1. New Developments in the Management of Aortic and Mitral Valve Disorders New Developments in the Management of Aortic and Mitral Valve Disorders Patricia A. Pellikka, M.D. Mayo Clinic, Rochester, MN Conflicts of interest: none

2. Prevalence of Valve Diseases Moderate or severe Prevalence of Valve Diseases Moderate or severe % <45 Prevalence (%) 45-54 55-64 65-75  75 0-39 40-49 Population-NIH Series Olmsted County Total Mitral valve Aortic valve 50-59 60-69 70-79  80 Valve disease

3. Burden of Valve Diseases in the U.S. Year20002030 AS 2.5 million 4.6 million MR 2.7 million 4.8 million Disease

4. Overview Natural history Natural history Assessment of morphology and severity Assessment of morphology and severity Guidelines Guidelines Surgical and percutaneous intervention Surgical and percutaneous intervention

5. Latent period (increasing obstruction, myocardial overload) Latent period (increasing obstruction, myocardial overload) Natural History of Aortic Stenosis Ross J Jr. and Braunwald E: Circ 38:61, 1968 Age (yr) 04050607080 Average death age (male) Average death age (male) Onset severe symptoms Onset severe symptoms Average survival (yr) Angina Syncope Failure CP1154825-3

6. Symptoms in Aortic Stenosis AnginaSyncopeDyspneaLV failure “Early” “Late” Initial symptoms in 1/3 Elderly CP1154825-4

7. Years No. at risk3972651851288047251596 Survival free of symptoms (%) Survival Free of Symptoms Censored at AV Surgery CP1154825-22 Pellikka, Circulation 111:3290-5, 2005

8. Outcome of 622 Adults with Asymptomatic AS HRP Aortic valve area0.330.005 (per 1 cm) LVH1.390.04 HRP Aortic valve area0.330.005 (per 1 cm) LVH1.390.04 CP1154825-53 Multivariate Analysis – Symptoms Pellikka, Circulation 111:3290-5, 2005

9. Outcome of 622 Adults with Asymptomatic AS HRP Age (per year)1.05<0.0001 Chronic renal failure2.410.004 Inactivity2.00.001 Aortic valve velocity1.460.03 HRP Age (per year)1.05<0.0001 Chronic renal failure2.410.004 Inactivity2.00.001 Aortic valve velocity1.460.03 CP1154825-54 Multivariate Analysis – Mortality Pellikka, Circulation 111:3290-5, 2005

10. >4.0 m/s 3.0-4.0 m/s Vmax <3.0 m/s Survival in Asymptomatic AS Event- free survival Otto CM: Circulation 95:2262, 1997 Time from enrollment (months) CP1154825-31

11. AVA for Patients Who Developed Symptoms and Required AVR Compared with Valve Area of Asymptomatic Patients (n=123) Otto: Circulation, 1997 Aortic valve area (cm 2 ) Aortic valve area (cm 2 ) Clinical outcome Baseline Final AVR/died Asymptomatic CP1154825-33

12. Survival (%) Years MR with flail leaflet: Natural history NYHA Class 229 pts Class I-II 67±7% Class III-IV 21±11% P<0.0001

13. Survival (%) Years P=0.0001 MR with flail leaflet: Natural History Left Ventricular Ejection Fraction EF  60% (61±8%) EF <60% (40±12%)

14. Asymptomatic MVP Primary risk factors (mort) EF <50% EF <50% MR  moderate MR  moderate Risk Stratification Secondary risk factors (morb) Age  50 years Age  50 years AFib AFib Slight MR Slight MR Flail leaflet Flail leaflet LA  40 mm LA  40 mm

15. Outcome of Asymptomatic MVP Survival (%) Overall Survival Cardiac Survival Years after diagnosis P<0.001P<0.001 P(exp)=0.17 P(exp)=0.20 P(exp)=0.01 95±2 70±5 100 87±4 66±10 No or 1 secondary RF  2 secondary RF Primary RF 55±9

