753. Abstract 3166.

8. Bach DS, Siao D, Girard SE, Duvernoy C, McCallister BD Jr, Gualano SK. Evaluation of patients with severe symptomatic aortic stenosis who do not undergo aortic valve replacement: the potential role of subjectively overestimated operative risk. Circ Cardiovasc Qual Outcomes. 2009;2:533-539.

9. Freed BH, Sugeng L, Furlong K, et al. Reasons for nonadherence to guidelines for aortic valve replacement in patients with severe aortic stenosis and potential solutions. Am J Cardiol. 2010;105:1339-1342.

10. Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and evaluation of the Kansas City Cardiomyopathy Questionnaire: a new health status measure for heart failure. J Am Coll Cardiol. 2000;35:1245-1255.

11. Soto GE, Jones P, Weintraub WS, Krumholz HM, Spertus JA. Prognostic value of health status in patients with heart failure after acute myocardial infarction. Circulation. 2004;110:546-551.

12. Spertus J, Peterson E, Conard MW, et al. Monitoring clinical changes in patients with heart failure: a comparison of methods. Am Heart J. 2005;150:707-715.

13. Reynolds, Magnuson EA, Lei Y, et al. Health-related quality of life after transcatheter aortic valve replacement in inoperable patients with severe aortic stenosis. Circulation. 2011;124:1964-1972.

Edwards SAPIEN Transcatheter Heart Valve and RetroFlex 3 Delivery System

Indications: The Edwards SAPIEN transcatheter heart valve, model 9000TFX, sizes 23 mm and 26 mm, is indicated for transfemoral delivery in patients with severe symptomatic native aortic valve stenosis who have been determined by a cardiac surgeon to be inoperable for open aortic valve replacement and in whom existing co-morbidities would not preclude the expected benefit from correction of the aortic stenosis.

Indications: The RetroFlex 3 delivery system is indicated for the transfemoral delivery of the Edwards SAPIEN transcatheter heart valve.

