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PROTECT II

PROTECT II. Prospective Multicenter Randomized Trial Comparing IMPELLA to IABP in High Risk PCI: 90 Day Results.

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PROTECT II

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  1. PROTECT II Prospective Multicenter Randomized Trial Comparing IMPELLA to IABP in High Risk PCI: 90 Day Results William O’Neill, Neal Kleiman, Jose Henriques, Simon Dixon, Joseph Massaro, Ioana Ghiu, Brijeshwar Maini, Suresh Mulukutla, Vladimir Dzavik, James Revenaugh, Hadley Wilson, Karim Benali, Magnus Ohman On behalf of all PROTECT II Investigators 2011

  2. Background • Patients with depressed LV function and complex anatomy have limited treatment options with the majority not eligible for CABG • Prophylactic IABP hemodynamic support is used for ~28,000 high risk PCI patients annually in the US1 • Impella provides superior hemodynamic support compared to IABP2,3 • PROTECT II is the first FDA approved, prospective, multicenter study for patients requiring hemodynamic support during high risk PCI comparing outcomes between IABP and Impella 2.5 2Maini et al, USpella registry TCT 2010. 3Seyfarth et al. JACC 2008;52(19):1584-8 1 Health Research International 2009 report: - #0514-1-US-1209-204.

  3. Trial Hypothesis & Assumption Hypothesis: That the Impella system is superior to Intra-aortic balloon pump (IABP) in preventing intra- and post-procedural major adverse events. Assumption: 20% Major Adverse Events (MAE) rate for Impella vs. 30% for IABP, Power=80%, alpha=5%, N=654 patients. ClinicalTrials.gov identifier: NCT00562016

  4. PROTECT II Trial Design Patients Requiring Prophylactic Hemodynamic Support During Non-Emergent High Risk PCI on Unprotected LM/Last Patent Conduit and LVEF≤35% OR 3 Vessel Disease and LVEF≤30% R 1:1 IABP + PCI IMPELLA 2.5 + PCI Primary Endpoint = 30-day Composite MAE* rate Follow-up of the Composite MAE* rate at 90 days *Major Adverse Events (MAE) : Death, Stroke/TIA, MI (>3xULN CK-MB or Troponin) , Repeat Revasc, Cardiac or Vascular Operation of Vasc. Operation for limb ischemia, Acute Renal Dysfunction, Increase in Aortic insufficiency, Severe Hypotension, CPR/VT, Angio Failure

  5. PROTECT II Committees & Partners SPONSOR ABIOMED, Inc. DATA SAFETY MONITORING BOARD (DSMB) Regional Leaders: Brij Maini (North-East, USA) Hadley Wilson (South-East, USA) Suresh Mulukutla (East, USA) Simon Dixon (Central, USA) Neal Kleiman (Plains, USA) Jim Revenaugh (West, USA) Vlad Dzavik (Canada) Jose Henriques (Europe) EXECUTIVE COMMITTEE William O’Neill (Chair), Magnus Ohman, Neal Kleiman, Simon Dixon, Jose Henriques CLINICAL EVENTS COMMITTEE (CEC) DATA MANAGEMENT, DATA MONITORING, EVENTS ADJUDICATION, STATISTICAL ANALYSES Harvard Clinical Research Institute ANGIO CORELAB Harvard Beth Israel Deaconess 112 INVESTIGATOR SITES OPENED Principal Investigators and Clinical Research Coordinators USA, Canada, Europe ECHO CORELAB Duke Clinical Research Institute

  6. PROTECT II Sites That Enrolled Royal Alexandra St. Joseph’s Univ. of Alberta Univ. of Washington Ottawa Heart Boston, MA: Boston Medical Ctr Brigham & Women’s Mass General Hosp St. Elizabeth’s Toronto General Strong Memorial Northern Michigan Henry Ford Aurora St. Luke’s Robert Packer Providence Hospital Sutter Memorial William Beaumont Moffitt Heart Hartford Hospital Intermountain Med Ctr Calif. Cardiovascular UPMC AGH Oakwood Lankenau Winthrop Univ. Loyola Bryan LGH York Univ of Chicago New York City: Columbia University Mt. Sinai Weill Cornell Riverside Morristown St. Vincent’s Ruby Memorial Liberty Hospital Indiana Univ. Geisinger Good Samaritan St. Louis Univ. Univ. of Cincinnati Univ. of Kansas Univ of Maryland King’s Daughters Duke Owensboro Washington Adventist USC Banner Good Sam Lourdes Hospital Integris Baptist Forsyth Carolina Med Ctr Scripps Clinic Centennial Mercy Gilbert Univ. of OK Alvarado Hospital Emory University UAB VA Dallas Med College of GA Univ. of Texas Texas Heart Institute Methodist DeBakey Munroe Regional Clear Lake Regional Southwest Methodist AMC Amsterdam Univ. of Miami Texsan 72 Sites Enrolled 67 USA, 4 Canada, 1 Netherlands