16. Asymptomatic MR Natural History Survival (%) Years P<0.01 91±3 66±6 58±9 1-19 ERO mm 2 20-39  40 P=0.03 vs expected

17. % of Aortic Stenosis Patients Undergoing Invasive Hemodynamics, After Complete Doppler Exam, Prior to Valve Replacement Mayo Clinic Roger: Mayo Clinic Proc, 2/96 CP1008395-3 Early 1980s 95 13 9899 Pt undergoing invasive hemodynamics (%) Year (no.) 1990 91 92 93 94 (122) (149) (152) (160) (145) 54 40 35 29 23 0 20 40 60 80 100

18. CP984907-31 Simplified Bernoulli Equation P = 4V 2

19. CP1009156-1 Aortic Stenosis CW Doppler

20. CP984907-42 AVA = = x x A A TVI Continuity Equation

21. Mild >1.5 0.9<25 25-40 Moderate1-1.5  0.625-40 >40 Severe 40 ACC/AHA 2006 Guidelines Severity of Aortic Stenosis ACC/AHA 2006 Guidelines Severity of Aortic Stenosis AVAMean (cm 2 )cm 2 /m 2 grad AVAMean (cm 2 )cm 2 /m 2 grad CP1284125-5

22. Echo/Doppler assessment Morphology Morphology Severity of obstruction Severity of obstruction Associated conditions- LV size, function, hypertrophy, aortic root size, diastolic function, pulmonary artery pressure Associated conditions- LV size, function, hypertrophy, aortic root size, diastolic function, pulmonary artery pressure

23. Flow Calculation

24. RVolERO ASE grade(mL)(mm 2 ) MildGrade I<30<20 ModerateGrade II30-4420-29 Grade III45-5930-39 SevereGrade IV  60  40 Mitral Regurgitation Grading of Severity

25. Mitral Regurgitation Mitral Valve Repair vs Replacement Years Expected Replacement-214 pts Overall survival (%) Repair-195 pts P=0.0004

26. Carpentier’s classification Type I Normal valve movement Normal valve movement Class II Excessive movement Excessive movement Class IIIa Diastolic restric Diastolic restric Class IIIb Systolic restric Systolic restric examples annular dilatation annular dilatation leaflet perforation leaflet perforation prolapse prolapse rheumatic rheumatic functional functional

27. Data 5,000-40,000 pts RCTs Data 50-600 pts Observational Studies Heart Failure STEMI Unstable angina Heart Failure STEMI Unstable angina Valvular Heart Disease Valvular Heart Disease Expert opinion ACC/AHA Guidelines

28. ACC/AHA 2006 Guidelines for Valvular Heart Disease Indications for AVR ACC/AHA 2006 Guidelines for Valvular Heart Disease Indications for AVR CP1284125-11 Symptomatic pt with severe AS Symptomatic pt with severe AS Pt with severe AS undergoing CABG or surgery on aorta or other valves Pt with severe AS undergoing CABG or surgery on aorta or other valves Severe AS and EF < 50% Severe AS and EF < 50% Symptomatic pt with severe AS Symptomatic pt with severe AS Pt with severe AS undergoing CABG or surgery on aorta or other valves Pt with severe AS undergoing CABG or surgery on aorta or other valves Severe AS and EF < 50% Severe AS and EF < 50% Class I BCCBCC

29. ACC/AHA 2006 Guidelines for Valvular Heart Disease Indications for AVR ACC/AHA 2006 Guidelines for Valvular Heart Disease Indications for AVR CP1284125-11 Pt with moderate AS undergoing CABG or surgery on aorta or other valves Pt with moderate AS undergoing CABG or surgery on aorta or other valves Class IIa BB

30. Should CABG Surgery Patients with Mild or Moderate AS Undergo Concomitant AVR? CP1284125-6 Smith: JACC, 2004 Markov decision analysis: Long-term, quality-adjusted outcomes of pt with AS – CABG or CABG/AVR Markov decision analysis: Long-term, quality-adjusted outcomes of pt with AS – CABG or CABG/AVR Outcome influenced by AS rate of progression: 10 mm Hg/yr, CABG/AVR except if >80 yr and gradient 10 mm Hg/yr, CABG/AVR except if >80 yr and gradient <25 Peak aortic valve gradient by echo Age at time of CABG CABG preferred CABG/AVR preferred 28 mm Hg