Contraindications: The bioprosthesis and delivery system are contraindicated in patients who cannot tolerate an anticoagulation/antiplatelet regimen or who have active bacterial endocarditis or other active infections. Warnings: Observation of the pacing lead throughout the procedure is essential to avoid the potential risk of pacing lead perforation. There may be an increased risk of stroke in transcatheter aortic valve replacement procedures, as compared to balloon aortic valvuloplasty or other standard treatments. The devices are designed, intended, and distributed for single use only. Do not re-sterilize or reuse the devices. There are no data to support the sterility, non-pyrogenicity, and functionality of the devices after reprocessing. Incorrect sizing of the bioprosthesis may lead to paravalvular leak, migration, embolization and/or annular rupture. Accelerated deterioration of the bioprosthesis may occur in patients with an altered calcium metabolism. Bioprosthesis must remain hydrated at all times and cannot be exposed to solutions other than its shipping storage solution and sterile physiologic rinsing solution. Bioprosthesis leaflets mishandled or damaged during any part of the procedure will require replacement of the bioprosthesis. Caution should be exercised in implanting a bioprosthesis in patients with clinically significant coronary artery disease. Patients with pre-existing mitral valve devices should be carefully assessed prior to implantation of the bioprosthesis to ensure proper bioprosthesis positioning and deployment. Patients presenting with combination AV low flow, low gradient should undergo additional evaluation to establish the degree of aortic stenosis. Do not use the bioprosthesis if the tamper evident seal is broken, the storage solution does not completely cover the bioprosthesis, the temperature indicator has been activated, the bioprosthesis is damaged, or the expiration date has elapsed. Do not mishandle the RetroFlex 3 delivery system or use it if the packaging or any components are not sterile, have been opened or are damaged (e.g. kinked or stretched), or the expiration date has elapsed. Use of excessive contrast media may lead to renal failure. Measure the patient’s creatinine level prior to the procedure. Contrast media usage should be monitored. Patient injury could occur if the delivery system is not un-flexed prior to removal. Precautions: Long-term durability has not been established for the bioprosthesis. Regular medical follow-up is advised to evaluate bioprosthesis performance. Glutaraldehyde may cause irritation of the skin, eyes, nose, and throat. Avoid prolonged or repeated exposure to, or breathing of, the solution. Use only with adequate ventilation. If skin contact occurs, immediately flush the affected area with water; in the event of contact with eyes, seek immediate medical attention. For more information about glutaraldehyde exposure, refer to Material Safety Data Sheet available from Edwards Lifesciences. To maintain proper valve leaflet coaptation, do not overinflate the deployment balloon. Appropriate antibiotic prophylaxis is recommended post-procedure in patients at risk for prosthetic valve infection and endocarditis. Bioprosthetic valve recipients should be maintained on anticoagulant and antiplatelet therapy (e.g. clopidogrel or ticlopidine [75 mg/day]) for 6 months post-procedure and aspirin (75-100 mg/day) for life, except when contraindicated, as determined by their physician. The safety of the bioprosthesis implantation has not been established in patients who have: pre-existing prosthetic heart valve in the aortic position; severe ventricular dysfunction with ejection fraction <20%; and hypertrophic cardiomyopathy with or without obstruction (HOCM). Safety and effectiveness have not been established for patients who are candidates for surgical aortic valve replacement. Safety, effectiveness, and durability have not been established for valve-in-valve procedures. Safety and effectiveness have not been established for patients with the following characteristics/comorbidities: non-calcified aortic annulus; congenital unicuspid or congenital bicuspid aortic valve; mixed aortic valve disease (aortic stenosis and aortic regurgitation with predominant aortic regurgitation >3+); pre-existing prosthetic heart valve or prosthetic ring in any position; severe mitral annular calcification (MAC), severe (>3+) mitral insufficiency, or Gorelin syndrome; blood dyscrasias defined as: leukopenia (WBC <3000 mm3), acute anemia (Hb <9 mg%), thrombocytopenia (platelet count <50,000 cells/mm3), or history of bleeding diathesis or coagulopathy; hypertrophic cardiomyopathy with or without obstruction (HOCM); echocardiographic evidence of intracardiac mass, thrombus, or vegetation; a known hypersensitivity or contraindication to aspirin, heparin, ticlopidine (Ticlid), or clopidogrel (Plavix), or sensitivity to contrast media, which cannot be adequately premedicated; native aortic annulus size <18mm or >25mm as measured by echocardiogram; Patient has been offered surgery but has refused surgery; significant aortic disease, including abdominal aortic or thoracic aneurysm defined as maximal luminal diameter 5 cm or greater, marked tortuosity (hyperacute bend), aortic arch atheroma (especially if thick [> 5 mm], protruding, or ulcerated) or narrowing (especially with calcification and surface irregularities) of the abdominal or thoracic aorta, severe “unfolding” and tortuosity of the thoracic aorta; iliofemoral vessel characteristics that would preclude safe placement of 22F or 24F introducer sheath such as severe obstructive calcification, severe tortuosity or vessels size less than 7 mm in diameter; and bulky calcified aortic valve leaflets in close proximity to coronary ostia. Potential Adverse Events: Potential risks associated with the overall procedure including potential access complications associated with standard cardiac catheterization for the transfemoral access procedure, balloon valvuloplasty, and the potential risks of local and/or general anesthesia: death; stroke/transient ischemic attack clusters or neurological deficit; paralysis; permanent disability; respiratory insufficiency or respiratory failure; hemorrhage requiring transfusion or intervention; cardiovascular injury including perforation or dissection of vessels, ventricle, myocardium or valvular structures that may require intervention; pericardial effusion or cardiac tamponade; embolization including air, calcific valve material or thrombus; infection including septicemia and endocarditis; heart failure; myocardial infarction; renal insufficiency or renal failure; conduction system injury (defect) which may require a permanent pacemaker; arrhythmia; retroperitoneal bleed; femoral AV fistula or pseudoaneurysm; reoperation; peripheral ischemia or nerve injury; restenosis; pulmonary edema; pleural effusion; bleeding; anemia; abnormal lab values (including electrolyte imbalance); hypertension or hypotension; allergic reaction to anesthesia or to contrast media; hematoma; syncope; pain or changes at the access site; exercise intolerance or weakness; inflammation; angina; heart murmur; and fever. Additional potential risks specifically associated with the use of the bioprosthesis include, but may not be limited to the following: cardiac arrest; cardiogenic shock; emergency cardiac surgery; cardiac failure or low cardiac output; coronary flow obstruction/transvalvular flow disturbance; device thrombosis requiring intervention; valve thrombosis; device embolization; device migration or malposition requiring intervention; valve deployment in unintended location; valve stenosis; structural valve deterioration (wear, fracture, calcification, leaflet tear/tearing from the stent posts, leaflets retraction, stent creep, suture line disruption of components of a prosthetic valve, thickening, stenosis, or other); device degeneration; paravalvular or transvalvular leak; valve regurgitation; hemolysis; device explants; nonstructural dysfunction; and non-emergent reoperation. All listed risks may include symptoms associated with the above mentioned medical conditions.

