CDRH Panel Meeting June 22, 2005

1. 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 FDA Clinical Review

2. 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.” FDA Clinical Review

3. 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 FDA Clinical Review

4. 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 FDA Clinical Review

5. 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. FDA Clinical Review

6. 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. FDA Clinical Review

7. 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 cardiacprocedures and mortality • # of hospitalizations, hospital days and ICU days FDA Clinical Review

8. Baseline Characteristics FDA Clinical Review

9. 50 45 40 35 MLWHF 30 % Missing follow-up data SF36 25 20 Peak VO2 15 6' walk 10 5 0 Treatment Control 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. FDA Clinical Review

10. Results: Primary Composite Endpoint FDA Clinical Review

11. Mortality (as of April 15, 2005) % of patients FDA Clinical Review

12. 30 Day Operative Mortality by YearNoMVR Stratum FDA Clinical Review

13. Hospitalized Patients for HF REMATCH VMAC OPT FIRST OMM ESCAPECorCap Control SBP 121 120 107 103 106111 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 FDA Clinical Review

14. 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) ESCAPE 17.4 vs. 20.9 (6 mos) CorCap 14 vs. 13 1 year Mortality Study Control vs Tx FDA Clinical Review Adapted from LW Stevenson, presentation for REMATCH

15. 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 FDA Clinical Review

16. 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 FDA Clinical Review

17. Major CardiacProcedures: MVR Stratum FDA Clinical Review

18. Major CardiacProcedures: NoMVR Stratum FDA Clinical Review

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

20. Cardiac Transplant Status FDA Clinical Review

21. 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 FDA Clinical Review

22. 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 FDA Clinical Review

23. NYHA by Core Lab FDA Clinical Review

24. NYHA-Site Assessed FDA Clinical Review

25. QOL by MLWHF FDA Clinical Review

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

27. CPX data, peak VO2 FDA Clinical Review

28. 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. FDA Clinical Review

29. Structural Endpoints (at 12 mos) FDA Clinical Review

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

31. 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 FDA Clinical Review

32. 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 FDA Clinical Review

33. 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 FDA Clinical Review

34. Clinical Experience (Charité) 10 10 10 9 8 10 11 10 11 Values are averages 10 8 10 FDA Clinical Review

35. Clinical Experience (Charité) FDA Clinical Review

36. n-71 n=106 n=80 n=104 Brain Natriuretic Peptide (BNP) FDA Clinical Review

37. 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. FDA Clinical Review

38. Adverse Events Related to Hemodynamic Compromise p =0.053 p =0.14 Treatment group n=148 Control group n=152 FDA Clinical Review

39. <30 days SAE’s FDA Clinical Review

40. 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 FDA Clinical Review

41. 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. FDA Clinical Review

42. 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. FDA Clinical Review

43. FDA Clinical Review

44. Structural Endpoints (at 12 mos) FDA Clinical Review

45. Brain Natriuretic Peptide (BNP) FDA Clinical Review

46. Adverse Events Related to Hemodynamic Compromise FDA Clinical Review