1 edwards sapien transcatheter heart valve model 9000tfx and retroflex 3 and ascendra delivery...

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Edwards SAPIEN Transcatheter Heart Valve Edwards SAPIEN Transcatheter Heart Valve Model 9000TFX and RetroFlex 3 and Ascendra Model 9000TFX and RetroFlex 3 and Ascendra

Delivery SystemsDelivery Systems

FDA Review of P110021FDA Review of P110021

Lisa KennellLisa Kennell

Division of Cardiovascular DevicesDivision of Cardiovascular DevicesOffice of Device EvaluationOffice of Device Evaluation

Food and Drug AdministrationFood and Drug Administration

Circulatory System Devices Panel MeetingCirculatory System Devices Panel MeetingJune 13, 2012June 13, 2012

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FDA Team PresentersFDA Team Presenters

Lisa KennellLisa KennellIntroduction and Pre-ClinicalIntroduction and Pre-Clinical

Xiting (Cindy) Yang, PhDXiting (Cindy) Yang, PhDStatistical SummaryStatistical Summary

Julie Swain, MDJulie Swain, MDClinical SummaryClinical Summary

Veronica Sansing, PhDVeronica Sansing, PhDPost-Approval StudyPost-Approval Study

Sonna Patel-Raman, PhDSonna Patel-Raman, PhDSummarySummary

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OutlineOutline

• Regulatory HistoryRegulatory History• Proposed Indications for useProposed Indications for use• Device DescriptionDevice Description• Pre-Clinical TestingPre-Clinical Testing• Overview of PARTNER studyOverview of PARTNER study• Statistical ReviewStatistical Review• Clinical ReviewClinical Review• Post-Approval StudyPost-Approval Study• FDA SummaryFDA Summary

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• SAPIEN IDE Study G030069SAPIEN IDE Study G030069– Pivotal PARTNER study began in 2007Pivotal PARTNER study began in 2007

• Premarket Approval (PMA) Application Premarket Approval (PMA) Application – PMA application received May 2, 2011PMA application received May 2, 2011– Amended February 17, 2012Amended February 17, 2012– Data “freeze” or “lock” date September 21, 2011Data “freeze” or “lock” date September 21, 2011

• Ongoing Study (Continued Access)Ongoing Study (Continued Access)– Currently approved for 1984 patients at 23 sitesCurrently approved for 1984 patients at 23 sites

Regulatory HistoryRegulatory History

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Proposed Indications for UseProposed Indications for Use

The Edwards SAPIEN Transcatheter Heart Valve The Edwards SAPIEN Transcatheter Heart Valve (THV) is indicated for use in the following clinical (THV) is indicated for use in the following clinical conditions:conditions:

TransfemoralTransfemoral

For use in patients with severe symptomatic native aortic For use in patients with severe symptomatic native aortic valve stenosis who have been examined by a heart team valve stenosis who have been examined by a heart team including a cardiac surgeon and found to be:including a cardiac surgeon and found to be:• inoperable and in whom existing co-morbidities would not inoperable and in whom existing co-morbidities would not

preclude the expected benefit from correction of the aortic preclude the expected benefit from correction of the aortic stenosis, orstenosis, or

• operable candidates for aortic valve replacement but who operable candidates for aortic valve replacement but who are at a greater than or equal to 15% (high) risk of are at a greater than or equal to 15% (high) risk of mortality for surgical aortic valve replacement.mortality for surgical aortic valve replacement.

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Proposed Indications for Use Proposed Indications for Use (continued)(continued)

Transapical

For use in patients with severe symptomatic native aortic valve stenosis who have been examined by a heart team including a cardiac surgeon and found to be operative candidates for aortic valve replacement but who are at a greater than or equal to 15% (high) risk of mortality for surgical aortic valve replacement.

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Device DescriptionDevice Description

• The Edwards SAPIEN THVThe Edwards SAPIEN THV – Heterologous (bovine) tissue sutured within a stainless steel stentHeterologous (bovine) tissue sutured within a stainless steel stent– Aortic Sizes: 23 and 26 mmAortic Sizes: 23 and 26 mm– Polyethylene terephthalate (PET) cuffPolyethylene terephthalate (PET) cuff

• RetroFlex 3 or RetroFlex delivery system RetroFlex 3 or RetroFlex delivery system available in sizes 20 and 23 mm for pre-dilating to ease crossing size 23 and 26 mm valve (transfemoral applications)

• Ascendra Balloon Aortic Valvuloplasty and Balloon Catheters for pre-dilating and delivering the valve (transapical applications)

• Sheath Set with Introducer, Sheath, and Loader with Cap• A dilator kit

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FDA Pre-Clinical Review TeamFDA Pre-Clinical Review Team

• Co-Team LeadersCo-Team Leaders– Lisa KennellLisa Kennell– Changfu Wu, PhDChangfu Wu, PhD

• EngineeringEngineering– Changfu Wu, PhDChangfu Wu, PhD– Nandini Duraiswamy, PhDNandini Duraiswamy, PhD– Sandy Stewart, PhDSandy Stewart, PhD– Stephen Retta, MSStephen Retta, MS– Albert Rodriguez, BSAlbert Rodriguez, BS

