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FDA Recommended Study Design for CABG Anastomosis Devices

Cardica Proximal Anastomosis System 510k 0304034 Wolf Sapirstein MPH, FACS Clinical Review FDA/CDRH/ODE. FDA Recommended Study Design for CABG Anastomosis Devices. Observational Study 510K clearance Effectiveness: LCB for 95% CI, 80% angiographic patency at 6-months

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FDA Recommended Study Design for CABG Anastomosis Devices

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  1. Cardica Proximal Anastomosis System510k 0304034Wolf Sapirstein MPH, FACSClinical ReviewFDA/CDRH/ODE FDA Clinical Presentation

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

  3. PAS-Port Study 1 • Enrolled 55 patients • Failed Use 8 patients • Implanted 47 patients; 54 devices • Not Evaluated 2 withdrew; 1 discontinued • Angiograms 39 in 44 patients; 42 grafts 82.9% cases implanted • Patent grafts 36 of 42 grafts 85.7%, LCB 73.7% • Not followed 2 Deaths; 3 discontinued • Stress-ECG 36 of 42 patients/1 positive 78.2% living FDA Clinical Presentation

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

  5. PAS-Port Study 1Safety • MACE (12/24 months 42 patients) • Deaths 2 (4.7%) • Myocardial Infarction 1 (2.3%) • Graft occlusion 6 (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 • Myocardial Ischemia 3; Infarction 1; Revasc 4 • Hospital event rates similar to historical data bases FDA Clinical Presentation

  6. Enrolled 54 patients (133 Consented and 118 enrolled in parent study) PAS-Port Intended 63 devices Failed Implant 2 patients Implanted 52 patients, 59 devices Hospital Death 2 patients Discontinued 4 patients Six-month Angio. 38 of 46 patients 45 of 47 grafts patent One-year Follow-up: 46 patients One-year Stress-ECG: 42 patients Negative Stress test 38 patients PAS-Port StudyCohort 2 FDA Clinical Presentation

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

  8. PAS-Port Study Cohort 2Safety • MACE • Death 4 (7.6%) • Myocardial Infarction 0 • Graft Occlusion/stenosis 5 (9.6%) • 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 • Myocardial Ischemia 6 (11.5%) • Revascularization 9 (17.3%) • Graft stenosis 11 (21.1%) FDA Clinical Presentation

  9. PAS-PortCombined Study 1 and Cohort 2 • Enrollment 109 patients • Failed Implants 12 patients • Implants 97 patients • Hospital deaths 2 patients • Lost follow-up 7 patients • 6-month Angio 77 patients (90 grafts) • Angio patent 81 grafts (89 grafts) • Imputed Patency 17 patients • MSCT/MRI patent 10 patients • Stress-ECG negative 5 patients • CCS 2 patients • 12/24 Month Stress-ECG 78 patients • Ischemic 5 patients FDA Clinical Presentation

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

  11. PAS-Port Patency Imputation • 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 ECG 2 patients • Died 1 patient • Suture Conversions (8 patients) • Stress ECG 7 patients • CCS 1 patient FDA Clinical Presentation

  12. PAS-PortImputed Patency • Cohort 2 • Implants (50 patients) • Angio 38 patients (73.7 % all implants) 45 grafts of 47 implants (95.7%) • MSCT 5 patients • Stress-ECG 3 patients • CCS 2 patients • Suture Conversions (2 patients) • CCS 2 patients FDA Clinical Presentation

  13. Study Design Limitations • Modification to study protocols after study initiation • 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: • Inclusion criteria different • Cohort 2 retrospective enrollment • Cohort 2 employed 2 experimental devices • Baseline variability • Instrument modification FDA Clinical Presentation

  14. Safety and Effectiveness Concerns • Angiography • Study 1: 39 of 47 patients implanted (82.9%) • Cohort 2: 38 of 52 patients implanted (73%) • Imputation of Patency (Combined groups) • 20 of 97 implanted patients (20%) • 26 of 109 intent to treat (23.8%) • Imputation Criteria (Combine groups) • MRI/MSCT 10 • Stress ECG 11 • CCS 5 FDA Clinical Presentation

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

  16. PAS-Port Anastomosis System Study Conclusions • Study 1 did not meet the pre-specified effectiveness hypothesis. • 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. • The attribution of several adverse events as “non-device related” is questionable. FDA Clinical Presentation

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