1. FDA Clinical Presentation1 Cardica Proximal Anastomosis System 510k 0304034 Wolf Sapirstein MPH, FACS Clinical Review FDA/CDRH/ODE

2. FDA Clinical Presentation2 FDA Recommended Study Design for CABG Anastomosis Devices Observational Study Observational Study 510K clearance 510K clearance Effectiveness: Effectiveness: LCB for 95% CI, 80% angiographic patency at 6-months LCB for 95% CI, 80% angiographic patency at 6-months One year clinical evaluation with Stress-ECG. One year clinical evaluation with Stress-ECG. Safety: Safety: Procedure adverse events. Adverse events to 1 year Procedure adverse events. Adverse events to 1 year MACE (Mortality; TVR; Myocardial infarction) MACE (Mortality; TVR; Myocardial infarction) Control: Control: Sutured anastomosis Sutured anastomosis Historical Historical FitzGibbon FitzGibbon

3. FDA Clinical Presentation3 PAS-Port Study 1 –Enrolled 55 patients –Failed Use8 patients –Implanted47 patients; 54 devices –Not Evaluated2 withdrew; 1 discontinued –Angiograms39 in 44 patients; 42 grafts 82.9% cases implanted –Patent grafts36 of 42 grafts 85.7%, LCB 73.7% –Not followed2 Deaths; 3 discontinued –Stress-ECG 36 of 42 patients/1 positive 78.2% living

4. FDA Clinical Presentation4 PAS-Port Study 1 Effectiveness Observed Patency (6-Month Angio.) Observed Patency (6-Month Angio.) 36 of 42 implants in 39 patients 36 of 42 implants in 39 patients 85.7%, LCB 73.7% Imputed Patency Imputed Patency 43 of 50 implants in 47 implanted patients 43 of 50 implants in 47 implanted patients 86.0%, LCB 75.3% Intention to treat (Imputed) Intention to treat (Imputed) CABG procedures patent in 50 of 60 grafts 83.3%, LCB 71.4% CABG procedures patent in 50 of 60 grafts 83.3%, LCB 71.4% Device grafts patent in 43 of 60 grafts Device grafts patent in 43 of 60 grafts 71.1%, LCB 59.0%

5. FDA Clinical Presentation5 PAS-Port Study 1 Safety MACE (12/24 months 42 patients) MACE (12/24 months 42 patients) –Deaths2 (4.7%) –Myocardial Infarction1 (2.3%) –Graft occlusion6 (14%) –K-M estimate of rate at 24 Months: 20.2% (UCB 30.1%) of 47 patients per protocol 17.5% (UCB 26.2%) of 55 intent to treat patients Non-Device Adverse events Non-Device Adverse events –Myocardial Ischemia 3; Infarction 1; Revasc 4 –Hospital event rates similar to historical data bases

6. FDA Clinical Presentation6 PAS-Port Study Cohort 2 Enrolled54 patients Enrolled54 patients (133 Consented and 118 enrolled in parent study) –PAS-Port Intended 63 devices –Failed Implant 2 patients Implanted52 patients, 59 devices Implanted52 patients, 59 devices –Hospital Death 2 patients –Discontinued4 patients Six-month Angio.38 of 46 patients Six-month Angio.38 of 46 patients –45 of 47 grafts patent One-year Follow-up:46 patients One-year Follow-up:46 patients –One-year Stress-ECG:42 patients –Negative Stress test 38 patients

7. FDA Clinical Presentation7 PAS-Port Study Cohort 2 Effectiveness Observed Patency (6-month angio) Observed Patency (6-month angio) 45 of 47 grafts patent in 38 patients 45 of 47 grafts patent in 38 patients 95.7%, LCB 87.2% 95.7%, LCB 87.2% Imputed Patency (All device grafts) Imputed Patency (All device grafts) 55 of 59 grafts 55 of 59 grafts 93.0%, LCB 85% 93.0%, LCB 85% Imputed Patency (Intent to treat) Imputed Patency (Intent to treat) 57 of 63 CABG procedures (all intended) 57 of 63 CABG procedures (all intended) 90.5%, LCB 80% 90.5%, LCB 80%

8. FDA Clinical Presentation8 PAS-Port Study Cohort 2 Safety MACE MACE Death4 (7.6%) Death4 (7.6%) Myocardial Infarction0 Myocardial Infarction0 Graft Occlusion/stenosis5 (9.6%) Graft Occlusion/stenosis5 (9.6%) K-M estimated rates at 1 year: K-M estimated rates at 1 year: –Per Protocol (50 patients) 12.7% (UCB 20.7%) –Intent to Treat (54 patients) 15.5% (UCB 23.6%) Adverse Events Adverse Events Myocardial Ischemia6 (11.5%) Myocardial Ischemia6 (11.5%) Revascularization9 (17.3%) Revascularization9 (17.3%) Graft stenosis 11 (21.1%) Graft stenosis 11 (21.1%)