• Animal StudyAnimal Study– Michael John, MPHMichael John, MPH

• Patient Labeling ReviewPatient Labeling Review– David Windt, MPHDavid Windt, MPH

• MRIMRI– Terry Woods, PhDTerry Woods, PhD– Wolfgang Kainz, PhDWolfgang Kainz, PhD

• MicrobiologyMicrobiology – Lisa Kennell, BSLisa Kennell, BS

• Bio-Research Bio-Research MonitoringMonitoring

– Adam Donat, MSAdam Donat, MS

• Manufacturing Manufacturing – Andrea Artman, MSAndrea Artman, MS

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Pre-Clinical TestingPre-Clinical Testing• BiocompatibilityBiocompatibility• Sterility & PackagingSterility & Packaging• Magnetic Resonance Imaging Magnetic Resonance Imaging

(MRI)(MRI)• Delivery systemDelivery system• ManufacturingManufacturing• Bio-research monitoringBio-research monitoring

• Corrosion resistance Corrosion resistance evaluation of the valve stentevaluation of the valve stent

• Fatigue evaluation of the valve Fatigue evaluation of the valve stentstent

• Hydrodynamic and durability Hydrodynamic and durability testing of the whole valvetesting of the whole valve

• Valve migration potential Valve migration potential evaluationevaluation

• In VivoIn Vivo sheep studies sheep studies

Most testing done as part of P100041 for inoperable PMA; only Most testing done as part of P100041 for inoperable PMA; only Ascendra accessories were new in this PMA. No further Ascendra accessories were new in this PMA. No further concerns about the majority of testing.concerns about the majority of testing.

However, no testing was conducted on However, no testing was conducted on valve-valve-in-valvein-valve implantation. implantation.

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Valve-in-Valve

• At least 2 cases of valve-in-valve in Cohort A study

• Many more cases outside of the U.S., as reported in the literature

• Different valve positions– Aortic, mitral, tricuspid, and pulmonic

• Different configurations– TAV-in-TAV– TAV-in-SAV– TAV-in-Ring

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Valve-in-Valve: Potential Risks

• Size mismatch – 2 sizes for SAPEN THV vs. various sizes for

surgically placed bioprosthetic valves– Impact on stable anchoring and uncompromised

hemodynamic performance

• Valve migration/embolization• Long term durability• Fretting fatigue• Galvanic corrosion• Access to the coronary ostia

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PARTNERIDE Trial

Cohort A(High Risk)

Cohort B(Inoperable)

OpenAVR*

SAPIEN(TA & TF)

ControlSAPIEN(TF only)

Open AVR refers to median sternotomy, partial sternotomy or limited thoracotomy (i.e., minimally invasive approach)

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Study Endpoints

• Primary endpoint was all cause mortality at 1 year in the Intent-To-Treat population

• FDA will focus mainly on totality of the data/clinically important endpoints

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FDA Clinically Important Secondary Endpoints

• Death• Neurological Events• Aortic Regurgitation• Bleeding• Vascular Complications• Atrial Fibrillation

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Secondary Endpoints Chosen by Sponsor for Labeling Purposes

• Time from randomization to the first occurrence of MACCE within 1 year– Death– MI– Stroke– Renal Failure

• Total hospital days from the index procedure to one year post procedure

• NYHA at 1 year• Six minute walk test at 1 year

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Other Analyses

• Primary endpoint in transapical and transfemoral groups separately

• Gender differences for primary endpoint

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FDA Statistical Review of P110021FDA Statistical Review of P110021

Xiting Yang, Ph.D.Xiting Yang, Ph.D.

Cardiovascular and Ophthalmic Devices BranchCardiovascular and Ophthalmic Devices BranchDivision of BiostatisticsDivision of Biostatistics

Office of Surveillance and BiometricsOffice of Surveillance and Biometrics

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1. Study Design1. Study Design

2. Patient Accountability2. Patient Accountability

3. Primary Endpoint Results3. Primary Endpoint Results

4. Sponsor Secondary Endpoint Results4. Sponsor Secondary Endpoint Results

5. Summary5. Summary

OutlineOutline

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Study DesignStudy Design

• Prospective, non-blinded, randomized, controlled, multi-center clinical trial

• Sample size ranges 690 to 750

• Transfemoral: minimum 450

• Transapical: minimum 200

• Assume 65% patients in Transfemoral approach

Transfemoral Access

Transfemoral (TF)(n=492)

Transapical (TA)(n=207)

1:1 Randomization 1:1 Randomization

TF SAPIEN(n=244)

AVR (Control)(n=248)

TA SAPIEN(n=104)


Yes No

Transfemoral Access

Transfemoral (TF)(n=492)

Transapical (TA)(n=207)

1:1 Randomization 1:1 Randomization

TF SAPIEN(n=244)


TA SAPIEN(n=104)


Yes No

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Patient Accountability

Control: AVR (n= 351)• 5 died prior to the procedure• 5 deteriorated prior to the procedure• 28 either refused AVR or withdrew• 1 patient started with AVR and converted to SAPIEN

SAPIEN: TAVR (n= 348)• 2 died prior to the procedure• 1 deteriorated prior to the procedure • 1 refused SAPIEN • 11 patients started with SAPIEN but converted to AVR

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Analysis PopulationsAnalysis Populations

• Intent-To-Treat (ITT) – All randomized patients

• “As Treated” (AT)– AT AVR: patients randomized to the AVR arm for

whom the valve implant procedure has begun.– AT SAPIEN: patients randomized to the treatment

arm for whom the study valve implant procedure has begun.