31. ACC/AHA 2006 Guidelines Indications for AVR ACC/AHA 2006 Guidelines Indications for AVR CP1284125-11 Extremely severe AS, mean grad>60, operative mortality ≤ 1% Extremely severe AS, mean grad>60, operative mortality ≤ 1% Mild AS undergoing CABG with evidence for rapid progression Mild AS undergoing CABG with evidence for rapid progression Severe AS and likelihood of rapid progression or if surgery would be delayed at symptom onset Severe AS and likelihood of rapid progression or if surgery would be delayed at symptom onset Severe AS and abnormal response to exercise Severe AS and abnormal response to exercise Extremely severe AS, mean grad>60, operative mortality ≤ 1% Extremely severe AS, mean grad>60, operative mortality ≤ 1% Mild AS undergoing CABG with evidence for rapid progression Mild AS undergoing CABG with evidence for rapid progression Severe AS and likelihood of rapid progression or if surgery would be delayed at symptom onset Severe AS and likelihood of rapid progression or if surgery would be delayed at symptom onset Severe AS and abnormal response to exercise Severe AS and abnormal response to exercise Class IIb CCCCCCCC

32. MR: Indications for Mitral Valve Operation Class I Symptomatic patients with acute severe MR Symptomatic patients with acute severe MR Patients with chronic severe MR and NYHA class II, III or IV symptoms in absence of severe LV dysfunction (EF 55 mm Patients with chronic severe MR and NYHA class II, III or IV symptoms in absence of severe LV dysfunction (EF 55 mm Asymptomatic patients with chronic severe MR and mild to mod LV dysfunction, EF 30-60% and/or end- sys dimension  40 mm Asymptomatic patients with chronic severe MR and mild to mod LV dysfunction, EF 30-60% and/or end- sys dimension  40 mm MV repair recommended over replacement in majority of patients with severe chronic MR who require surgery MV repair recommended over replacement in majority of patients with severe chronic MR who require surgery B B B C ACC/AHA 2006 Guidelines for Valvular Heart Disease

33. MR: Indications for Mitral Valve Operation Class IIa MV repair in experienced surgical center for asymptomatic pts with chronic severe MR, preserved LV function if repair likely MV repair in experienced surgical center for asymptomatic pts with chronic severe MR, preserved LV function if repair likely MV surgery for asx pts with chronic severe MR, preserved LV function and new atrial fib MV surgery for asx pts with chronic severe MR, preserved LV function and new atrial fib Asymptomatic patients with chronic severe MR, preserved LV function and pulmonary hypertension Asymptomatic patients with chronic severe MR, preserved LV function and pulmonary hypertension MV surgery for patients with chronic severe MR due to abnormality of mitral apparatus, class II-IV sx and severe LV dysfunction if repair likely MV surgery for patients with chronic severe MR due to abnormality of mitral apparatus, class II-IV sx and severe LV dysfunction if repair likely B C C C ACC/AHA 2006 Guidelines for Valvular Heart Disease

34. Transapical Minimally-Invasive Aortic Valve Implantation CP1284125-3 Walther: Circulation, 2007 59 patients, 81±6 years 59 patients, 81±6 years EuroSCORE  9 EuroSCORE  9 Predicted mortality 26.8% Predicted mortality 26.8% Follow-up 110±77 days, mortality 22% Follow-up 110±77 days, mortality 22% 59 patients, 81±6 years 59 patients, 81±6 years EuroSCORE  9 EuroSCORE  9 Predicted mortality 26.8% Predicted mortality 26.8% Follow-up 110±77 days, mortality 22% Follow-up 110±77 days, mortality 22%

35. PARTNER Trial PARTNER Trial Proposal (with Transapical) Operable assessment Cohort B No 1:1 randomization Yes No Yes Not in study Subgroup analyses: TA vs control, TF vs control Primary analyses: TF and TA vs control (combined) vs Trans- femoral AVR control vs Trans- femoral AVR control vs Trans femoral Medical mgmt control 1:1 randomization Femoral access eval Y/N Cohort A Eligibility met for high-risk symptomatic, critical calcific aortic stenosis YesNo Femoral access eval Y/N 1:1 randomization

