1. Panel PresenationFDA Clinical Review1 CDRH Panel Meeting June 22, 2005 Ileana L. Piña, M.D. Professor of Medicine Case Western Reserve University Director Heart Failure/Transplantation Julie Swain, M.D. Cardiovascular Surgeon Consultants Clinical Reviewers for PMA P040049

2. Panel PresenationFDA Clinical Review2 Intended Use of the CorCap “… provides beneficial changes in cardiac structure associated with a reverse remodeling effect as defined by a reduction in LV size, an increase in EF and a change to a more elliptical shape. … provides a decrease in the need for additional major cardiac procedures associated with the progression of HF and an overall improvement in QOL. ”

3. Panel PresenationFDA Clinical Review3 CorCap Clinical Trial Prospective Randomized Controlled 2-arm trial (heart failure patients either with mitral insufficiency requiring MVR or without mitral insufficiency) stratified by MVR

4. Panel PresenationFDA Clinical Review4 CorCap Clinical Trial Hypothesis: The CorCap would improve patient functional status as measured by a clinical composite consisting of  mortality  major cardiac procedure for worsening heart failure (MCP)  change in NYHA Class

5. Panel PresenationFDA Clinical Review5 CorCap Clinical Trial Primary Objective: To compare the functional status after a minimum of 12 months of follow-up for patients randomly assigned to Treatment (CorCap) or Control (no CorCap). Secondary Objective: To determine the rate of death and other SAE’s experienced by patients randomized to CorCap implant and to compare this rate with that for patients assigned to the control group. To compare patient functional status and structural changes in the heart for the Treatment and the Control groups.

6. Panel PresenationFDA Clinical Review6 CorCap Clinical Trial Primary Composite Efficacy Endpoint: Composite endpoint of : all-cause mortality NYHA class as per core lab Major Cardiac Procedures (MCP) indicative of progression of HF.

7. Panel PresenationFDA Clinical Review7 CorCap Clinical Trial Secondary Efficacy Endpoints:  Reduction in LV size, LV function and re-shape of the LV  Functional status: Improvement in QOL at 6 and 12 months (MLWHF, SF36), exercise status 6 and 12 months (6 min walk, CPX testing ) and site-determined NYHA  Changes in CPX, Peak VO2, VT, and exercise time at 6 and 12 mo  Changes in BNP  All cause mortality and hospitalizations  Incidence of Major Cardiac Procedures  Safety: hospitalization, adverse events, major cardiac procedures and mortality  # of hospitalizations, hospital days and ICU days

8. Panel PresenationFDA Clinical Review8 Baseline Characteristics ParameterValue Age52.5 years Men55.3% Caucasian65% Etiology : Ischemic10% Non-ischemic (dilated)81.6% Valvular11.3% EF27.4% LVEDD7.2 cm Peak VO215.0 ml/min/kg 6 min walk340.9 m MLWHF59.3

9. Panel PresenationFDA Clinical Review9 Missing Data Missing tests occurred in 47% of patients. In the Treatment arm, 59% of patients did not have a baseline CoreLab NYHA assessment. In the Control arm, 57% of the patients did not have a baseline CoreLab NYHA assessment. 0 5 10 15 20 25 30 35 40 45 50 % Missing follow-up data TreatmentControl MLWHF SF36 Peak VO 2 6' walk

10. Panel PresenationFDA Clinical Review10 Results: Primary Composite Endpoint Treatment (Average %) Control (Average %) Odds Ratio T/C (95% CI) P-value Improved37.727.3 1.73 (1.07- 2.79) 0.024 Same25.127.7 Worsened37.245.1

11. Panel PresenationFDA Clinical Review11 Mortality (as of April 15, 2005) % of patients

12. Panel PresenationFDA Clinical Review12 30 Day Operative Mortality by Year NoMVR Stratum

13. Panel PresenationFDA Clinical Review13 Hospitalized Patients for HF REMATCH VMAC OPT FIRST OMM ESCAPE CorCap Control SBP 121 120 107 103 106 111 LVEF 26% 24% 19% 17% <30% 27.3 Na 138 138 135 136.7 6 mo 23% 10% 37% 48% 19% 7.7% Mortality Adapted from LW Stevenson, presentation for REMATCH

14. Panel PresenationFDA Clinical Review14 SOLVD 14 vs 11 (ACE Inhibitor) CONSENSUS 62 vs 45 (ACE Inhibitor) COPERNICUS 18.5 vs 11 (Beta Blocker) RALES 25 vs 17 (Spironolactone) REMATCH 76 vs 49 (LVAD) ESCAPE17.4vs.20.9 (6 mos) CorCap14vs.13 Adapted from LW Stevenson, presentation for REMATCH 1 year Mortality Study Control vs Tx