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Primary Safety and Effectiveness EndpointPrimary Safety and Effectiveness Endpoint

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Primary Safety and Effectiveness Endpoint (ITT)Primary Safety and Effectiveness Endpoint (ITT)

•The upper bound of the one-sided 95% C.I. of mortality difference for (SAPIEN -AVR) is 3.0%•p-value (non-inferiority, 7.5% margin): 0.001

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Missing Data and Worst Case Missing Data and Worst Case Analysis (ITT)Analysis (ITT)

• Missing data- unknown status at 1 year– 26 patients in AVR– 4 patients in SAPIEN

• Worst Case Analysis Assumptions– Missing patients in AVR are counted as alive

(success) and those in SAPIEN as dead (failure)

• Non-inferiority endpoint is still met (7.5% margin)

• Does NOT address– SAPIEN patients receiving AVR– AVR patients undergoing concomitant operations

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Gender Analysis (ITT)• Male/Female Composition

– Males compose 56.7% (198/351) of AVR arm – Males compose 57.8% (201/348) of SAPIEN arm

• Significant Interaction (p-value < 0.10)Significant Interaction (p-value < 0.10)• Primary Endpoint by Gender

• Nonrandomized Continued Access Protocol CohortNonrandomized Continued Access Protocol Cohort– 770/1588 (48.5%) female770/1588 (48.5%) female

– Female mortality rate (K-M estimated): 18.5%Female mortality rate (K-M estimated): 18.5%

– Male mortality rate (K-M estimated): 25.9%Male mortality rate (K-M estimated): 25.9%

Gender Control (AVR) SAPIEN (TAVR) 95% one-sided upper confidence limit of mortality rate difference

(SAPIEN - AVR )

Male 25.2% 28.5% 10.7%

Female 29.0% 18.4% -2.4%

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Primary Endpoint on Different Approaches (ITT)

• Non-significant Interaction (p-value > 0.15)Non-significant Interaction (p-value > 0.15)• Primary Endpoint by Approach

• Nonrandomized Continued Access Protocol CohortNonrandomized Continued Access Protocol Cohort– Transfemoral mortality rate (K-M estimated): 20.6%Transfemoral mortality rate (K-M estimated): 20.6%– 745/1588 (46.9%) transfemoral approach/1588 (46.9%) transfemoral approach

– Transapical mortality rate (K-M estimated): 24.1%Transapical mortality rate (K-M estimated): 24.1%

Approach Control (AVR) SAPIEN (TAVR) 95% one-sided upper confidence limit of mortality rate

difference (SAPIEN - AVR )

Transfemoral 26.4%(n=248)

22.2%(n=244)

2.3%

Transapical 27.9%(n=103)

29.0%(n=104)

11.7%

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Sponsor Secondary Endpoint: MACCE Sponsor Secondary Endpoint: MACCE (AT)(AT)

• Definition:– Time from randomization to the first occurrence of an

MACCE event (death, MI, all stroke and renal failure) within one year

• KM event rates at 1 year are 26.6% and 27.4% for SAPIEN and AVR respectively for the AT population

• Each of MACCE components are weighted equally

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Sponsor Secondary Endpoint: Sponsor Secondary Endpoint: Hospitalization (ITT)Hospitalization (ITT)

• Definition– Total Hospital Days Through One Year– Does not count rehabilitation days– Index procedure days are included– Actual number of hospital days used for patients who

died before one year

• Observed– AVR Median: 13 days (range: 0-280)– SAPIEN Median: 10 days (range: 0-187)

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Secondary Endpoint: NYHA at One Year (ITT)Secondary Endpoint: NYHA at One Year (ITT)• No statistically significant difference at baseline• At 1 Year

– AVR Mean: 1.70 ± 0.76 based on 226/351(64%) patients– SAPIEN Mean: 1.70 ± 0.77 based on 250/348(72%) patients

• Sensitivity analyses regarding missing data conducted• Conclusions indefinite• Difficult to draw firm conclusion due to death & missing data• Possible systematic bias for non-blinded trials

AT population Missing Dead I II III IV Total

AVR 16 77 103 91 21 5 313

SAPIEN 15 80 119 93 32 5 344

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Sponsor Secondary Endpoint: 6MWT (ITT)Sponsor Secondary Endpoint: 6MWT (ITT)

• Observed – AVR mean (150/351 = 43%): 169.8 ± 134.4 meters– SAPIEN mean (198/348 = 57%): 165.0 ± 128.4

meters• Missing Data Among Alive Patients*

– AVR : 118/268 (44%)– SAPIEN : 71/269 (26%)– *Sponsor calculation:

– AVR: 87/268 (32.5%); SAPIEN: 44/269 (16.4%)• Sensitivity analyses regarding missing data conducted• Conclusions indefinite• Difficult to draw firm conclusion because of missing data

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30 Day QoL• Observed Measurements

• Sponsor “Predicted” Values

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SummarySummary

• The study met its pre-specified non-inferiority primary endpoint with a non-inferiority margin of

7.5% on all cause mortality at 1 year.