9. FDA Clinical Presentation9 PAS-Port Combined Study 1 and Cohort 2 Enrollment109 patients Enrollment109 patients Failed Implants12patients Failed Implants12patients Implants97patients Implants97patients Hospital deaths2patients Hospital deaths2patients Lost follow-up7patients Lost follow-up7patients 6-month Angio77 patients (90 grafts) 6-month Angio77 patients (90 grafts) Angio patent81 grafts (89 grafts) Angio patent81 grafts (89 grafts) Imputed Patency17patients Imputed Patency17patients MSCT/MRI patent 10patients MSCT/MRI patent 10patients Stress-ECG negative 5 patients Stress-ECG negative 5 patients CCS2 patients CCS2 patients 12/24 Month Stress-ECG78 patients 12/24 Month Stress-ECG78 patients Ischemic5patients Ischemic5patients

10. FDA Clinical Presentation10 PAS-Port Combined Study 1 and Cohort 2 Effectiveness Observed Patency for 99 patients Observed Patency for 99 patients 81 of 89 grafts in 77 patients 81 of 89 grafts in 77 patients 91%, LCB 84% 91%, LCB 84% Imputed Patency Device for 107 patients Imputed Patency Device for 107 patients 98 of 109 grafts 98 of 109 grafts 89.9%, LCB 83.8% 89.9%, LCB 83.8% Imputed Patency Intent to Treat (grafts) Imputed Patency Intent to Treat (grafts) 107 patent CABG grafts in 123 grafts 107 patent CABG grafts in 123 grafts 87%, LCB 87%, LCB

11. FDA Clinical Presentation11 PAS-Port Patency Imputation Study 1: Study 1: –Implants (47 patients) –Angio: 39 patients evaluated 36 (85.7%) of 42 grafts patent 72% of all 50 implants –MRI 5 patients –Stress ECG2 patients –Died1 patient –Suture Conversions (8 patients) –Stress ECG 7 patients –CCS1 patient

12. FDA Clinical Presentation12 PAS-Port Imputed Patency Cohort 2 Cohort 2 Implants (50 patients) Implants (50 patients) –Angio 38 patients (73.7 % all implants) 45 grafts of 47 implants (95.7%) –MSCT5 patients –Stress-ECG3 patients –CCS2 patients Suture Conversions (2 patients) Suture Conversions (2 patients) –CCS2 patients

13. FDA Clinical Presentation13 Study Design Limitations Study Design Limitations Modification to study protocols after study initiation Modification to study protocols after study initiation Cohort 2 sample stratified from a study enrolled under a different protocol for a different CABG device Cohort 2 sample stratified from a study enrolled under a different protocol for a different CABG device Problems with Pooling of Study 1 and Cohort 2: Problems with Pooling of Study 1 and Cohort 2: Inclusion criteria different Inclusion criteria different Cohort 2 retrospective enrollment Cohort 2 retrospective enrollment Cohort 2 employed 2 experimental devices Cohort 2 employed 2 experimental devices Baseline variability Baseline variability Instrument modification Instrument modification

14. FDA Clinical Presentation14 Safety and Effectiveness Concerns Safety and Effectiveness Concerns Angiography Angiography –Study 1: 39 of 47 patients implanted (82.9%) –Cohort 2: 38 of 52 patients implanted (73%) Imputation of Patency (Combined groups) Imputation of Patency (Combined groups) –20 of 97 implanted patients (20%) –26 of 109 intent to treat (23.8%) Imputation Criteria (Combine groups) Imputation Criteria (Combine groups) MRI/MSCT10 MRI/MSCT10 Stress ECG11 Stress ECG11 CCS5 CCS5

15. FDA Clinical Presentation15 Safety and Effectiveness Concerns (cont’d) Safety and Effectiveness Concerns (cont’d) Stress ECG Stress ECG 36 of 45 survivors  1 Ischemia 36 of 45 survivors  1 Ischemia 39 of 48 survivors  4 Ischemia 39 of 48 survivors  4 Ischemia Thrombo-Embolism Thrombo-Embolism Two events Two events Stenosis/Occlusion Stenosis/Occlusion 11 Stenoses 11 Stenoses 9 Ischemia 9 Ischemia 1 Myocardial infarction 1 Myocardial infarction MACE MACE PAS-Port CABG supplied <= 22% Left Ventricle PAS-Port CABG supplied <= 22% Left Ventricle

16. FDA Clinical Presentation16 PAS-Port Anastomosis System Study Conclusions Study 1 did not meet the pre-specified effectiveness hypothesis. Study 1 did not meet the pre-specified effectiveness hypothesis. The poolability of Study 1 and Cohort 2 is problematic. The poolability of Study 1 and Cohort 2 is problematic. Angiographic follow-up of patients is incomplete. The Sponsor relied on imputations with non-invasive technologies to assess patency. Angiographic follow-up of patients is incomplete. The Sponsor relied on imputations with non-invasive technologies to assess patency. The attribution of several adverse events as “non-device related” is questionable. The attribution of several adverse events as “non-device related” is questionable.