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FDA Advisory Panel March 5, 2002

FDA Advisory Panel March 5, 2002

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FDA Advisory Panel March 5, 2002

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  1. Medtronic InSync® ICD Cardiac Resynchronization System FDA Advisory Panel March 5, 2002

  2. Agenda

  3. Introduction and Background William T. Abraham, MD

  4. Introduction • Over a third of moderate to severe heart failure patients (in NYHA Functional Class III or IV) have ventricular dysynchrony, evidenced by a QRS duration  130 ms1 • Associated with • Limited exercise tolerance • Impaired quality of life and functional capacity • Poor left ventricular systolic function2 1 Aaronson KD, et al. Circulation 1997; 95:2660-2667. 2 Zardini M, et al. Eur Heart J 2000; 2(Suppl J): J16-J22

  5. InSync Study Design Implant Attempt Successful Implant Pre-discharge Randomization Baseline  1 week Stable Medical Therapy Double Blinded Control CRT 1, 3, 6 Month Follow-up 1, 3, 6 Month Follow-up • Control: VDI mode • Treatment (CRT):VDD mode CRT CRT Long term follow up every 6 months

  6. InSync Study Primary Endpoints* * PMA# P010015, approved 8/28/01

  7. Endpoint Control CRT P value Peak VO2 (ml/kg/min) 0.1 1.0 0.038 Exercise Time (sec) 12 85 <0.001 Composite Response (%) 42,35,23 66,20,14 <0.001 InSync Study Secondary Clinical Endpoints

  8. InSync Primary Safety Results Summary Achieved all primary 6-month safety objectives including: • Implant success 6-month device related complications attributed to: • InSync Model 8040 • Attain Models 2187 and Model 2188 LV leads • InSync system • Attain Models 2187 and 2188 LV lead 6-month pacing threshold

  9. —Control 231 209 197 178 157 150 62 — CRT 230 219 211 184 162 157 73 InSyncDeath or Worsening Heart Failure RequiringHospitalization or IV Medications P = 0.02 CRT Control Patients At Risk

  10. Combining Resynchronization and ICD Function in a Single Device • Model 7272 InSync ICD • Dual-chamber VT and VF detection • Antitachycardia (ATP) pacing, cardioversion and defibrillation VT and VF therapies • Simultaneous biventricular pacing • RV sensing only

  11. Study Design, Methodology andPatient Population James B. Young, MD

  12. Entry Criteria • Chronic heart failure •  18 years of age • NYHA Functional Class II, III or IV • QRS duration  130 ms • LVEF  35% • LVEDD  55 millimeters (echo measure) • Stable HF medical regimen for  1 month • ACE-I or substitute, if tolerated • β-blocker - stable regimen for  3 months • Indication for an ICD

  13. InSync ICD Study Design Implant Attempt Successful Implant Pre-discharge Randomization Baseline  1 week Stable Medical Therapy Double Blinded Control CRT 1, 3, 6 Month Follow-up 1, 3, 6 Month Follow-up • Control: DDI mode • Treatment (CRT):DDD mode • ICD active in all patients • Heart failure medication stability maintained CRT CRT Long term follow up every 6 months

  14. Timing of Baseline Tests

  15. Study Features to Maintain the Blind • Blinded: • Patients (study ID card) • Heart failure staff • Listed on study blinding log • Blinded to ECGs • Conducted QOL, 6 minute hall walk, patients global assessment, NYHA classification and HF exam • Events Classification Committee • Unblinded: • EP staff • Listed on study blinding log • Viewed ECGs, device printouts, etc • Data placed into secure study envelopes

  16. Primary Safety Objectives • InSync ICD-related complication-free survival at 3 months • Attain Model 4189 LV lead-related complication-free survival at 6 months • Attain Model 2187/2188 LV lead- related complication-free survival at 6 months • InSync ICD system-related complication-free survival at 6 months

  17. Secondary Safety Objectives • Characterize patient survival • Characterize complication events • Characterize observation events

  18. Lead Effectiveness Objectives • Implant success • Evaluate the electrical performance of the Model 4189 LV lead • Evaluate the electrical performance of the Model 2187 and Model 2188 LV leads

  19. Evaluation of Integrity of ICD Function • Spontaneous VT/VF therapy effectiveness • Comparison of VT/VF event rates in the control and treatment arms • ATP therapy efficacy with biventricular pacing • Implant ventricular defibrillation criterion

  20. Primary Effectiveness Endpoints • As pre-specified in the investigational plan for NYHA Class III and IV patients, the following change from baseline to 6-month visit between control and treatment groups in: • Quality of life (MLWHF Questionnaire) • NYHA class • 6-minute hall walk distance • As pre-specified in the investigational plan, all 3 endpoints must be met at P < 0.05, or 2 met at P < 0.025, or 1 met at P < 0.0167

  21. Secondary Effectiveness Endpoints Clinical endpoints • Exercise performance • Clinical composite response • Health care utilization Physiological variables • Echocardiographic variables • QRS duration • Neurohormonal variables

  22. Study Milestones PMA Update submitted November 9, 2001 PMA submitted May 3, 2001 1st implant October 4, 1999 100 NYHA Class III & IV 6-month visitsMarch, 2001 224 NYHA Class III & IV 6-month visitsOctober, 2001