• Males seemed to perform better with Males seemed to perform better with AVR (Control) • Females seemed to perform better with Females seemed to perform better with SAPIEN

• FDA clinical reviewer will discuss key effectiveness and safety issues

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FDA Clinical Review of P100041FDA Clinical Review of P100041

Julie A. Swain, MDJulie A. Swain, MDCardiovascular SurgeonCardiovascular Surgeon

Division of Cardiovascular DevicesDivision of Cardiovascular DevicesOffice of Device EvaluationOffice of Device Evaluation

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SAPIEN Clinical ExperienceSAPIEN Clinical Experience• 11stst US Feasibility US Feasibility• 22ndnd US Feasibility US Feasibility• Roll-in Registry IDE TrialRoll-in Registry IDE Trial

• Randomized, Controlled IDE TrialRandomized, Controlled IDE Trial• Continued Access RegistryContinued Access Registry

• European data 7000+ patientsEuropean data 7000+ patients– EuroScore as inclusion (invalid for isolated valves, over EuroScore as inclusion (invalid for isolated valves, over

predicts mortality 3-7 times)predicts mortality 3-7 times)– Surgeon determination of inoperability or high risk not Surgeon determination of inoperability or high risk not

requiredrequired

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Patient Selection for TAVR

Operable High Risk Inoperable Inoperable Operable (Benefit (No Benefit to Patient) to Patient)

A?? BB

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Totality of the DataTotality of the Data

Statistical non-inferiority (mortality: delta 7.5% with actual AVR 27%)

vs.

Judgement of Clinical Equivalence(i.e., substitute for AVR in this population)

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Mean F/U time: AVR 1.6 ±1.0 years, TAVR 1.8±1.0 years

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PARTNERIDE Trial

Cohort A(High Risk Operable)

Open SurgicalIsolated AVR

TranscatheterSAPIEN TAVR

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0

20

40

60

80

100

Access for TAVR and AVRAVR SAPIEN SAPIEN TF only TF+TA

% Pts

40

Important Considerations

1. Trial conduct Issues2. Neurological damage

3. Aortic Insufficiency

4. Vascular injury/ Bleeding

5. Atrial Fibrillation

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Trial Conduct Issue:Heterogeneity of Treatment

Control AVR (n= 351)• isolated AVR (222)

• AVR + concomitant operations (40)• No AVR – nothing (38)• Delayed AVR (49)• Unsuccessful AVR (2 [1 TAVR])

SAPIEN (n= 348)• isolated TAVR (<306)

• TAVR – no Rx concomitant (? Assume same)

• No TAVR – nothing (4)• Delayed TAVR (20)• Unsuccessful TAVR (18 [11 AVR])

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0

5

10

15

AVR SAPIEN

Deteriorate

Withdraw

Refuse

Died

Trial Conduct Issues:No Attempt to Treat

% Pts

n = 5

n = 11

n = 17

n = 5

n = 1

n = 2

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AVR SAPIEN

Trial Conduct Issue:Failed Treatment (AT)

% Pts

0

5

10

15

N = 2

N = 18

44

AVRto

SAPIEN

SAPIENto

AVR

0

5

10

15

Trial Conduct Issue:Crossover

% Ptsn = 11

n = 1

45

0

5

10

15

AVR SAPIEN

Trial Conduct Issue:Concomitant Operations

% Pts

Not count surgical injury

n = 40

42.5% dead at 1 year

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Concomitant OperationsCABG 20

CABG + aortic endarterectomy 1

MV repair 4

MV replacement 1

MV repair, annular enlargement 1

MV repair, root enlargement 1

TV repair 1

TV annuloplasty, Root replacement 1

Root/arch replacement 3

Aortoplasty 2

Ascending Aortic endarterectomy 3

Ablation for Atrial Fibrillation 1

Excision Left Atrial Appendage 1

TOTAL Patients with concomitant operations (% total 40/313) (As Treated)

40(12.8%)

• 42.5% (17/40) had died by 1 year

• confounds analysis of adverse events

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Trial Conduct Issue: Delay between Randomization and Procedure

• Median Delay: AVR 9 days, SAPIEN 7 days • Not Counted in Graph: Pt ID xx030: no AVR because of

“worsening lab values” 14 months after randomization

0

5

10

15

20

% PtsAVR

SAPIEN

48

Trial Conduct Issue:Amount of Missing Data

• 6 MWT Missing Data– AVR : 118/268 (44%)– SAPIEN : 71/269 (26%)

0

10

20

30

40

Pts with AF at Baseline:% missing data at 1 yrfor determination of AF

% Pts

AVR SAPIEN

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Trial Conduct Issue: Large Variations Among Sites

• Ratio of total screened to enrolled (14% to 63%) [4.5 X] Allocation bias?

• Control Patients not receiving AVR (1% to 20%) [20 X] Treatment/Selection bias?