15. Panel PresenationFDA Clinical Review15 Concerns There are remaining concerns regarding:  Disagreement with CERC Adjudication of several MCP’s  Bias against re-op of pts with CorCap  NYHA Class for Status II Transplant patients  Reverse remodeling  Significance of BNP  Clinical relevance of MLWHF differences

16. Panel PresenationFDA Clinical Review16 Major Cardiac Procedures Major Cardiac Procedures (MCP) were defined as surgical interventions for worsening heart failure including CABG, MVR, TVR and BiV pacing. Progression of heart failure  Hx and P.E.  Decreased exercise tolerance, JVD, rales  CXR  Laboratory Studies  Right Heart Cath  Lack of Clinical Response to Conservative Rx

17. Panel PresenationFDA Clinical Review17 Major Cardiac Procedures: MVR Stratum Treatment (n=91) Control (n=102) # Pts# EventsRate# Pts# EventsRateHR (T/C) (95% CI) p-value Cardiac Transplant 663.810126.20.63 (0.23, 1.74) 0.37 LVAD331.9673.60.57 (0.14, 2.28) 0.43 MVR110.6331.8NA NA Bi-Ventricular Pacing 663.8784.30.75 (0.24, 2.36) 0.62 TVR 000.0221.2NA NA Any of above procedures 14169.3213214.20.57 (0.28, 1.16) 0.12

18. Panel PresenationFDA Clinical Review18 Major Cardiac Procedures: NoMVR Stratum TreatmentControl # patients# eventsRate# patients# eventsRatep value Cardiac Transplant 111.1667.50.06 LVAD000222.4NA MVR000000NA Bi-Ventricular Pacing 444.0789.20.24 TVR 000000NA Any of above procedures 555.8121016.80.03

19. Panel PresenationFDA Clinical Review19 CRT (BiV Pacing) and Open Procedures by Group 0 5 10 15 20 25 30 NO treat NO con MVR treat MVR con Total treat Total con Open CRT % of patients

20. Panel PresenationFDA Clinical Review20 Cardiac Transplant Status GroupNoMVR Control MVR Control MVR Treatment UNOS StatusIbII Ib Months enrollment to transplant 81369

21. Panel PresenationFDA Clinical Review21 LVAD as MCP None of the 11 patients who received an LVAD were listed for transplantation prior to enrollment 6 were listed prior to LVAD insertion as a bridge to transplant 3 patients were not on the transplant list 2 were listed after the LVAD was placed 3 patients who received LVAD’s were never listed for transplant

22. Panel PresenationFDA Clinical Review22 Functional Measures Placebo effect possible in less objective measures  QOL  NYHA, site assessed Placebo effect less likely in objective measures of function  VO2  6 min walk

23. Panel PresenationFDA Clinical Review23 NYHA by Core Lab

24. Panel PresenationFDA Clinical Review24 NYHA-Site Assessed

25. Panel PresenationFDA Clinical Review25 QOL by MLWHF NoMVR Stratum Treatment (n=57) Control (n=50) # Patients Mean Change (95% CI) # Patients Mean Change (95% CI) 12 Months 45-11.3 (-17.1, -5.5) 42-6.4 (-12.4, -0.3) MVR Stratum Treatment (n=91) Control (n=102) # Patients Mean Change (95% CI) # Patients Mean Change (95% CI) 12 Months 80-21.9 (-26.9, -16.9) 77-18.3 (-23.3, -13.3)

26. Panel PresenationFDA Clinical Review26 6 minute walk 0 10 20 30 40 50 60 70 % of patients with 12 mos data Decreased or dead >65 m0-65 m No Control No+ treatment MVR+control MVR+treatment

27. Panel PresenationFDA Clinical Review27 CPX data, peak VO 2

28. Panel PresenationFDA Clinical Review28 Functional Summary Placebo effects are most likely in subjective testing, such as QOL and NYHA Class. Neither 6 min walk nor CPX testing showed clinically significant improvements in the CorCap group.

29. Panel PresenationFDA Clinical Review29 Structural Endpoints (at 12 mos) Treatment (n=132) Control (n=134) LVEDV(ml)-32.7(n=97)-17.2 (n=88) LVESV(ml)-25.9(n=97)-8.2 (n=88) LV EF(%)3.70.2 Sphericity0.100.03 LV mass gm/m 2 -14.9 (n=50)-13.6 (n=53) LVEDD(mm)-5.8 (n=114)-3.6 (n=107) LVESD(mm)-4.8 (n=114)-2.5 (n=105)

30. Panel PresenationFDA Clinical Review30 Structural Endpoints (at 12 mos) (n=64/91) (n=60/102) (n=33/57) (n=28/50)

31. Panel PresenationFDA Clinical Review31 Reverse Remodeling? Treatment At 6 mos, 30% pts with no data At 12 mos, 34% pts with no data Control At 6 mos, 37% pts with no data At 12 mos, 42% pts with no data

