David H. Adams, MD On Behalf of the US CoreValve Investigators
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Transcript of David H. Adams, MD On Behalf of the US CoreValve Investigators
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ACC 2014
David H. Adams, MDOn Behalf of the US CoreValve Investigators
A Randomized Comparison of Self-expanding Transcatheter and Surgical Aortic Valve Replacement in Patients with Severe Aortic Stenosis Deemed High-Risk for Surgery
CoreValve US Pivotal TrialCoreValve US Pivotal Trial
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ACC 2014
David H. Adams, MD
I receive royalties through the Icahn School of Medicine at Mount Sinai related to intellectual property for mitral and tricuspid valve repair products now owned by Edwards Lifesciences and Medtronic
Presenter Disclosure InformationPresenter Disclosure Information
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ACC 2014
Many Patients with Symptomatic Severe Aortic Stenosis are not Ideal Candidates for Surgery due to Increased Risks
• TAVR with a balloon expandable valve improved survival compared to medical therapy in inoperable patients
• TAVR with a balloon expandable valve had similar survival compared to surgery in patients at high risk for surgery
BackgroundBackground
Leon MB, Smith CR, Mack M, et al. N Engl J Med 2010;363:1597–1607.Smith CR, Leon MB, Mack M, et al. N Engl J Med 2011;364: 2187–2198.
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ACC 2014
TAVR with the self-expanding CoreValve prosthesis reduced the composite endpoint of death from any cause or major stroke at 1 year compared to a performance goal in symptomatic patients with severe aortic stenosis at extreme surgical risk
Extreme Risk TrialExtreme Risk Trial
Popma JJ, Adams DH, Reardon MJ, et al. J Am Coll Cardiol 2014; March 19 (Epub ahead of print).
CoreValve US Pivotal Trial
Extreme Risk High Risk
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ACC 2014
To assess the safety and effectiveness of TAVR with the CoreValve prosthesis compared to surgical valve replacement in symptomatic patients with severe aortic stenosis at increased surgical risk
Study PurposeStudy Purpose
CoreValve US Pivotal Trial
Extreme Risk High Risk
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Adams DH, Popma JJ, Reardon MJ, et al. New Engl J Med 2014; in press.
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ACC 2014
18Fr delivery system
4 valve sizes (18-29 mm annular range)
TransfemoralSubclavian
Direct Aortic
Study Device and Access RoutesStudy Device and Access Routes
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ACC 2014Pivotal Trial DesignPivotal Trial Design
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ACC 2014Study AdministrationStudy Administration
Co-Principal InvestigatorsCo-Principal InvestigatorsJ. Popma, BIDMC, Boston
D. Adams, Mount Sinai, New York
Data & Safety Monitoring BoardData & Safety Monitoring BoardChair: D. Faxon, Brigham and Women’s Hospital
Steering CommitteeSteering CommitteeCS’s: M. Reardon, G.M. Deeb, J. Coselli, D. Adams, T. Gleason
IC’s: J. Hermiller, S. Yakubov, M. Buchbinder, J. Popma
Consultants: B. Carabello, P. Serruys
Quality of Life and Cost-Effective Quality of Life and Cost-Effective AssessmentsAssessments
Chair: D. Cohen, Mid-America Heart Institute
M. Reynolds, HCRI
Screening CommitteeScreening CommitteeChair: M. Reardon, D. Adams, J. Conte, G.M. Deeb, T. Gleason, J. Popma, S. Yakubov
Pathology Core LaboratoryPathology Core Laboratory Chair: R. Virmani, CV Path
ECG Core LaboratoryECG Core LaboratoryChair: P. Zimetbaum, HCRI
Rotational X-ray Core LaboratoryRotational X-ray Core LaboratoryChair: P. Genereux, CRF
Echo Core LaboratoryEcho Core LaboratoryChair: J. Oh, Mayo Clinic
Sponsor Sponsor Medtronic, Inc.