36. 56 mm Hg to 8 mm Hg TEE PrePost

37. TF (n=463)TA (n=575)P Age (yr)81.780.7NS Female55%56%NS Pulmonary disease25%29%NS Renal dysfunction26%33% 0.024 Logistic EuroSCORE25.729.2<0.005 Peripheral vascular disease11%28%<0.001 Carotid artery stenosis (>50%) 8%17% 50%) 8%17%<0.001 Incidence of CAD47%56%<0.006 Porcelain aorta 5%12%<0.001 Prior CABG18%27%<0.001 Mitral valve disease16%33%<0.001 Baseline Demographics and Risk Factors

38. No.%No.%No.% Acute procedure43695.652392.995994.1 success Device success comp*42892.452290.895091.5 Conversion to sAVR 8 1.7 20 3.5 28 2.7 AR >+2** 15 3.2 34 5.9 49 4.7 Valve migration 0 0.0 3 0.5 3 0.3 Valve malposition 8 1.7 8 1.4 16 1.5 Coronary obstruction 3 0.7 3 0.5 6 0.6 Implantation Success *Device success is a composite including AR <2+ and no valve in valve **Site reported TF (n=463) TA (n=575) Total (n=1,038) All procedural X1 to aorta X2 to ventricle

39. No.%No.%No.% Death296.35910.3888.5 Stroke112.416 2.6272.5 Renal failure235.06911.7928.7 requiring dialysis Permanent316.742 7.3737.0 pacemaker Major Complications (≤30 Days) TF n=463 TA n=575 Total n=1,038

40. Related to implant* (9/463) Heart failure4 Bleeding event major2 Cardiac tamponade1 Annular dissection 1 Multiple organ failure1 Causes of Death ≤30 Days – Transfemoral 30-day mortality – transfemoral (29/463) = 6.3% Related to procedure** (20/463) Multiple organ failure4 Sudden death (3 unk)4 Sepsis3 Heart failure2 Gastrointestinal1 Cardiac arrest 1 Bleeding event major1 Circulatory disorder1 Hematologic disorder1 Cardiogenic shock1 Renal failure1 *Related to implant: direct result of valve implant **Related to procedure: result of procedure

41. Related to implant* (16/575) Heart failure9 Hemorrhage3 Multiple organ failure1 Bleeding event major1 Aortic dissection1 Cardiac arrest1 Causes of Death ≤30 Days – Transapical 30-day mortality – transapical (59/575) = 10.3% Related to procedure** (43/575) Multiple organ failure14 Gastrointestinal 5 Cardiac arrest 4 Heart failure 4 Sepsis 4 Respiratory failure 2 Bleeding event major 1 Sudden death 1 Circulatory disorder 1 Hematologic disorder 1 Cardiac decompensation 1 Pneumonia 1 Pulmonary embolism 1 Myocardial inarction 1 Stroke 1 Renal failure 1 *Related to implant: direct result of valve implant **Related to procedure: result of procedure

42. 30 days (%) Steadily Improving Outcomes 94% survival at 30 days

43. Aortic mitral fibrosa Posterior medial commissure Anterior lateral commissure Anterior leaflet P1 A1 A2 A3 P3 P2 Posterior leaflet Normal Resection of flail segmentRepaired mitral valve CP1023486-1 Flail posterior leaflet

44. D'Gara et al: JACC CV Imaging, 2008 Percutaneous MV Repair Mitral Annuloplasty Alfieri Procedure

45. Years No. at risk4693492631771167441261611 Survival (%) P<0.001 Patients Referent group CP1154825-24 Survival of Patients Censored at Surgery vs Referent Group Pellikka, Circulation 111: 3290-5, 2005

46. Mitral Regurgitation Due to Flail Leaflet Multicenter European Experience 304 pts with nonsurgical management Incidence (%) Follow-up (years) MV surgery/CVD 88±2% AFib30±7% HF57±9% Grigioni F et al: J Am Coll Cardiol Img 1:133, 2008

47. Summary Follow-up is needed to understand safety and durability of percutaneous devices Follow-up is needed to understand safety and durability of percutaneous devices Prospective, randomized clinical trials needed Prospective, randomized clinical trials needed

48. Summary Less-invasive alternatives to conventional valve surgery will result in earlier intervention and intervention in a larger number of patients Less-invasive alternatives to conventional valve surgery will result in earlier intervention and intervention in a larger number of patients