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RetroFlex Balloon Catheter

Indications: The RetroFlex balloon catheter is indicated for valvuloplasty of a stenotic cardiac valve prior to implantation of an Edwards SAPIEN transcatheter heart valve.

Contraindications: Other than standard risks associated with insertion of a cardiovascular catheter, there are no known contraindications for valvuloplasty. The patient’s medical condition could affect successful use of this catheter. Warnings: The device is designed, intended, and distributed for single use only. Do not resterilize or reuse the device. There are no data to support the sterility, nonpyrogenicity, and functionality of the device after reprocessing. Do not mishandle the device or use it if the packaging or any components are not sterile, have been opened or are damaged (e.g. kinked or stretched), or the expiration date has elapsed. Precautions: For special considerations associated with the use of this device prior to transcatheter heart valve implantation, refer to the bioprosthesis Instructions for Use. Use only appropriate balloon inflation medium. Do not use air or gaseous medium to inflate the balloon. The device is not intended for post-dilatation of deployed transcatheter heart valves. While exposed within the body, device advancement and retrieval should not be done without the aid of fluoroscopy. Do not advance or retract the device unless the balloon is fully deflated under vacuum. Potential Adverse Events: Complications associated with standard catheterization, balloon valvuloplasty, and the use of angiography include, but are not limited to, allergic reaction to anesthesia or to contrast media, injury including perforation or dissection of vessels, thrombus formation, plaque dislodgement and embolization that may result in myocardial infarction, stroke, distal peripheral occlusion and/or death, arrhythmia development, cardiac perforation, conduction system injury, hematoma, infundibulum injury, annular tear or rupture and/or valve leaflet dehiscence, severe valve insufficiency, valve restenosis, valve damage, balloon rupture.

Crimper

Indications: The crimper is indicated for use in preparing the Edwards SAPIEN transcatheter heart valve for implantation.

Contraindications: No known contraindications.Warnings: The device is designed, intended, and distributed for single use only. Do not resterilize or reuse the device. There are no data to support the sterility, nonpyrogenicity, and functionality of the device after reprocessing. Do not mishandle the device or use it if the packaging or any components are not sterile, have been opened or are damaged, or the expiration date has elapsed. Precautions: For special considerations associated with the use of this device prior to transcatheter heart valve implantation, refer to the bioprosthesis Instructions for Use. Potential Adverse Events: No known potential adverse events.

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Irvine, USA I Nyon, Switzerland I Tokyo, Japan I Singapore, Singapore I São Paulo, Brazil

Edwards, Edwards Lifesciences, the stylized E logo, Edwards SAPIEN, PARTNER, RetroFlex, RetroFlex 3, and SAPIEN are trademarks of Edwards Lifesciences Corporation. All other trademarks are the property of their respective owners.

© 2012 Edwards Lifesciences Corporation. All rights reserved. AR07323

CAUTION: Federal (United States) law restricts the Edwards SAPIEN transcatheter heart valve to sale by or on the order of a physician. This device has been approved by the FDA for specific indications for use. See instructions for use for full prescribing information, including indications, contraindications, warnings, precautions and adverse events.

CAUTION: Federal (United States) law restricts the RetroFlex 3 delivery system, RetroFlex 3 introducer sheath set, RetroFlex dilator kit, RetroFlex balloon catheter, crimper and Atrion inflation device to sale by or on the order of a physician. See instructions for use for full prescribing information, including indications, contraindications, warnings, precautions and adverse events.