• Ratio of enrollment in Cohort A to Cohort B (1.0 to 4.1) [4.1 X] Treatment/Selection bias?

• Bleeding complication [3.6 X] Treatment/Assessment bias?

• Variation of missing data between sites (?) and between armsAssessment bias?

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Mean F/U time: AVR 1.6 ±1.0 years, TAVR 1.8±1.0 years

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1. Trial conduct Issues

2. Neurological damage3. Aortic Insufficiency



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Prespecified Definition of Stroke and TIAPrespecified Definition of Stroke and TIA(CEC Adjudicated)(CEC Adjudicated)

Stroke is a neurological deficit lasting ≥ 24 hours, or lasting < 24 hours with a brain imaging study showing infarction

A transient ischemic attack (TIA) is a fully reversible neurologic event that lasts less than 24 hours and if an imaging study is performed, shows no evidence of infarction.

• DW-MRI Imaging to detect acute infarction rarely done• All SAPIEN TIA’s and 3/5 AVR had a motor deficit• All patients in both arms had general anesthesia

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Antithrombotic Regimen

Medication Pre-Procedure During Catheterization Post-Procedure 30-Day Follow-up 6 month follow-up

IV Heparin PRN 5000 IU bolus, then as needed to achieve/maintain ACT ≥250 sec

Aspirin 75-100 mg QD 75-100 mg QD 75-100 mg QD 75-100 mg QD

Clopidogrel* 300 mg (if not on long-term therapy)

75 mg QD 75 mg QD 75 mg QD for 6 months

Recommendations for SAPIEN Arm

Recommendations for AVR Arm

Standard of Care at each institution

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Neurological Events[Miller, et al. J Thorac Cardiovasc Surg 2012;143:832-43]

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0

25

50

75

100

%Patients

CrossAV(Omran)

Ghanem Kahlert Rodes-Cabau

Astarci Arnold

22

73

84

68

91

68

AVR

(Knipp)

48

AVR

(Astarci)

8

DW-MRI Lesions

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Cerebral Infarction after TAVI

• ~ 60% scans not done (death, CVA, complications, refusal, etc.)

• Limitations in clinical assessment of stroke, no long-term F/U

• Possible mechanisms of injury: – catheter in arch - crossing stenotic AV– Balloon valvuloplasty - TAVI positioning– TAVI expansion - Corrective manipulation

Future TAVI IDE studies – protocolized neurological assessment by neurologists in at least 50% of patients

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Transfemoral vs. Transapical: 1 year KM Mortality (AT)

% mortality

0

20

40

AVR SAPIEN

TF TATFTA

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Transfemoral vs. Transapical: Neurological Events

[Miller, et al. J Thorac Cardiovasc Surg 2012;143:832-43]

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2. Neurological damage

3. Aortic Insufficiency4. Vascular injury/ Bleeding


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Association Between AR and Mortality

1. Long-term outcomes after transcatheter aortic valve implantation in high-risk patients with severe aortic stenosis: the U.K. TAVI (United Kingdom Transcatheter Aortic Valve Implantation) Registry. Moat NE, et al. J Am Coll Cardiol 2011; 58:2130-2138.

2. Transcatheter aortic valve implantation in patients with severe symptomatic aortic valve stenosis-predictors of mortality and poor treatment response. Gotzmann M, et al. Am Heart J 2011; 162:238.e1-245.e1.

3. Aortic Regurgitation after Transcatheter Aortic Valve Implantation: Incidence and Early Outcome. Results from the German Transcatheter Aortic Valve Interventions Registry.Abdel-Wahab, et al. Heart 2011; 899-906

4. Incidence and Predictors of Early and Late Mortality after Transcatheter Aortic Valve Implantation in 663 Patients with Severe Aortic Stenosis. (Tamburino, et. al, Circulation 2011;123:299-308)

5. Registry of Transcatheter Aortic-Valve Implantation in High-Risk Patients. Gilard M, et al. N Engl J Med 2012;366:1705-1715.

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Total Aortic RegurgitationTotal Aortic RegurgitationMild (1+) or Greater Mild (1+) or Greater (Central + Paravalvular)(Central + Paravalvular)

0

20

40

60

80

30d 6mos 1yr

% pts

AVR

SAPIEN

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Total Aortic Regurgitation and Mortality

Kodali, et al. Two-Year Outcomes after Transcatheter or Surgical Aortic-Valve Replacement. NEJM 2012

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Total AR and Mortality (SAPIEN)

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4. Vascular injury/ Bleeding5. Atrial Fibrillation

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Vascular Complications

1. Hematoma at access site >5 cm

2. False aneurysm

3. Arterio-venous fistula

4. Retroperitoneal bleeding

5. Peripheral ischemia/nerve injury

6. transfusion for cath complication.