Clinical Events CommitteeClinical Events Committee Chair: D. Cutlip, HCRI
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ACC 2014
Primary Endpoint: All-cause mortality at 1 year
Non-inferiority Testing: TAVR with the CoreValve prosthesis was non-inferior to SAVR for 1 year all-cause mortality with a 7.5% non-inferiority margin
Primary EndpointPrimary Endpoint
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ACC 2014
Hierarchical Testing of Secondary Endpoints
•Δ mean gradient baseline to 1 year (non-inferior)
•Δ effective orifice area baseline to 1 year (non-inferior)
•Δ NYHA class baseline to 1 year (non-inferior)
•Δ KCCQ baseline to 1 year (non-inferior)
•Difference in MACCE* rate at hospital discharge or 30 days, whichever is later (superiority)
•Δ SF-12 baseline to 30 days (inequality)
* Major adverse cardiovascular and cerebrovascular events, defined as a composite of all-cause mortality, myocardial infarction, all stroke, or aortic-valve reintervention
Secondary EndpointsSecondary Endpoints
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ACC 2014
Hypothesis: TAVR with the CoreValve prosthesis is non-inferior (7.5% margin) to SAVR in 1 year all-cause mortality
H0: πMCS TAVR ≥ πSAVR + 7.5%
HA: πMCS TAVR < πSAVR + 7.5%
Sample Size Determination:
1:1 treatment allocationOne-sided alpha = 0.05
Power ≥ 80%
πSAVR = 20%πMCS TAVR = 20%
10% attrition rateStudy Size: 790 patients for a minimum of 355 patients in each arm
Sample Size DeterminationSample Size Determination
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ACC 2014Participating SitesParticipating Sites
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ACC 2014
Kaiser Permanente – Los AngelesLos Angeles, CAV. Aharonian, T. Pfeffer
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The Johns Hopkins HospitalBaltimore, MDJ. Conte, J. Resar
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Saint Luke’s Episcopal HospitalHouston, TXJ. Coselli, J. Diez
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Aurora St. Luke’s Medical CenterMilwaukee, WIT. Bajwa, D. O’Hair
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St. Vincent Heart Center of Indiana Indianapolis, IND. Heimansohn, J. Hermiller
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Mercy Medical CenterDes Moines, IAA. Chawla, D. Hockmuth
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Banner Good Samaritan Phoenix, AZT. Byrne, M. Caskey
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Riverside Methodist HospitalColumbus, OH D. Watson, S. Yakubov
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Methodist DeBakey Heart & VascularHouston, TXN. Kleiman, M. Reardon
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University of Michigan Health SystemsAnn Arbor, MIS. Chetcuti, G.M. Deeb
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Spectrum Health HospitalsGrand Rapids, MIJ. Heiser, W. Merhi
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University of Kansas Hospital Kansas City, KS P. Tadros, G. Zorn
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St. Francis HospitalRoslyn, NYG. Petrossian, N. Robinson
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Duke University Medical Center Durham, NC K. Harrison, C. Hughes
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Harrisburg HospitalWormleysburg, PAB. Maini, M. Mumtaz
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University of PittsburghPittsburgh, PAT. Gleason, J. Lee
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Clinical Sites ≥ 20 High Risk EnrollmentsClinical Sites ≥ 20 High Risk Enrollments
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ACC 2014
• NYHA functional class II or greater
• Severe aortic stenosis: AVA ≤ 0.8 cm2 or AVAI ≤ 0.5 cm2/m2 AND mean gradient > 40 mm Hg or peak velocity > 4 m/sec at rest or with dobutamine stress echocardiogram
Inclusion CriteriaInclusion Criteria
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ACC 2014
