SAPIEN 3 Transcatheter Aortic Valve
`Replacement Compared with Surgery in
`Intermediate-Risk Patients:
`A Propensity Score Analysis
`
`Vinod H. Thourani, MD
`on behalf of The PARTNER Trial Investigators
`
`ACC 2016 | Chicago | April 3, 2016
`
`Page 01 of 32
`
`
`Replacement Compared with Surgery in
`Intermediate-Risk Patients:
`A Propensity Score Analysis
`
`Vinod H. Thourani, MD
`on behalf of The PARTNER Trial Investigators
`
`ACC 2016 | Chicago | April 3, 2016
`
`Page 01 of 32
`
`
`
`Disclosure Statement of
`Financial Interest
`Vinod H. Thourani, MD
`
`Within the past 12 months, I or my spouse/partner have had a financial
`interest/arrangement or affiliation with the organization(s) listed below.
`
`Affiliation/Financial Relationship
`• Grant/Research Support
`
`• Consulting Fees/Honoraria
`
`Company
`• Boston Scientific, Claret Medical, Edwards
`Lifesciences, Medtronic, St. Jude Medical
`
`• Abbott Vascular, Edwards Lifesciences,
`St. Jude Medical
`
`• Major Stock Shareholder/Equity
`
`• None
`
`Page 02 of 32
`
`
`
`Background
`
`• The 3rd generation SAPIEN 3 transcatheter heart valve has
`demonstrated improved clinical outcomes in high-risk
`patients at 1 year.
`
`• The 30-day outcomes in intermediate-risk patients treated
`with SAPIEN 3 in PARTNER 2 were…
`– All-cause Mortality:
`1.1%
`– Disabling Stroke:
`1.0%
`– PVL > Moderate:
`3.8%
`
`• There is a paucity of longer-term data in intermediate-risk
`patients with SAPIEN 3 and there have been no rigorous
`comparisons with surgery in intermediate-risk patients.
`
`Page 03 of 32
`
`
`
`Purpose
`
`• To evaluate the 1-year clinical and echo outcomes of
`SAPIEN 3 TAVR in intermediate-risk patients.
`
`• To compare these intermediate-risk patient outcomes
`using SAPIEN 3 TAVR with surgery results in similar
`intermediate-risk patients from the PARTNER 2A trial
`using a rigorous pre-specified propensity score
`analysis.
`
`Page 04 of 32
`
`
`
`The PARTNER 2A and S3i Trials
`Study Design
`
`Intermediate Risk Symptomatic Severe Aortic Stenosis
`
`
`
`Intermediate Risk ASSESSMENT by Heart Valve TeamIntermediate Risk ASSESSMENT by Heart Valve Team
`
`
`P2 S3iP2 S3i
`
`n = 1078n = 1078
`
`
`ASSESSMENT:ASSESSMENT:
`
`Optimal ValveOptimal Valve
`
`Delivery AccessDelivery Access
`
`
`P2AP2A
`
`n = 2032n = 2032
`
`
`ASSESSMENT:ASSESSMENT:
`
`TransfemoralTransfemoral
`
`AccessAccess
`
`Transfemoral (TF)
`
`Transapical /
`Transaortic (TA/TAo)
`
`Transfemoral (TF)
`
`Transapical /
`TransAortic (TA/TAo)
`
`1:1 Randomization
`
`1:1 Randomization
`
`TF TAVR
`SAPIEN 3
`
`TA/TAo TAVR
`SAPIEN 3
`
`
`
`The PARTNER 2A and S3i Trials
`Study Design
`
`Intermediate Risk Symptomatic Severe Aortic Stenosis
`
`
`
`Intermediate Risk ASSESSMENT by Heart Valve TeamIntermediate Risk ASSESSMENT by Heart Valve Team
`
`
`P2 S3iP2 S3i
`
`n = 1078n = 1078
`
`
`ASSESSMENT:ASSESSMENT:
`
