1. Transcatheter Aortic Valve Replacement: Expanding to “Intermediate Risk” Patients
Jeffrey J. Popma, MD
Director, Interventional Cardiology
Clinical Services
Beth Israel Deaconess Medical Center
Associate Professor of Medicine
Harvard Medical School
Boston, MA

2. Jeffrey J. Popma, MD Contracted Research / Grant Support:
Abbott Vascular
Abiomed, Inc.
Atrium Medical Corporation
Boston Scientific Corporation
Cordis Corporation
IDEV Technologies, Inc.
Medtronic, Inc.

3. Consulting Fees:
Abbott Vascular
Boston Scientific Corporation
My presentation will include off label discussions:
Percutaneous aortic valves

4. Conflict of Interest Statement
Within the past 12 months, I have had a financial interest/arrangement or affiliation with the organization(s) listed below.
Physician Name Company/Relationship
Jeffrey J. Popma, MD Research Grants: Cordis, Boston Scientific,
Medtronic, Abbott-Guidant, eV3, LabCoat
Medical Advisory Board: Cordis, Boston Scientific, Abbot Vascular

5. Better TAVR Outcomes in Lower Risk Patients
N=420 patients (105 per quartile)
Quartile 1
Quartile 4
Age, years
81.1 years
78.9 years
Logistic Euroscore, %
25.4%
17.8%
STS-PROM, %
7.13%
4.8%
Crude 30 day Mortality, %
11.4%
3.8%
Lange JACC 2012;59:280–7

6. European ‘’On-Label’’ and ‘’Off-Label ’’ Use
Piazza Heart 2010;96:19–26.

7. European ‘’On-Label’’ and ‘’Off-Label ’’ Use
Better Survival in “Off-Label”
No Change in Stroke
But at an increased risk of bleeding (5% on-label; 14% off label)
Piazza Heart 2010;96:19–26.

8. Intermediate Populations
“Risk Creep” Favors TAVR Preferentially

9. “Risk Creep” Favors TAVR Preferentially
Bern Windecker

10. Expanding Into Risk Populations
Top 33% Surgical Risk
STS ≥ 4
Top 7% Surgical Risk
STS > 8
“Cohort C”
Two-thirds of patients will remain optimal surgical candidates
Extreme
Risk
Surgical Aortic Valve Replacements 70-90,000 yearly
PARTNER IIA
SURTAVI
Intermediate
≈ 26%
STS PROM < 4%
30-Day Mortality < 2-4%
CoreValve Extreme Risk
PARTNER B
CoreValve High Risk
PARTNER A
Inoperable 20-50K

11. Patient Selection
Presented By Prof. Patrick Serruys, MD on behalf of

12. SURTAVI Trial Leadership
Chairmen:
Prof. P.W. Serruys (Chair)
Dr. N. van Mieghem (Deputy Chair)
Principal Investigators:
Prof. S. Windecker
Prof. A.P. Kappetein
Prof. R. Lange
Prof. T. Walther
Dr. J. Popma
Dr. D. Adams
Dr. M. Reardon
Serruys SURTAVI TCT2011

13. Identifying Intermediate Risk Patients
Serruys SURTAVI TCT2011

14. Identifying Intermediate Risk Patients
Serruys SURTAVI TCT2011

15. Operability is a Risk Continuum
TAVR or
AVR
Surgery (AVR)
Low
Risk
Intermed
Risk
High
Risk
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OR risk
< 5%
5-15%
>15%
% patients
~65-70%
~20-25%
~10%
Serruys SURTAVI TCT2011 15

16. STS ≥ 3 46% STS ≥ 4 33% STS ≥ 5 25% STS PROM (2006-2010)
Leon PARTNERII A TCT2011

17. BERMUDA Results
Serruys SURTAVI TCT2011

18. Heart Team Assesment May Vary From STS
Serruys SURTAVI TCT2011

19. BERn – MUnich – rotterDAm Registry
3666 patients enrolled
TAVI – 782
SAVR – 2884
2882 patients excluded based on propensity scores
784 matched patients
TAVI – 392
SAVR - 392
510 matched patients (STS scores 3-8%)
274 patients excluded based on STS score <3% and >8%
TAVI
255 patients analyzed
SAVR
Serruys SURTAVI TCT2011