  23. Patient Disposition As pre-specified in the I.P., data from NYHA Class III/IV patients are discussed in this presentation Implant Attempts n=636 NYHA Class III/IV n=421 NYHA Class II n=215 Randomized n=362 Randomized n=192 Control n=176 CRT n=186 Control n=106 CRT n=86

  24. Patient Disposition Implant Attempts n=421 Unsuccessful Implants n=50 Implant Success n=371 Not Randomized n=9 Randomized n=362 Control n=176 CRT n=186

  25. Patient Disposition Control n = 176 CRT n = 186

  26. Methodology Overview • Safety Data • As pre-specified in the investigational plan, data from NYHA Class II, III and IV patients were submitted to FDA for the primary safety objectives • At FDA’s request, safety data from NYHA Class III and IV patients only are included in the Panel Pack and in this presentation

  27. Methodology Overview • Efficacy Data • The investigational plan pre-specified that the primary efficacy analysis was to be based on patients with paired data at 6 months, excluding crossovers • Results presented are based on an intent-to-treat analysis for patients with paired data at 6 months, including crossovers • Results of the pre-specified crossover excluded and last-observation-carried forward analyses will also be summarized

  28. Patient Demographics

  29. Patient Demographics

  30. Safety Results Angel R. Leon, MD

  31. Primary Safety Objectives • InSync ICD-related complication-free survival at 3 months • Attain Model 4189 LV lead-related complication-free survival at 6 months • Attain Model 2187/2188 LV lead- related complication-free survival at 6 months • InSync ICD system-related complication-free survival at 6 months

  32. Secondary Safety Objectives • Characterize patient survival • Characterize complication events • Characterize observation events

  33. Lead Effectiveness Objectives • Implant success • Evaluate the electrical performance of the Model 4189 LV lead • Evaluate the electrical performance of the Model 2187 and Model 2188 LV leads

  34. Evaluation of Integrity of ICD Function • Spontaneous VT/VF therapy effectiveness • Comparison of VT/VF event rates in the control and treatment arms • ATP therapy efficacy with biventricular pacing • Implant ventricular defibrillation criterion

  35. Lead Placement and LV Venous Anatomy A. Lateral (marginal) cardiac vein B. Postero-lateral cardiac vein C. Posterior cardiac vein D. Middle cardiac vein E. Great cardiac vein A • Attain LV Model 4189 • Transvenous, 4 French • Stylet/catheter Delivered • Unipolar B C E D

  36. Adverse Event Definitions • Complication: An adverse event requiring invasive intervention or that results in the death of or serious injury to the patient or in the termination of a significant device function • Observation: An adverse event not requiring invasive intervention or resolves spontaneously • System-related complication: A device-related complication that occurs after the initially implanted functioning system, comprised of: Model 7272 InSync ICD, a Model 4189, 2187 or 2188 LV lead, and RA and RV leads

  37. Implant Success Patient Implant Attempts n=421 Unsuccessful Implants n=50 Implant Success n=371 • Implant success defined per the protocol as a successfully placed LV lead.

  38. Unsuccessful Implants (n=50) * Not mutually exclusive

  39. Adverse Events During the Implant Procedure

  40. Resolution of Adverse Events During the Implant Procedure *Categories not mutually exclusive.

  41. Resolution of Implant Dissection/Perforation Events 432 implant attempts 22 events (22 patients) No patient deaths related to these events.

  42. Primary Safety Objective 1: Freedom From InSync ICD Related Complications at 3 Months • 371 patients implanted • 7 complications in 7 patients • Observed 3-month rate = 98.6% • Lower 95% confidence bound = 97.6% • Performance objective: 95% LCB  89% Performance Objective

  43. Freedom From InSync ICD Related Complications at 3 Months 371 patients implanted 7 events (7 patients)

  44. Primary Safety Objective 2: Freedom From Attain Model 4189 LV Lead-Related Complications at 6 Months • 315 patients implanted • 49 events (in 44 patients) • Observed 6-month rate = 85.1% • Lower 95% confidence bound = 81.7% • Performance objective: 95% LCB  75% Performance Objective

  45. Freedom From Attain Model 4189 LV Lead-Related Complications at 6 Months 315 patients implanted 49 events (44 patients) * Not mutually exclusive

  46. Attain Model 4189 LV Lead Related Complication Event Resolution * Not mutually exclusive

  47. Primary Safety Objective 3:Freedom From Attain Model 2187/2188 LV Lead-Related Complications at 6 Months • 56 patients implanted • 5 events in 5 patients • Observed 6-month rate = 89.9% • Lower 95% confidence bound = 82.9% • Performance objective: 95% LCB  75% Performance Objective

  48. Freedom From Attain Model 2187/2188 LV Lead-Related Complications at 6 Months 56 patients implanted 5 events (5 patients)

  49. Primary Safety Objective 4:InSync ICD System-Related Complications at 6 Months • 371 patients implanted • 79 events in 65 patients • Observed 6 month rate = 81.1% • Lower 95% confidence bound = 77.6% • Performance objective: 95% LCB  67% Performance Objective

  50. Primary Safety Results: Summary All primary safety objectives satisfied • Device-related complications attributed to: • InSync ICD Model 7272 • Attain Models 4189, 2187 and 2188 leads • InSync ICD system