`Optimal ValveOptimal Valve
`
`Delivery AccessDelivery Access
`
`
`P2AP2A
`
`n = 2032n = 2032
`
`
`ASSESSMENT:ASSESSMENT:
`
`TransfemoralTransfemoral
`
`AccessAccess
`
`Transfemoral (TF)
`
`Transapical /
`Transaortic (TA/TAo)
`
`Transfemoral (TF)
`
`Transapical /
`TransAortic (TA/TAo)
`
`1:1 Randomization
`
`1:1 Randomization
`
`TF TAVR
`SAPIEN 3
`
`TA/TAo TAVR
`SAPIEN 3
`
`Surgical
`AVR
`
`Surgical
`AVR
`
`
`
`SAPIEN Platforms in PARTNER
`Device Evolution
`
`SAPIEN
`
`SAPIEN XT
`
`SAPIEN 3
`
`Valve
`Technology
`
`Sheath
`Compatibility
`
`22-24F
`
`16-20F
`
`14-16F
`
`Available
`Valve Sizes
`
`23 mm
`
`26 mm
`
`23 mm
`
`26 mm
`
`29 mm
`
`20 mm
`
`23 mm
`
`26 mm
`
`29 mm
`
`Page 07 of 32
`
`
`
`The PARTNER 2A and S3i Trials
`Inclusion Criteria
`
`• Severe AS: Echo-derived AVA ≤ 0.8 cm2 (or AVA index
`< 0.5 cm2/m2) and mean AVG > 40 mmHg or peak jet
`velocity > 4.0 m/s
`
`• Cardiac Symptoms: NYHA Functional Class ≥ II
`
`• Intermediate Risk:
`1. Determined by a multi-disciplinary Heart Team
`2. Using a guideline STS between 4-8%*, and
`3. Adjudicated by case review committee
`
`* PARTNER 2A used guideline STS ≥ 4%
`
`Page 08 of 32
`
`
`
`The PARTNER 2A and S3i Trials
`Key Exclusion Criteria
`
`Anatomic:
`• Aortic annulus diameter < 18 mm or > 28 mm (echo or CT)
`• Bicuspid AV or predominant AR (> 3+)
`• Severe LV dysfunction (LVEF < 20%)
`• Untreated CAD requiring revascularization with either
`unprotected LM coronary disease or Syntax score > 32
`• Pre-existing surgical valve in any position
`Clinical:
`•Serum Cr > 3.0 mg/dL or dialysis dependent
`•Acute MI within 1 month
`•CVA or TIA within 6 months
`•Hemodynamic instability
`•Life expectancy < 24 months
`
`Page 09 of 32
`
`
`
`The PARTNER 2A and S3i Trials
`Primary Endpoint
`
`• Non-hierarchical composite of all-cause mortality,
`all stroke, or ≥ moderate aortic regurgitation at
`one year
`• Propensity score analysis of the valve implant (VI)
`populations from S3i compared to the surgical arm of
`the PARTNER 2A trial
`• All patients followed for at least 1 year
`• Event rates by Kaplan-Meier estimates
`• Non-inferiority trial design followed by superiority
`testing for the primary endpoint and components
`
`Page 10 of 32
`
`
`
`Other Important Endpoints
`VARC 2 Definitions
`
`SAFETY
`• Cardiac mortality
`• Major vascular complications
`• All strokes and TIAs
`• Repeat hospitalizations
`• Peri-procedural MIs
`• Acute kidney injury
`• Life-threatening or disabling
`bleeding
`• New permanent pacemakers
`• New onset atrial fibrillation
`• Repeat AV intervention
`• Endocarditis
`
`EFFICACY
`• NYHA class
`• QOL instruments
`• 6-minute walk test
`• Days alive out-of-hospital
`• ICU and index hospital LOS
`
`ECHO VALVE
`PERFORMANCE
`• Mean AV gradient
`• Effective orifice area (and index)
`• LV function (ejection fraction)
`• Paravalvular AR
`
`Page 11 of 32
`
`
`