20. BERn – MUnich – rotterDAm Registry
Matched Cohort
STS
<3
n=184
STS
3-8
n=510
STS
>8
n=90
Age (years)
77.3 (4.7)
80.1(5.3)
81.7 (5.3)
Logistic ES (%)
13.5 (8.4)
17.6 (10.5)
25.1(17.1)
TAVI vs. SAVR
92 vs. 92
255 vs. 255
45 vs. 45
Serruys SURTAVI TCT2011

21. BERn – MUnich – rotterDAm Registry
One Year Outcome In Intermediate Risk Patients
Serruys SURTAVI TCT2011

22. SURTAVI: Primary Objective
Evaluate in a prospective randomized fashion whether TAVI is non-inferior to SAVR with respect to the event free survival of the combined endpoint of all-cause mortality and major stroke at 24 months in patients with symptomatic severe aortic stenosis and at intermediate surgical risk.
Serruys SURTAVI TCT2011

23. SURTAVI: Study Design Patient population
Symptomatic severe aortic stenosis
Intermediate surgical risk, defined by Society of Thoracic Surgeons (STS) mortality risk:
≥ 3% and ≤ 8-10% (OUS)
≥ 4% and ≤ 8-10% (US)
Long-term follow-up through 5 years
Enrollment phase ~ 20 months
Trial duration ~ 7 years
Serruys SURTAVI TCT2011

24. SURTAVI: Inclusion Criteria
Subject must have STS mortality risk score ≥ 3% and ≤ 8% (in United States, STS mortality risk score ≥4% and ≤8%)
Heart Team consisting of at least one interventional cardiologist and one cardiac surgeon agree on indication, treatment proposal, and eligibility for randomization based on their clinical judgment
Critical aortic valve area defined as an initial aortic valve area of ≤1.0 cm2 or aortic valve area index < 0.6 cm2/m2

25. SURTAVI: Inclusion Criteria
In presence of normal LV function: mean gradient > 40mmHg OR Vmax > 4m/sec .
In the presence of reduced LV function and a mean gradient < 40 mmHg AND Vmax < 4 m/sec, dobutamine stress echo may be give to increase the mean gradient >40mmHg or Vmax < 4 m/sec
Subject is symptomatic from his/her aortic valve stenosis, as demonstrated by New York Heart Association (NYHA) Functional Class II or greater

26. SURTAVI: Exclusion Criteria
Active Gastrointestinal (GI) bleeding within the past 3 months
Subject refuses a blood transfusion
Severe dementia (resulting in either inability to provide informed consent for the trial/procedure, prevents independent lifestyle outside of a chronic care facility, or will fundamentally complicate rehabilitation from the procedure or compliance with follow-up visits)
Multivessel coronary artery disease with a Syntax score >22

27. SURTAVI: Exclusion Criteria
True porcelain aorta
Extensive mediastinal radiation
Liver failure (Child-C)
Reduced ventricular function with left ventricular ejection fraction (LVEF) <30% as measured by resting echocardiogram
Uncontrolled atrial fibrillation
Pregnancy or intent to become pregnant prior to completion of all protocol follow-up requirements
End stage renal disease requiring chronic dialysis or creatinine clearance < 20 cc/min

28. SURTAVI: Exclusion Criteria
Native aortic annulus size < 20 mm or > 29 mm
Pre-existing prosthetic heart valve in any position
Mixed aortic valve disease [AS and AR with predominant AR (3-4+)]
Severe mitral or severe tricuspid regurgitation
Severe mitral stenosis
Hypertrophic obstructive cardiomyopathy
Echocardiographic or Multislice Computed Tomography (MSCT) evidence of intracardiac mass, thrombus or vegetation
Ascending aorta diameter > 43 mm unless the aortic annulus is mm in which case the ascending aorta diameter > 40 mm