• Risk of death at 30 days after surgery was ≥ 15% and the risk of death or irreversible complications within 30 days was < 50%
• Surgical risk assessment included consideration of STS Predicted Risk of Mortality estimate and other risk factors not captured in the STS risk model
Inclusion CriteriaInclusion Criteria
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ACC 2014
Clinical and Anatomic Exclusion Criteria Included:•Recent active GI bleed (< 3 mos), stroke (< 6 mos), or
MI (≤ 30 days)•Any interventional procedure with bare metal stents (< 30 days) and drug eluting stents (< 6 months)•Creatinine clearance < 20 mL/min•Significant untreated coronary artery disease•LVEF < 20%•Life expectancy < 1 year due to co-morbidities
Exclusion CriteriaExclusion Criteria
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ACC 2014
Chairman: Michael J. Reardon, M.D. •Two clinical site cardiac surgeons and one interventional cardiologist determined patient eligibility•All patients were reviewed on web-based conference calls with site investigators to confirm eligibility and access route •Detailed portfolio included:
• STS PROM and all other risk factors • Independent review of transthoracic echocardiogram• Independent review of chest/abdominal CTA findings
• Two senior surgeons and one cardiologist on the screening committee had to concur with the local heart team assessment to qualify the patient for trial enrollment
National Screening CommitteeNational Screening Committee
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ACC 2014Study DispositionStudy Disposition
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ACC 2014
As Treated As Treated All randomized patients with an attempted implant procedure, defined as when the patients is brought into the procedure room and any of the following have occurred: anesthesia administered, vascular line placed, TEE placed or any monitoring line placed
Primary Analysis CohortPrimary Analysis Cohort
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ACC 2014Study ComplianceStudy Compliance
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ACC 2014
CharacteristicTAVRN=390
SAVRN=357
Age, years 83.1 ± 7.1 83.2 ± 6.4
Men, % 53.1 52.4
STS Predicted Risk of Mortality, % 7.3 ± 3.0 7.5 ± 3.4
Logistic EuroSCORE, % 17.7 ± 13.1 18.6 ± 13.0
NYHA Class III/IV, % 85.6 86.8
Diabetes Mellitus, % 34.9* 45.4*
Insulin Requiring Diabetes, % 11.0 13.2
Prior Stroke, % 12.6 14.0
Modified Rankin 0 or 1, % 74.5 87.2
Modified Rankin > 1, % 25.5 12.8
STS Severe Chronic Lung Disease, % 13.3 9.0
Baseline DemographicsBaseline Demographics
*P < 0.01 21
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ACC 2014
AssessmentTAVRN=390
SAVRN=357
Home Oxygen, % 12.9 11.5
Liver Cirrhosis, % 2.6 2.0
Anemia With Prior Transfusion, % 18.2 15.9
Immunosuppressive therapy, % 10.5 8.5
Severe (> 5) Charlson Co-Morbidity*, % 54.1 57.9
Falls in Past 6 Months, % 18.5 18.2
5 Meter Gait Speed > 6 secs, % 79.3 80.4
Assisted Living, % 9.7 10.9
Katz ≥ 1 ADLs Deficits, % 10.5 12.3
*Charlson Score: = 1 MI, CHF, PVD, CVD, dementia, chronic lung disease, connective tissue disease, ulcer, mild liver disease, DM; = 2 hemiplegia, mod-severe kidney disease, diabetes with end organ damage, leukemia, lymphoma; = 3 moderate or severe liver disease; = 6 metastatic solid tumor, AIDS
Non-STS Co-Morbidity, Frailty, DisabilityNon-STS Co-Morbidity, Frailty, Disability
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ACC 2014
CoreValve US Pivotal Trial CoreValve US Pivotal Trial High Risk ResultsHigh Risk Results
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ACC 2014
19.1%
4.5%
Surgical
14.2%
P = 0.04 for superiority
3.3%
Transcatheter
Primary Endpoint: 1 Year All-cause MortalityPrimary Endpoint: 1 Year All-cause Mortality ACC 2014
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ACC 2014Primary EndpointPrimary Endpoint
Non-inferiority and superiority thresholds were met in both AT and ITT cohorts
-5.0 -4.0 -3.0 -2.0 -1.0 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0