`Study Methodology
`
`• Every patient reviewed (including imaging studies) by
`multi-disciplinary Heart Team AND case review committee
`
`• Systematic assessment by neurologists before and after index
`procedures for ascertainment of neurologic events
`
`• MDCT evaluation of annulus dimensions for all TAVR S3i
`patients (with core laboratory analyses)
`
`• In patients with CAD requiring revascularization: treatment (PCI
`or CABG) allowed (unless unprotected left main disease or
`Syntax score > 32) at the discretion of the Heart Team
`
`• CEC adjudication of major clinical events (VARC 2 definitions
`whenever possible)
`
`Page 12 of 32
`
`
`
`Baseline Patient Characteristics
`Demographics (AT)
`
`Characteristic
`
`Age - yrs
`
`Male - %
`
`BMI - kg/m2
`
`TAVR
`(n = 1077)
`
`Surgery
`(n = 944)
`
`p-value
`
`81.9 ± 6.6
`
`81.6 ± 6.8
`
`61.7
`
`55.0
`
`28.7 ± 6.1
`
`28.4 ± 6.2
`
`0.23
`
`0.002
`
`0.32
`
`Median STS Score - %
`
`5.2 [4.3, 6.3]
`
`5.4 [4.4, 6.7]
`
`0.0002
`
`NYHA Class III or IV - %
`
`72.5
`
`76.1
`
`0.07
`
`mean ± SD, median [IQR]
`
`Page 13 of 32
`
`
`
`Baseline Patient Characteristics
`Other Co-morbidities (AT)
`
`Characteristic (%)
`
`CAD
`Previous CABG
`Cerebrovascular Disease
`PVD
`COPD
`Cr level > 2 mg/dL
`Atrial Fibrillation
`Permanent Pacemaker
`15 ft Walk Test > 7s
`
`TAVR
`(n = 1077)
`
`Surgery
`(n = 944)
`
`p-value
`
`69.6
`27.9
`9.0
`28.2
`30.0
`7.5
`36.0
`13.2
`41.3
`
`66.5
`25.7
`10.3
`32.2
`30.2
`5.4
`34.9
`12.0
`45.7
`
`0.14
`0.27
`0.36
`0.05
`0.92
`0.06
`0.61
`0.42
`0.06
`
`Page 14 of 32
`
`
`
`Statistical Analysis Plan - 1
`
`• Pre-specified propensity score analysis of SAPIEN 3 TAVR
`vs. P2A surgery for the composite primary endpoint (all-
`cause mortality, all stroke, or total AR ≥ moderate at 1
`year).
`• The analysis incorporated 22 pre-specified baseline
`characteristics that were factored through a logistic
`regression into a propensity score.
`• Patient population was divided into quintiles based on
`propensity scores.
`• Quintile stratification (unlike patient matching) allows for
`the use of data from all patients, minimizing selection bias.
`
`Page 15 of 32
`
`
`
`Statistical Analysis Plan - 2
`
`• The primary hypothesis was non-inferiority of SAPIEN 3
`vs. surgery from P2A for the primary endpoint at 1 year.
`• Non-inferiority:
`– One-sided alpha: 0.05
`– Hypothesis testing: upper bound of the one-sided 95% CI of
`the primary weighted difference of proportions endpoint
`(weighted avg test - control) < 7.5%
`• Superiority:
`– Two-sided alpha: 0.05
`– Hypothesis testing: upper or lower bound of the two-sided
`95% CI of the primary weighted difference of proportions
`endpoint (weighted avg test - control) < 0 for TAVR and
`> 0 for surgery
`
`Page 16 of 32
`
`
`
`Quintile Propensity Score Analysis:
`Primary Endpoint
`
`Surgery
`
`TAVR
`
`# Patients
`
`Mortality, Stroke,
