Cardiovacular Research Technologies When to Repair Functional MR The Interventional Cardiologist’s Perspective Ted Feldman, M.D., FSCAI FACC FESC Evanston Hospital CRT Cardiovacular Research Technologies Washington, D.C. February 23 – 26, 2013

Ted E. Feldman, MD Consulting: Abbott Laboratories Boston Scientific Corporation Edwards Lifesciences, LLC

INDICATIONS FOR MITRAL VALVE OPERATION ACC/AHA VHD Guidelines: 2008 Focused Update JACC Vol. 52, No. 13, 2008 September 23, 2008:e1–142

Mitral valve surgery in heart failure Acorn Clinical Trial Serious adverse events by treatment group Mean age 53.4±12.6 yrs bjective: The study objective was to evaluate in a prospective, randomized, multicenter trial the safety and efficacy of mitral valve surgery with and without the CorCap cardiac support device (Acorn Cardiovascular, St Paul, Minn) in patients with New York Heart Association Class II to IV heart failure. Background: Although mitral valve surgery has been performed successfully in patients with heart failure, the safety and long-term efficacy have not been estab- lished in a multicenter prospective trial. Cardiac support devices that reduce ven- tricular wall stress and promote beneficial reverse remodeling have been proposed as a new treatment option as a stand-alone procedure and as an adjunct to mitral valve surgery. Methods: A subgroup of 193 patients were enrolled in the mitral valve repair or replacement stratum of the Acorn Clinical Trial; 102 patients were randomized to the mitral valve surgery alone group (control) and 91 patients were randomized to mitral valve surgery with implantation of the CorCap cardiac support device. Patients were followed for a median duration of 22.9 months. Results: For the entire mitral valve surgery group, the 30-day operative mortality rate was only 1.6% at 30 days. Mitral surgery was associated with progressive reductions in left ventricle end-diastolic volume, left ventricle end-systolic volume, and left ventricular mass, and increases in left ventricle ejection fraction and sphericity index, all consistent with reverse remodeling. Recurrence of clinically significant mitral regurgitation was uncommon. Quality of life, exercise perfor- mance, and New York Heart Association functional class were all improved. Finally, the addition of the CorCap cardiac support device led to greater decreases in left ventricular end-diastolic volume and left ventricular end-systolic volume, a more elliptical shape, and a trend for a reduction in major cardiac procedures and improvement in quality of life compared with mitral surgery alone. Conclusions: These findings suggest that there is clear benefit to the surgical elimination of mitral regurgitation and that there is additional benefit with the CorCap cardiac support device. Given the improvement in left ventricle structure and function, along with a low mortality rate, physicians should strongly consider offering mitral valve surgery in combination with the CorCap cardiac support device to patients with heart failure who are on an optimal medical regimen. any in SAE 82% J Thorac Cardiovasc Surg 2006;132:568-77

Guidelines on the management of valvular heart disease 2012 With CABG European Heart Journal (2012) 33, 2474

Patient Selection for MR Therapies Trial inclusion and exclusion criteria determine patient population Resultant patient profile variable

EVEREST II Key Eligibility Criteria Age 18 years or older Moderate to severe (3+) or severe (4+) MR Symptomatic Asymptomatic with LVEF <60% or LVESD >45mm ACC/AHA Task Force Guidelines JACC 1998;32:1486 MR originates from A2-P2 mal-coaptation Core lab echo assessment ASE Guideline - JASE 2003;16:777-802 Candidate for mitral valve surgery including CPB Transseptal deemed feasible Key Exclusions EF < 25% or LVESD > 55 mm Renal insufficiency Endocarditis, rheumatic heart disease

EVEREST II Randomized Clinical Trial Baseline Demographics & Co-morbidities Device (%) n=184 Control (%) n=95 P Age (mean) 67.3 years 65.7 years 0.32 Male 62.5 66.3 0.60 Congestive heart failure 90.8 77.9 <0.01 Coronary artery disease 47.0 46.3 >0.99 Myocardial infarction 21.9 21.3 Atrial fibrillation 33.7 39.3 0.42 Cerebrovascular disease 7.6 5.3 0.62 Cardiomyopathy 17.9 14.7 0.61 Diabetes 10.5 0.50 Previous cardiovascular surgery 22.3 18.9 0.54 MR Severity: 3+ to 4+ 95.7 92.6 0.48 MR Etiology: Degenerative / Functional 73 / 27 0.81

EVEREST II Randomized Clinical Trial Demographic Comparison EVEREST II RCT n=279 2008 STS Database Isolated 1st Elective Operation for MR* Repair Replace High Volume Hospitals (>140/Yr) Age yrs (mean) 68 60 61 59 ≥65 yrs 58% 37% 45% n/a ≥75 yrs 32% 0% NYHA Class III or IV 50% 26% CHF 86% 41% Hypertension 75% 60% 67% 43% Diabetes Mellitus 9% 13% 23% 6.5% COPD / Chronic Lung Disease 15% 17% 29% EF (mean) 53% 55% 56% *Partial year; **61% elective; ***81% elective +Preliminary; STS 1.8 Font on top row *Gammie JS et al Influence of Hospital Procedural Volume on Care Process and Mortality for Patients Undergoing Elective Surgery for Mitral Regurgitation. Circ 2007;115:881-887. 10