Non-inferiority Margin
Upper 1-sided 95% CL of Difference
7.5-0.4-4.9
Observed Difference (TAVR – SAVR)
Superiority Non-inferiority
P = 0.04 P < 0.001
All-cause Mortality at 1 Year
AT ITT
TAVRN=390
SAVRN=357
TAVRN=394
SAVRN=401
14.2% 19.1% 13.9% 18.7%
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ACC 20142-Year All-cause Mortality2-Year All-cause Mortality ACC 2014
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ACC 2014All StrokeAll Stroke
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ACC 2014Major StrokeMajor Stroke
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ACC 2014All-Cause Mortality or Major StrokeAll-Cause Mortality or Major Stroke
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ACC 2014
• Results with surgical aortic valve replacement were outstanding (O/E ratio 0.61 vs. STS PROM)
• Results with transcatheter CoreValve prosthesis were outstanding (O/E ratio 0.45 vs. STS PROM)
• Prior to the beginning of the CoreValve US Pivotal Trial, our Heart Teams had no TAVR experience
• Our findings were not influenced by poor outcomes in either arm of the trial
Clinical ResultsClinical Results
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ACC 2014
Hierarchical Testing of Secondary Endpoints
•Δ mean gradient baseline to 1 year (non-inferior; P<0.001)
•Δ effective orifice area baseline to 1 year (non-inferior; P<0.001)
•Δ NYHA class baseline to 1 year (non-inferior; P<0.001)
•Δ KCCQ baseline to 1 year (non-inferior; P=0.006)
•Difference in MACCE rate at hospital discharge or 30 days, whichever is later (superiority; P=0.103)
•Δ SF-12 baseline to 30 days (inequality; nominal P<0.001)
Secondary EndpointsSecondary Endpoints
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ACC 20141 Year MACCE1 Year MACCE
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ACC 2014Other EndpointsOther Endpoints
Events* 1 Month 1 Year
TAVR SAVR P Value TAVR SAVR P Value
Vascular complications (major), % 5.9 1.7 0.003 6.2 2.0 0.004
Pacemaker implant, % 19.8 7.1 <0.001 22.3 11.3 <0.001Bleeding (life threatening or disabling),% 13.6 35.0 <0.001 16.6 38.4 <0.001
New onset or worsening atrial fibrillation, % 11.7 30.5 <0.001 15.9 32.7 <0.001
Acute kidney injury, % 6.0 15.1 <0.001 6.0 15.1 <0.001
* Percentages reported are Kaplan-Meier estimates and log-rank P values
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ACC 2014NYHA Class SurvivorsNYHA Class Survivors
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ACC 2014Echocardiographic FindingsEchocardiographic Findings
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ACC 2014Paravalvular RegurgitationParavalvular Regurgitation
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ACC 2014
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Subgroup Analysis for 1 Year MortalitySubgroup Analysis for 1 Year Mortality
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ACC 2014
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Subgroup Analysis for 1 Year MortalitySubgroup Analysis for 1 Year Mortality
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• More patients refused surgical replacement after randomization assignment than refused transcatheter replacement (there were no important differences between treated and withdrawn patients)
• Patients had a lower 30-day mortality rate than was specified in our study inclusion criteria, and therefore the trial population may have been at lower risk than was intended
LimitationsLimitations
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• We assessed the safety and effectiveness of TAVR with the CoreValve prosthesis compared to surgical valve replacement in symptomatic patients with severe aortic stenosis at increased surgical risk
• The rate of death from any cause at 1 year was significantly reduced with TAVR performed with the CoreValve prosthesis
ConclusionConclusion
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ACC 2014
Thank YouThank YouOn Behalf of the US CoreValve Investigators