`AR > Mod
`
`# Patients
`
`Mortality, Stroke,
`AR > Mod
`
`Proportional
`Difference
`
`Weighting
`
`191
`
`175
`
`147
`147
`
`126
`
`108
`
`28.3%
`
`22.9%
`
`19.7%
`19.7%
`
`23.0%
`
`19.4%
`
`138
`
`171
`
`197
`197
`
`219
`
`238
`
`13.8%
`
`9.9%
`
`10.7%
`10.7%
`
`14.6%
`
`15.1%
`
`-14.5%
`
`-12.9%
`
`-9.1%-9.1%
`
`-8.4%
`
`-4.3%
`
`0.14
`
`0.18
`
`0.200.20
`
`0.23
`
`0.25
`
`Overall weighted
`difference of proportions
`- 9.2%
`[-12.4%,-6.0%] two-sided 90% CI
`
`Page 17 of 32
`
`
`
`Primary Endpoint - Non-inferiority
`Death, Stroke, or AR ≥ Mod at 1 Year (VI)
`
`
`Weighted Difference -9.2%Weighted Difference -9.2%
`
`Upper 1-sided 95% CI -6.0%Upper 1-sided 95% CI -6.0%
`
`
`Non-InferiorityNon-Inferiority
`
`p-value < 0.001p-value < 0.001
`
`Pre-specified non-inferiority margin = 7.5%
`
`-10
`
`-8
`
`-6
`
`-4
`
`-2
`
`0
`
`2
`
`4
`
`6
`
`8
`
`10
`
`Favors TAVR
`
`Favors Surgery
`
`Primary Non-Inferiority Endpoint Met
`
`Page 18 of 32
`
`
`
`Primary Endpoint - Superiority
`Death, Stroke, or AR ≥ Mod at 1 Year (VI)
`
`-9.2%
`Weighted Difference
`Upper 2-sided 95.0% CI -5.4%
`
`Superiority Testing
`p-value < 0.001
`
`-10
`
`-8
`
`-6
`
`-4
`
`-2
`
`0
`
`2
`
`4
`
`6
`
`8
`
`10
`
`Favors TAVR
`
`Favors Surgery
`
`Superiority Achieved
`
`Page 19 of 32
`
`
`
`Superiority Analysis
`Components of Primary Endpoint (VI)
`
`Mortality
`
`Favors Surgery
`Favors TAVR
`Weighted Difference -5.2%
`Upper 2-sided 95% CI -2.4%
`
`Superiority Testing
`p-value < 0.001
`
`-6
`
`-4
`
`-10
`-8
`Stroke
`
`4
`2
`0
`-2
`Weighted Difference -3.5%
`Upper 2-sided 95% CI -1.1%
`
`10
`8
`6
`Superiority Testing
`p-value = 0.004
`
`-10
`-8
`-6
`-4
`AR > Moderate
`
`4
`2
`0
`-2
`Weighted Difference +1.2%
`Lower 2-sided 95% CI +0.2%
`
`10
`8
`6
`Superiority Testing
`p-value = 0.0149
`
`-10
`
`-8
`
`-6
`
`-4
`
`-2
`
`0
`
`2
`
`4
`
`6
`
`8
`
`10
`
`Page 20 of 32
`
`
`
`Unadjusted Clinical Events
`At 30 Days and 1 Year (AT)
`
`Events (%)
`
`Death
`All-cause
`Cardiovascular
`Neurological Events
`Disabling Stroke
`All Stroke
`All-cause Death and
`Disabling Stroke
`
`30 Days
`TAVR
`Surgery
`
`1 Year
`TAVR
`Surgery
`
`1.1
`0.9
`
`1.0
`2.7
`
`2.0
`
`4.0
`3.1
`
`4.4
`6.1
`
`8.0
`
`7.4
`4.5
`
`2.3
`4.6
`
`8.4
`
`13.0
`8.1
`
`5.9
`8.2
`
`16.6
`
`Page 21 of 32
`
`
`
`18.8%
`
`10.8%
`
`12
`
`743
`930
`
`Unadjusted Time-to-Event Analysis
`All-Cause Mortality and All Stroke (AT)
`
`P2A Surgery
`SAPIEN 3 TAVR
`
`9.7%
`
`3.7%
`
`40
`
`30
`
`20
`
`10
`
`0
`
`All-CauseMortality/StrokeRate(%)
`
`0
`
`Number at risk:
`P2A Surgery
`944
`S3 TAVR
`1077
`
`3
`
`805
`1012
`
`6
`Months from Procedure
`
`786
`987
`
`9
`
`757
`962
`
`Page 22 of 32
`
`
`
`13.0%
`
`7.4%
`
`12
`
`795
`963
`
`Unadjusted Time-to-Event Analysis
`All-Cause Mortality (AT)
`
`P2A Surgery
`SAPIEN 3 TAVR
`
`4.0%
`
`1.1%
`
`40
`
`30
`
`20
`
`10
`
`0
`
`All-CauseMortality(%)
`
`0
`
`Number at risk:
`P2A Surgery