7. Vascular surgical repair **

0

20

40

60

TF TA

% Pts AVR

SAPIEN

66

Vascular Complication in SAPIEN (CEC adjudicated) #events

Myocardial perforation 3

VSD 1

Thoracic aortic dissection 3

Abdominal aortic dissection 1

Iliac or Ileofemoral artery dissection 16

Femoral artery dissection 11

Iliac artery perforation 6

Femoral artery perforation 6

Femoral pseudoaneurysm 6

Iliac or femoral artery embolus 7

Femoral or retroperitoneal hematoma 16

AV fistula 2

Total Events 78

# patients with Vascular Complication 64

Total patients 344

% patients with vascular complication 18.6%

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Bleeding (<30d)Definition: >3uPRBC or procedure

0

10

20

30

AVR SAPIEN

0

25

50

%Pts

% AVR Pts

Site

• concomitant operations not accounted for• 3.6 fold variation by site• Blood conservation protocols are important (STS guidance)

23%

11%

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Mortality and Blood Transfusion

Koch CG, et al. Transfusion in Coronary Artery Bypass Grafting is Associated with Reduced Long-Term Survival. Ann Thorac Surg 2006;81:1650-1657

0

2u

3-5u

>6u

“X”u = amount of RBC transfused

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70

“New Onset” Atrial Fibrillation

0

5

10

15

20

25

AVR SAPIEN

• Defined as any event >31 seconds• Does not require that patient be treated• Does not count abolishment of AF• Does not consider concomitant operations

% Pts

1.5X difference

71

Presence of Atrial Fibrillation at Followup(FDA Analysis – AT)

0

10

20

30

40

6 mos 1 yr Missingdata 1yr

0

10

20

30

40

6mos 1yr MissingData 1yr

No AF at Baseline:% who developed AF

AF at Baseline:% no AF at Followup

AVR SAPIEN

% Pts% Pts

72

0

10

20

30

13 d

3.6% yr 10 d

2.7% yr

# Days(median)

Total Acute Care Hospital Days to 1 Year

Post Procedure (median)

AVR SAPIENDifference0.8% of year

∆ Percent Hospital Days to 1 Year Post Procedure (median)

OUT

IN

73

Reverse Remodeling(1 yr – baseline)

0

5

10

15

-20

-10

0

-20

-10

0

-40

-30

-20

-10

0

EF %

LVESV ml

LVEDV ml

LV Mass g

AVR SAPIEN

74

Informed Consent• Ensuring true informed consent is important

• Comparison of adverse events needs to be presented.– Death – Neurological events– Vascular complications– Bleeding– Long-term effects of aortic insufficiency– Access incisions

• Panel input: If SAPIEN is approved, how should informed consent be handled?

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Neuro Events (2X)

Aortic Regurg (4X)

Vascular SAE (3X)

Men?

Proven Durability

Bleeding (2X)

Women ?

Mortality

Atrial Fib

NYHA, QOL, 6MWT

Hosp Days 1 yr

AVR BETTER NO Clinically SAPIEN BETTER Important Difference

AVR vs TAVR in High Risk Operable Patients

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Summary

• Trial met primary statistical non-inferiority endpoint (mortality non-inferiority delta 7.5%)

• Assessment of Risk/Benefit needs to include consideration of neurological events, aortic insufficiency, vascular complications, gender, and access approach.

• Due to limited clinical data, long term durability still remains in question

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Post-Approval Study Considerations for

SAPIEN (Cohort A) Transcatheter Heart Valve

Veronica V. Sansing, PhD, MS

Division of Epidemiology

Office of Surveillance and Biometrics / CDRH

June 13, 2012

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Reminder

• The discussion of a PAS prior to FDA determination of device approvability should not be interpreted to mean FDA is suggesting the device’s safety and effectiveness have been established.

• The plan to conduct a PAS does not decrease the threshold of evidence required by FDA for device approval.

• The premarket IDE data submitted to the Agency and discussed today must stand on its own in demonstrating a reasonable assurance of safety and effectiveness.

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Need for Post-Approval Studies for PMA

• Gather postmarket information– Long-term performance including effects of re-

treatments & device changes– Broader device performance (patients and clinicians) – Effectiveness of training programs– Sub-group performance

– Outcomes of concern (safety and effectiveness)

• Account for Panel recommendations

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Post-Approval Study Components

• Fundamental study question or hypothesis

• Safety endpoints and methods of assessment

• Safety & effectiveness endpoints and methods of assessment

• Duration of follow-up

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Summary of Postmarket Concerns for SAPIEN THV

• Long term device durability

• Long term patient quality of life (QoL)

• Learning curve assessment

• Comparison of

– Postmarket patients with premarket cohort

– Patient populations (gender & race) and outcomes

– Device performance

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Important Postmarket Concerns for SAPIEN THV

• Long term (5-year) performance– Most IDE patients already have 2-3 years of follow-up data

– Analyses of echo data (durability) & QoL data (yrs. 2-5)

• Learning curve consists of:1) Technical aspects of procedure

• Technical complexity may vary by approach (TA and TF)

2) Appropriate patient selection

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Important Postmarket Concerns for SAPIEN THV (cont.)

• Performance in gender and minority groups– Gender interaction: Males – Control better, Females – SAPIEN

better

– <10% of IDE patients were minorities, though minorities have poorer outcomes following AVR.1

• Assess valve-in-valve performance– Valve-in-valve implant method rarely seen premarket study

– Reports of this method in literature

[1] Taylor NE, O'Brien S, Edwards FH, Peterson ED, Bridges CR. Relationship between race and mortality and morbidity after valve replacement surgery. Circulation. 2005 Mar 15;111(10):1305-12.