EVEREST II High Risk Registry Subject screened for EVEREST II Evalve Mitraclip Surgery Good Surgical Candidate? Yes No High Risk Registry Predicted operative mortality ≥12% Primary Endpoint: Mortality at 30 days Randomized THIS IS THE CURRENT EFFICACY ENDPOINT: The major effectiveness endpoint is descriptive statistics comparing the following measures: MR severity grade, need for surgery, NYHA, QOL, re-hospitalization and LV function compared to published reports for similar patients treated medically or surgically. The endpoint will be analyzed per the surviving intent to treat population at 12 months. or in the judgment of the surgeon investigator the patient is considered a high risk surgical candidate

High Risk Registry Inclusion Criteria STS surgical risk calculator ≥ 12% or judgment of surgeon investigator the patient is considered high risk due to one of the following: Porcelain aorta or mobile ascending aortic atheoroma Post-radiation mediastinum Previous mediastinitis Functional MR with EF<40 Over 75 years old with EF<40 Re-operation with patent grafts Two or more prior chest surgeries Hepatic cirrhosis Three or more of the following STS high risk factors: Creatinine > 2.5 mg/dL Prior chest surgery Age over 75 EF<35

EVEREST II High Surgical Risk and Concurrent Control Baseline Demographics and Co-morbidities High Risk Cohort N=211 Concurrent Control N=36 Euro Heart Survey^ Not Operated, N=193 Operated, N=203 Age (years) 76 ±10 77 ±13 69 ±13 63 ±12 ≥ 75 years, (%) 57% 64% 65% 35% Predicted Mortality*, (%) 15.0% 16.4% n/a Prior Cardiac Surgery, (%) 58% 50% 7% 3% History Myocardial Infarction, (%) 49% 36% 28% 18% Prior Stroke, (%) 14% COPD / Chronic Lung Disease, (%) 30% 31% 21% 11% Moderate to Severe Renal Failure, (%) History Atrial Fibrillation, (%) 53% 32% Diabetes Mellitus, (%) 40% 42% 10% Mean Ejection Fraction, (%) 49 55 48 56 LV ESD (mm) 4.2 3.8 41 40 NYHA Class III or IV, (%) 86% 84% 70% Etiology – Functional MR, (%) 71% 12% 26% * Based on STS ≥ 12% or an assigned mortality 12% for pre-specified comorbidities Mirabel et al. European Heart Journal, 2007 EVEREST II High Surgical Risk Cohort – EuroPCR 2011

Key exclusion criteria Inclusion criteria dilated ischaemic or non-ischaemic cardiomyopathy ≥moderate (2+) FMR LV EF <40% NYHA class II–IV 6 min walk distance (6MWD) 150–450m stable heart failure medication for 3 months Key exclusion criteria IV inotrope infusion ≤30 days severe tricuspid regurgitation serum Cr.2.2 mg/dL organic mitral valve pathology pacing lead already in the CS

Randomize 1:1 ~420 patients enrolled at up to 75 US sites Clinical Outcomes Assessment of the MitraClip Percutaneous Therapy for High Surgical Risk ~420 patients enrolled at up to 75 US sites Significant FMR ≥3+ core lab High risk for mitral valve surgery Specific valve anatomic criteria Randomize 1:1 Control group Standard of care MitraClip Safety: Composite death, stroke, worsening renal function, LVAD implant, heart transplant at 12 months Effectiveness: Recurrent heart failure hospitalizations Protocol conditionally approved by FDA July 26, 2012

Key Inclusion Criteria Functional MR ≥3+ ischemic or non-ischemic cardiomyopathy Symptomatic NYHA class II, III or ambulatory IV STS mortality risk is ≥ 8% or Local Site Heart Team concludes that co-morbidities result in a prohibitive predicted operative risk of stroke or death ≥1 HF hospitalization during prior year and/or BNP ≥400 pg/ml or nT-proBNP ≥1600 pg/ml ≤90 days treated per standards for CAD, LV dysfunction, MR or HF including CRT, revascularization, OMT primary MR jet originates from malcoaptation of A2-P2 scallops Remove lvef 18

Key Exclusion Criteria severe LV dysfunction is defined as LVESD >55mm or LVEF<20% MV area <4 cm2 MI ≤90 days Untreated clinically significant CAD requiring revascularization CVA or TIA within 6 months or severe carotid stenosis Any percutaneous coronary, carotid or endovascular intervention or carotid surgery within 30 days, or any coronary or endovascular surgery within 6 months CRT and/or ICD implant or revision within 90 days Leaflet anatomy which may preclude MitraClip implantation, proper MitraClip positioning on the leaflets or sufficient reduction in MR Severe right ventricular failure or severe tricuspid regurgitation

Grossi EA, Patel N, Woo, YJ, Goldberg JD, Schwartz CF, Subramanian V, Feldman T, Bourge R, Baumgartner N, Genco C, Goldman S, Zenati M, Wolfe JA, Mishra YK, Trehan N, Mittal S, Shang S, Mortier TJ, Schweich CJ J Am Coll Cardiol 2010; 56: 1984-93 Mean age 35yrs, LVEF35-39% ?? Greater need for trials in conjunction with Revasc?? … improved survival and a significant decrease in major adverse outcomes… validates the concept of ventricular reshaping… Grossi EA, Patel N, Woo, YJ, Goldberg JD, Schwartz CF, Subramanian V, Feldman T, Bourge R, Baumgartner N, Genco C, Goldman S, Zenati M, Wolfe JA, Mishra YK, Trehan N, Mittal S, Shang S, Mortier TJ, Schweich CJ J Am Coll Cardiol 2010; 56: 1984-93