29. Neurological Assessments
SURTAVI: Study Design
OUS STS mortality risk ≥3% and ≤8%
US STS mortality risk ≥4% and ≤8%
Heart Team Evaluation including assessment for significant CAD with determination of need for revascularization
Meet I/E Criteria and eligible for SAVR and TAVI
QoL Questionnaire
Randomization with 5 year follow up
Neurological Assessments
Presence of significant CAD with intended revascularization
No intended revascularization
TAVI + PCI
SAVR + CABG
TAVI
SAVR

30. PARTNER II – Intermediate Risk
Symptomatic Severe Aortic Stenosis
ASSESSMENT by Heart Valve Team
Intermediate Risk
Inoperable
2 Parallel RCTs: Individually Powered
TF TAVR
Sapien
ASSESSMENT: Transfemoral Access
Not In Study
Sapien XT
Primary Endpoint: All-Cause Mortality + Major Stroke + Repeat Hospitalization at One Year (Non-inferiority)
1:1 Randomization VS
Yes No
ASSESSMENT: Transfemoral Access
Transapical (TA)
Transfemoral (TF)
1:1 Randomization
Yes No
TF TAVR Sapien XT
AVR
Primary Endpoint: All-Cause Mortality + Major Stroke at Two Years (Non-inferiority)
TA TAVR Ascendra 2 VS

31. PARTNER II – Intermediate Risk
Severe, symptomatic calcific AS (echo criteria)
Intermediate risk = STS score ≥ 4% OR specific qualifying intermediate risk criteria
Includes AS patients with CAD requiring treatment…
AS + CAD patients substratified to compared (TAVR + PCI vs. AVR + CABG)
“Complex” CAD excluded (unprotected LM lesions, MVD with Syntax score ≥ 33)
All CAD treatment patients reviewed by EC sub-committee for study inclusion
Less aggressive complete revascularization acceptable (both for TAVR and AVR)
TF-TAVR includes vascular anatomy appropriate for lower profile Sapien XT + Novaflex system

32. PARTNER II – Intermediate Risk
Non-inferiority of TAVR-Sapien XT vs. sAVR for the primary endpoint for the duration of the study (all patients followed for at least 2 years)
Primary endpoint is a nonhierarchical composite of all- cause mortality and major stroke (mRankin score ≥ 2 at 90 days)
Non-inferior if one-sided 95% upper confidence limit for the treatment difference (∆) is < 20% of control; α =0.05 and power = 80%
Based on PARTNER 1 High-risk study results in AVR control arm (death + stroke at 1-year = 28%); assumed event rate for primary endpoint in control 30% (discounted for intermediate risk and adjusted for longer 2-year FU)

33. PARTNER II – Intermediate Risk
1:1 randomization between TAVR (Sapien XT) vs. AVR
Estimated sample size = 1744 patients (872 patients per arm); study sample size = 2,000 patients to account for lost-to-FU, withdrawals, and other study contingencies; (? mid-course pre-specified adjustment in final SAP)

34. PARTNER II – Intermediate Risk
FDA approved for enrollment Nov 4, 2011
Up to 50 study sites (all U.S.)
VARC definitions
More intense neurologic assessments (100% qualified neurology pre- and post-evaluations) and neurocognitive function substudies
Detailed frailty assessments
Incorporate TAVR Best Clinical Practices, including adjunctive pharmacology regimens (anti-platelet and anti-thrombin therapy)
? Incorporate cerebral embolic protection (later portion of study)

35. Intermediate Risk Populations: Summary
Outcomes will definitely be better with TAVI in lower risk populations, but so will the outcomes in patients undergoing sAVR
Two big concerns: Perivalvular AR and Stroke
Aim to lower PPM rate with good implantation technique
Randomized trials are essential