`944
`1077
`S3 TAVR
`
`3
`
`859
`1043
`
`6
`Months from Procedure
`
`836
`1017
`
`9
`
`808
`991
`
`Page 23 of 32
`
`
`
`8.2%
`
`4.6%
`
`12
`
`743
`930
`
`Unadjusted Time-to-Event Analysis
`All Stroke (AT)
`
`P2A Surgery
`SAPIEN 3 TAVR
`
`6.1%
`
`2.7%
`
`40
`
`30
`
`20
`
`10
`
`0
`
`AllStroke(%)
`
`0
`
`Number at risk:
`P2A Surgery
`944
`1077
`S3 TAVR
`
`3
`
`805
`1012
`
`6
`Months from Procedure
`
`786
`987
`
`9
`
`757
`962
`
`Page 24 of 32
`
`
`
`Other Unadjusted Clinical Outcomes
`At 30 Days and 1 Year (AT)
`
`Events (%)
`
`Re-hospitalization
`MI
`Major Vascular Complication
`AKI (Stage III)
`Life-Threatening/Disabling
`Bleeding
`New Atrial Fibrillation
`New Permanent Pacemaker
`Re-intervention
`Endocarditis
`
`30 Days
`TAVR
`Surgery
`(n = 1077)
`(n = 944)
`4.6
`6.8
`0.3
`1.9
`6.1
`5.4
`0.5
`3.3
`
`1 Year
`TAVR
`Surgery
`(n = 1077)
`(n = 944)
`11.4
`15.1
`1.8
`3.1
`---
`---
`---
`---
`
`4.6
`
`5.0
`10.2
`0.1
`0.2
`
`46.7
`
`28.3
`7.3
`0.0
`0.0
`
`---
`
`5.9
`12.4
`0.6
`0.8
`
`---
`
`29.2
`9.4
`0.5
`0.7
`
`Page 25 of 32
`
`
`
`Paravalvular Regurgitation
`3-Class Grading Scheme (VI)
`
`P < 0.001
`
`P < 0.001
`
`≥ Moderate
`1.5%
`
`Mild
`39.8%
`
`No. of echos
`P2A Surgery
`S3i TAVR
`
`30 Days
`755
`992
`
`1 Year
`610
`875
`
`Page 26 of 32
`
`
`
`The PARTNER 2A and S3i Trials
`Conclusions - 1
`
`• In intermediate-risk patients, SAPIEN 3 TAVR
`resulted in low 1-year rates of all-cause mortality
`(7.4%), all stroke (4.6%), and moderate or severe
`aortic regurgitation (1.5%)
`
`Page 27 of 32
`
`
`
`The PARTNER 2A and S3i Trials
`Conclusions - 2
`
`• A rigorous propensity score analysis comparing
`SAPIEN 3 TAVR with surgery from PARTNER 2A in
`intermediate-risk patients at 1 year demonstrated:
`– Non-inferiority for the primary endpoint (composite
`of all-cause mortality, all stroke, or AR ≥ moderate)
`– Superiority of SAPIEN 3 TAVR for the
`primary endpoint, all-cause mortality, and all stroke
`– Superiority of surgery for AR ≥ moderate
`• Time-to-event analyses indicated that the benefits
`of SAPIEN 3 TAVR occurred in the first few
`months, suggesting procedure-related effects
`
`Page 28 of 32
`
`
`
`The PARTNER 2A and S3i Trial
`Clinical Implications
`
`• The conclusions from the PARTNER 2A
`randomized trial and this propensity score analysis
`provide strong evidence that in intermediate-risk
`patients with severe aortic stenosis, SAPIEN 3
`TAVR compared with surgery improves clinical
`outcomes and is the preferred therapy.
`
`Page 29 of 32
`
`
`
`The PARTNER 2A and S3i Trial
`Lancet On-line
`
`Special thanks to the PARTNER sites and
`patients, the clinical research teams, and
`the writing group!
`
`Page 30 of 32
`
`
`
`The PARTNER 2A and S3i Trial
`Lancet On-line
`
`Page 31 of 32
`
`
`
`The PARTNER 2A and S3i Trial
`Lancet On-line
`
`Page 32 of 32
`
`
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