84

Important Postmarket Concerns for SAPIEN THV

• Association between mortality and aortic regurgitation (AR) severity (no/trace vs. mild/moderate/severe) – 1 year: 53% of TAVR pts had mild-severe AR vs.14% AVR

– Increased hazard of mortality for mild-severe AR compared to no/trace AR in TAVR pts (HR – 2.1) premarket

85

Outline for Extended Follow-up of Premarket (PAS 1)

Study Design

Prospective, randomized-controlled, multi-center trial

Objective • Valve implant durability • Long term QoL

Population All IDE patients currently enrolled & alive

• 10-30% of the 699 TAVR pts estimated by year 5

Follow-up Annually through the 2-5 year visits

Endpoints • Durability: Additional analysis of Echocardiogram data– Consented through 5 years

• QoL: KCCQ, EQ5D, SF-12 – Reconsent to collect years 2-5

86

Outline for Newly Enrolled Study (PAS 2)

Study Design Non-randomized prospective, consecutively enrolled registry study

Objectives •Short-term (30-day) and long-term (1-year) safety•Adherence to indications for use/learning curve

1º Endpoint All stroke at 30 days and 1 year

Hypothesis H0: 30-day stroke rate ≥ Comparison rateH1: 30-day stroke rate < Comparison rate

One sided alpha 0.05Population Sites

•High Risk Patients: ≥700 TF & ≥1010 TA•35 sites

Study Design Non-randomized prospective, consecutively enrolled registry study

Objectives •Short-term (30-day) and long-term (1-year) safety•Adherence to indications for use/learning curve

1º Endpoint All stroke at 30 days and 1 year

Hypothesis H0: 30-day stroke rate ≥ Comparison rateH1: 30-day stroke rate < Comparison rate

One sided alpha 0.05Population Sites

•High Risk Patients: ≥700 TF & ≥1010 TA•35 sites

TF TA Pooled

IDE rate x 1.3 margin 14% x 1.3 21% x 1.3 16% x 1.3

Comparison Rate 19% 27% 21%

TF TA Pooled

IDE rate x 1.3 margin 14% x 1.3 21% x 1.3 16% x 1.3

Comparison Rate 19% 27% 21%

87

Outline for Newly Enrolled Study (PAS 2)

Effectiveness- Total days alive and out of hospital - Clinical improvement per NYHA

Class - Mean ICU and total index

procedure hospital length of stay

Follow-up Clinical visits: discharge, 30 days and 1 year (TVT registry)Telephone: annually 2-5 years (CMS linkage)

Additional Endpoints(30 days, 1 year)

Safety

– VARC composite– Major vascular

complications– All neurological events– New permanent

pacemaker– Stroke-free/

rehospitalization-freesurvival

Statistical Kaplan Meier estimate of primary endpoint Additional: Learning curve for VARC composite safety at 30 days

Effectiveness- Total days alive and out of hospital - Clinical improvement per NYHA

Class - Mean ICU and total index

procedure hospital length of stay

Follow-up Clinical visits: discharge, 30 days and 1 year (TVT registry)Telephone: annually 2-5 years (CMS linkage)

Additional Endpoints(30 days, 1 year)

Safety

– VARC composite– Major vascular

complications– All neurological events– New permanent

pacemaker– Stroke-free/

rehospitalization-freesurvival

Statistical Kaplan Meier estimate of primary endpoint Additional: Learning curve for VARC composite safety at 30 days

88

Years 2- 5 CMS Data

• Demographics & clinical status

• Primary Endpoints

• Safety & Effectiveness Outcomes

Year 1TVT Registry

TVT Registry & CMS Data

[1] ISO 5840 Standards for Cardiovascular Implants and Cardiac Valve Prostheses; FDA Draft Guidance for Industry and FDA Staff for Heart Valves; AATS/STS/EACTS Guidelines for Reporting Mortality and Morbidity After Cardiac Valve Interventions

• Link TVT patients to Medicare claims files by direct & indirect patient identifiers.– All claims 1 yr prior to TVT procedure

• Clinically Relevant Endpoints1

• Safety Outcomes & Overall Survival– Annually

89

FDA Assessment of Sponsor’s Proposed PAS

• PAS 1: The follow-up duration of the IDE is 5 years. FDA finds the sponsor’s plans to assess long-term durability and QoL adequate.

PAS 2: The gender*treatment interaction was significant (p<0.10; not powered). FDA recommends that the premarket data be pooled with the postmarket data in order to further analyze the differences by gender.

90

FDA Assessment of Sponsor’s Proposed PAS

PAS 2: Valve-in-valve procedures may occur postmarket. FDA recommends that the PAS be used to monitor short-term and long-term effects of safety and effectiveness of valve-in-valve implantation.

PAS 2: Premarket data showed an increased hazard of mortality in TAVR patients with mild-severe AR compared to those with no-trace AR. The FDA recommends that the PAS include a plan to analyze the association between AR severity and mortality.

91

Summary of FDA ReviewSummary of FDA ReviewP110021P110021

Sonna Patel-Raman, Ph.D.Sonna Patel-Raman, Ph.D.