32. Panel PresenationFDA Clinical Review32 Reverse Remodeling? Data are missing—not at random with more data missing in the Control group Remodeling is a time related process Should be linked to favorable outcome No difference in mortality Most changes occur early post CorCap application Less likely to be true reverse remodeling Most of the LV mass decrease is accounted for by the MVR procedure

33. Panel PresenationFDA Clinical Review33 Previous Clinical Experience (not published) (Charité) Single center, non randomized 29 patients  17 with other valve surgery  12 with CorCap only Baseline imbalances in sickness severity (duration of HF, beta blocker, #hospitalizations) 4 in-hospital deaths

34. Panel PresenationFDA Clinical Review34 Clinical Experience (Charité) 10 8 9 11 8 10 Values are averages

35. Panel PresenationFDA Clinical Review35 Clinical Experience (Charité)

36. Panel PresenationFDA Clinical Review36 Brain Natriuretic Peptide (BNP) n-71 n=106 n=80 n=104

37. Panel PresenationFDA Clinical Review37 Structural Summary Structural Changes support most of the benefit in LV mass reduction due to MVR and not to the CorCap + MVR. Structural changes occur by 3 mos suggestive of an early effect and not reverse remodeling which should occur and improve with time (beyond 3 months). The BNP measures do not support an improvement in filling pressures in the T arm. Correlations between structural and functional changes are difficult to interpret due to large amounts of missing data particularly in CPX testing and 6’ walk. Missing data may not be at random.

38. Panel PresenationFDA Clinical Review38 Adverse Events Related to Hemodynamic Compromise p =0.053 p =0.14 Treatment group n=148 Control group n=152

39. Panel PresenationFDA Clinical Review39 <30 days SAE’s NoMVRMVR ControlTreatpControlTreatp Hemodynamic compromise 5180.00724210.95 Infection060.0313180.23 Neurologic deficit 011.0250.23 Pulmonary Compromise 070.0112170.19 Any SAE/Death 7310.000154510.74

40. Panel PresenationFDA Clinical Review40 Constrictive Physiology 252 patients had echo data 18 patients in the Treatment arm and 30 in the Control arm without follow-up echo. 43 patients (33%) in the Treatment group and 16 patients (13%) in the Control group with at least 1 echo with possible or suggestion of constriction (p=0.0002). No patient had any action taken nor are there any AE’s related to constriction. There is more early hemodynamic compromise in the Treatment group when compared to Control, but no evidence of constriction at 18 months

41. Panel PresenationFDA Clinical Review41 Clinical Summary The Sponsor has met the primary endpoint.  The only component contribution of the primary endpoint that is significant is the MCP. There are no differences in mortality or rehospitalizations. There are large amounts of missing data which may not be at random, including baseline core lab NYHA Class.

42. Panel PresenationFDA Clinical Review42 Clinical Summary (cont) Unblinded trial with potential problems of known and unknown treatment and assessment bias. Upfront mortality cost to the device, with modest long term benefit. Only 10% of the patients tested had an ischemic etiology for HF.

43. Panel PresenationFDA Clinical Review43

44. Panel PresenationFDA Clinical Review44 Structural Endpoints (at 12 mos) MVR Treatment Control (n=91) (n=102) noMVR Treatment Control (n=57) (n=50) LVEDV-39.9(n=64)-25 (n=60)-25.9 (n=33)-12.4 (n=28) LVESV0.1(n=64)0 (n=60)-23.6 (n=33)-6.0 (n=28) LV EF2.9 (n=64)-1.2 (n=60)4.4 (n=33)1.5 (n=28) Sphericity0.12 (n=63)0.03 (n=58)0.08 (n=34)0.04 (n=29) LV mass-20.8(n=64)-18.4 (n=60)-8.2 (n=33)-9.3 (n=28) LVEDD-7.1 (n=62)-4.8 (n=53)-5.0 (n=27)-2.5 (n=26) LVESD-5.4 (n=60)-3.4 (n=53)-5.1 (n=27)-1.3 (n=26)

45. Panel PresenationFDA Clinical Review45 Brain Natriuretic Peptide (BNP) TreatmentControl #Mean + SD# 71176.0 + 229.980184.0 + 284.7 106238.3 + 307.6104176.7 + 211.4

46. Panel PresenationFDA Clinical Review46 Adverse Events Related to Hemodynamic Compromise Any Adverse Event Treatment (n=148) Control (n=152) # Pts% of 148 #Pts% of 152 p-value Hemodynamic Compromise 9060.87549.30.05 Any Serious Adverse Event Treatment (n=148) Control (n=152) # Pts% of 148 #Pts% of 152 p-value Hemodynamic Compromise 9060.87448.70.14