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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 1 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. Consulting Fees: Abbott Vascular Boston Scientific Corporation My presentation will include off label discussions: Percutaneous aortic valves Better TAVR Outcomes in Lower Risk Patients N=420 patients (105 per quartile) Quartile 1 Quartile 4 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% Age, years Lange JACC 2012;59:280–7 5 European ‘’On-Label’’ and ‘’Off-Label ’’ Use Piazza Heart 2010;96:19–26. 6 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. 7 Intermediate Populations “Risk Creep” Favors TAVR Preferentially 8 “Risk Creep” Favors TAVR Preferentially Bern Windecker 9 Expanding Into Risk Populations Top 33% Surgical Risk STS ≥ 4 30-Day Mortality < 2-4% Intermediate ≈ 26% Surgical Aortic Valve Replacements 70-90,000 yearly PARTNER B CoreValve Extreme Risk STS PROM < 4% PARTNER IIA SURTAVI PARTNER A CoreValve High Risk Two-thirds of patients will remain optimal surgical candidates Top 7% Surgical Risk “Cohort C” STS > 8 Extreme Risk Inoperable 20-50K 10 Patient Selection Presented By Prof. Patrick Serruys, MD on behalf of 11 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 12 Identifying Intermediate Risk Patients Serruys SURTAVI TCT2011 13 Identifying Intermediate Risk Patients Serruys SURTAVI TCT2011 14 Operability is a Risk Continuum ¿ TAVR or AVR Low Risk Intermed Risk High Risk < 5% 5-15% >15% ~20-25% ~10% Surgery (AVR) OR risk % patients ~65-70% Serruys SURTAVI TCT2011 15 STS PROM (2006-2010) STS ≥ 3 STS ≥ 4 STS ≥ 5 Leon PARTNERII A TCT2011 46% 33% 25% 16 BERMUDA Results Serruys SURTAVI TCT2011 17 Heart Team Assesment May Vary From STS Serruys SURTAVI TCT2011 18 BERn – MUnich – rotterDAm Registry 3666 patients enrolled TAVI – 782 SAVR – 2884 2882 patients excluded based on propensity scores 784 matched patients TAVI – 392 SAVR - 392 274 patients excluded based on STS score <3% and >8% 510 matched patients (STS scores 3-8%) TAVI 255 patients analyzed Serruys SURTAVI TCT2011 SAVR 255 patients analyzed 19 BERn – MUnich – rotterDAm Registry Matched Cohort Age (years) STS <3 n=184 STS 3-8 n=510 STS >8 n=90 77.3 (4.7) 80.1(5.3) 81.7 (5.3) 17.6 (10.5) 25.1(17.1) Logistic ES (%) 13.5 (8.4) TAVI vs. SAVR 92 vs. 92 Serruys SURTAVI TCT2011 255 vs. 255 45 vs. 45 20 BERn – MUnich – rotterDAm Registry One Year Outcome In Intermediate Risk Patients Serruys SURTAVI TCT2011 21 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 allcause mortality and major stroke at 24 months in patients with symptomatic severe aortic stenosis and at intermediate surgical risk. Serruys SURTAVI TCT2011 22 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 23 SURTAVI: Inclusion Criteria 1. Subject must have STS mortality risk score ≥ 3% and ≤ 8% (in United States, STS mortality risk score ≥4% and ≤8%) 2. 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 3. Critical aortic valve area defined as an initial aortic valve area of ≤1.0 cm2 or aortic valve area index < 0.6 cm2/m2 24 SURTAVI: Inclusion Criteria 4. In presence of normal LV function: mean gradient > 40mmHg OR Vmax > 4m/sec. 5. 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 5. Subject is symptomatic from his/her aortic valve stenosis, as demonstrated by New York Heart Association (NYHA) Functional Class II or greater 25 SURTAVI: Exclusion Criteria 9. Active Gastrointestinal (GI) bleeding within the past 3 months 10. Subject refuses a blood transfusion 11. 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) 12. Multivessel coronary artery disease with a Syntax score >22 26 SURTAVI: Exclusion Criteria 18. 19. 20. 21. 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 22. Uncontrolled atrial fibrillation 23. Pregnancy or intent to become pregnant prior to completion of all protocol follow-up requirements 24. End stage renal disease requiring chronic dialysis or creatinine clearance < 20 cc/min 27 SURTAVI: Exclusion Criteria 25. Native aortic annulus size < 20 mm or > 29 mm 26. Pre-existing prosthetic heart valve in any position 27. Mixed aortic valve disease [AS and AR with predominant AR (3-4+)] 28. Severe mitral or severe tricuspid regurgitation 29. Severe mitral stenosis 30. Hypertrophic obstructive cardiomyopathy 31. Echocardiographic or Multislice Computed Tomography (MSCT) evidence of intracardiac mass, thrombus or vegetation 32. Ascending aorta diameter > 43 mm unless the aortic annulus is 20-23 mm in which case the ascending aorta diameter > 40 mm 28 SURTAVI: Study Design OUS US STS mortality risk ≥3% and ≤8% 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 Neurological Assessments with 5 year follow up Presence of significant CAD with intended revascularization TAVI + PCI SAVR + CABG No intended revascularization TAVI SAVR 29 PARTNER II – Intermediate Risk Symptomatic Severe Aortic Stenosis ASSESSMENT by Heart Valve Team 2 Parallel RCTs: Individually Powered Intermediate Risk Inoperable ASSESSMENT: Yes Transfemoral (TF) 1:1 Randomization TF TAVR Sapien XT AVR VS ASSESSMENT: No Transfemoral Access Transfemoral Access Transapical (TA) 1:1 Randomization TA TAVR Ascendra 2 AVR VS Primary Endpoint: All-Cause Mortality + Major Stroke at Two Years (Non-inferiority) Yes No 1:1 Randomization TF TAVR Sapien XT Not In Study TF TAVR Sapien VS Primary Endpoint: All-Cause Mortality + Major Stroke + Repeat Hospitalization at One Year (Non-inferiority) 30 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 31 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 allcause 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) 32 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) 33 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) 34 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 35