Circulatory Support and Prosthetics BranchCirculatory Support and Prosthetics BranchDivision of Cardiovascular DevicesDivision of Cardiovascular Devices

Office of Device EvaluationOffice of Device Evaluation

92

Primary EndpointPrimary Endpoint

• Primary endpoint met statistical non-inferiority with 7.5% delta

• Consider additional factors when assessing benefit-risk:– Long-Term Performance and Outcomes– Trial Conduct– Patient Treatment– Neurological Events– Aortic Insufficiency– Vascular Complications

93

Long-Term and Trial ConductLong-Term and Trial Conduct

• Long-term Performance – Valve durability and performance– Patient outcomes

• Trial Conduct– Screening and enrollment– Patient selection– Missing data

94

Patient TreatmentPatient Treatment

• Trial– Open AVR versus Open TAVR?– Concomitant operations– Delay in treatment

• Interpretation of the Data– Males versus Females– Transapical versus Transfemoral

95

SafetySafety

• Neurological adverse events– Higher events in TA– Mitigate risk?

• Aortic Insufficiency– Aortic regurgitation is appreciable at 1-2 years – The long-term clinical significance is unknown

• Vascular complications– 1st generation device/delivery system– Does the training program adequately address

ways to minimize this risk?

96

Additional ConsiderationsAdditional Considerations

• Informed Consent– How much information is enough to convey benefit

versus risk to patients?

• Need for post-approval study– TVT Registry– Determine “real world” use– Interpretation of subjective measures such as

quality of life data in unblinded trials– How long should these patients be followed?

97

Questions?Questions?

98

Back Up Slides

99

Significant Interaction of Treatment*Gender

• Covariates – Treatment, sex, treatment*sex, age, race, BSA,

Diabetes Mellitus (Yes/No), smoking (Yes/No), Arrhythmia (Yes/No), Stroke or TIA within last 6 months (Yes/No), and prior cardiovascular intervention (yes/no), STS score and NYHA

• Logistic Regression – P-value < 0.10

• COX PH Regression – P-value < 0.05

100

30 Day QoL• Observed Measurement s

• Sponsor “Predicted” Values

101

TIAAVR•Garbled speech and altered mental status: (head CT same day, no new infarct)

•Numbness left side of body, blurred vision: (MRI negative)

•Confusion, intermittent confusion, amnesia for morning: (MRI not done (pacer), CT negative)•Right sided weakness and numbness. (No imaging done)

•Aphasia, right sided weakness , persistent dysarthria, 2 days later right sided facial drooping, right sided drooling, garbled speech, expressive aphasia. (Acute CT – no acute findings. No MRI done)

SAPIEN•altered mental status and transient aphasia, delirium, day after TAVR. (Acute CT scan neg for infarct) •2 days after TAVR right sided weakness. (No evidence of imaging)

•Dysarthria, dysphagia (no imaging listed)

•Aphasia, left sided facial droop (No imaging listed)

•Weakness right arm, dysphagia (No imaging listed)

•Loss of sensation and motor power in left upper ext with sudden numbness (No image listed)

102

CMS data & TVT registry

• The TVT registry requirement is for 1 year of follow-up1

– Registry collects all strokes, and does not distinguish between disabling and non-disabling strokes.

• CMS records linked with PAS patient study for 5 year study data– Patients matched on demographics, history of stroke

and heart disease. – However, the sponsor does not account for multiple

CMS records that can serve as a match for one patient.

1. Decision Memo for Transcatheter Aortic Valve Replacement (TAVR) (CAG-00430N)

103

Primary Endpoint (24M, ITT)

104

MACCE (12M, ITT)

105

MACCE (24M, AT)

106

Male(24M, ITT)

107

Female(24M, ITT)

108

TF (24M, ITT)

109

TA(24M, ITT)

110

Death and Missing on 6MWT (Sponsor Claim)

• Sponsor Claim: “Refer to Table 8.4 in Updated Clinical Report, AVR: 87/268 (32.5%), SAPIEN 24/269 (16.4%).”

• Inconsistencies in the sponsor’s calculation: – Number of death (Number of Alive patients)– Missing number among alive patients (Missing due to protocol or

medical reason are NOT counted as “missing”)

111

Death and Missing on 6MWT (FDA Calculation)

– Total: 351 for AVR and 348 for SAPIEN– Death at 1 year: 89 for AVR and 84 for SAPIEN– Observed 6MWT at 1 year: 150 for AVR and 198

for SAPIEN– Missing among alive:

• AVR: (351-89-150)/(351-89) = 112/262=43%• SAPIEN: (348-84-198)/(348-84) = 66/264=25%

112

KCCQ Summary and Physical Limitations

PREDICTIONvs.

OBSERVED

113

KCCQ Total Symptoms, Self-Efficacy, Quality of

Life and Social Limitation

PREDICTIONvs.

OBSERVED

114

SF-12 Physical, SF-12 Mental and EQ-5D Utilities

PREDICTION

vs.OBSERVED

1 edwards sapien transcatheter heart valve model 9000tfx and retroflex 3 and ascendra delivery...

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