  7. PROTECT II Enrollment & Milestones Goal: 654 pts 2/26 to 12/6/2010 Continued Enrollment 69% Achieved 4/3/2011 N=447, ACC Final analysis 2/26/2010 50% Enrollment Achieved Interim analysis Patients Enrolled 12/6/2010 DSMB recommends to halt the study for futility* based on assumption that trends in first half of trial (N=324) will be similar to trends in second half 6/2/2008 510(k) Clearance 2008 2009 2010 2011 11/27/2007 1st Patient *PROTECT II DSMB Stopping rule for futility = Conditional power at interim analysis <40%. All major adverse events were adjudicated. Database not locked yet at the time of ACC’2011

  8. PROTECT II Study Flow Assessed for Eligibility N=1082 • Not Eligible: N=635 • 47.8% Met Exclusion criteria • 30% Patient refusal, MD decision • 13% Unknown • 9.2% Referred for CABG Randomized Intent-to-Treat N=447 IABP N= 223 90day F/U, N=220 IMPELLA N= 224 90day F/U, N=222 Intent-To-Treat (ITT) population (N=447) 1 withdrew consent post PCI (alive) 1 EF >=35% 1 Not 3VD or ULM 3 Active MI 1 Severe PVD 1 Platelets<70000 1 Creatinine>4 2 withdrew consent post PCI (alive) 3 EF >=35% 3 Not 3VD or ULM 1 Active MI 2 Severe PVD or AS 1 Platelets<70000 (N=9) (N=12) Per Protocol (PP) population (N=426) IABP 30day N= 211 90day F/U, N=210 IMPELLA 30day N= 215 90day F/U, N=213 Per Protocol population= Patients that met all inclusion and exclusion criteria. Per Protocol population was pre-specified and patients were identified prospectively prior to the statistical analysis.

  9. Baseline Characteristics

  10. Hemodynamic Support Effectiveness Cardiac Power Output (Secondary Endpoint) Maximal Decrease in CPO on device Support from Baseline (in x0.01 Watts) Impella IABP N=138 N=141 - 4.2 ± 24 p=0.001 - 14.2 ± 27 CPO data available only for 279 patients (N=138 IABP and N=141 Impella) CPO= Cardiac Power Output = Cardiac Output x Mean Arterial Pressure x 0.0022 (Fincke R, Hochman J et al JACC 2004; 44:340-348)

  11. Procedural Differences

  12. PROTECT II MAE Outcome Intent to Treat (N=447) Per Protocol (N=426) IABP p=0.029 p=0.087 IMPELLA ↓ 21% MAE p=0.100 p=0.312 N=223 N=224 N=220 N=222 N=211 N=215 N=210 N=213 MAE= Major Adverse Event Rate Per Protocol= Patients that met all incl./ excl. criteria.

  13. Study Device Learning Curve Effect Per Protocol Population 90day Outcome (N=423) IABP IMPELLA N=68 N=82 N=82 N=65 N=63 N=63 MAE= Major Adverse Event Rate

  14. Pre-Specified Sub-group Analysis(PP) Overall – Per Protocol (n=423) PCI Procedure Without Atherectomy (n=371) 0.015 With Atherectomy (n=52) Anatomy ULM / Last conduit (n=100) 0.907 3VD (n=323) STS Mortality Score STS ≥ 10 (n=70) 0.043 STS < 10 (n=353) Roll in subject 1st Impella/IABP Pt per site (n=116) 0.923 After 1st Impella/IABP Pt (n=307) 0.0 0.5 1.0 1.5 2.0 Impella better IABP better Per Protocol (PP)= Patients that met all incl./ excl. criteria.

  15. PROTECT II 90-day Outcome (PP) HRPCI w/o Atherectomy (N=371, 88%) HRPCI with Atherectomy (N=52, 12%) IMPELLA IABP IMPELLA IABP Death 35.9% 51.1% (p=0.003) 68.8% 55.0% (p=0.316) Composite MI (>3x ULN) (p=0.784) (p=0.399) 12.5% 10.0% 11.6% 8.9% Stroke/TIA (p=0.03) (p=0.522) 14.9% 17.4% 37.5% 10.0% Repeat Revascularization (p=0.425) (p=0.280) 3.1% 0.0% 1.1% 2.6% Vascular Complication (p=0.006) (p=0.181) 3.1% 30.0% 6.6% 10.5% Acute Renal Dysfunction (p=0.616) (p=0.202) 0.0% 5.0% 2.8% 3.7% Severe Hypotension (p=0.271) (p=0.211) 21.9% 10.0% 7.7% 11.6% CPR / VT (p=0.911) (p=0.400) 9.4% 12.1% 18.8% 20.0% Aortic Insufficiency (p=0.537) 9.4% 15.0% (p=0.411) 12.7% 10.0% Angio Failure 0.0% 0.0% 0.0% 0.0% (p=0.208) 0.0% 0.0% 4.4% 2.1% Per Protocol (PP)= Patients that met all incl./ excl. criteria.

  16. PROTECT II MAE Outcome Pre-specified High Risk PCI Without Atherectomy Group Per Protocol (N=374) Per Protocol (N=374) p=0.003 ↓ 30% MAE p=0.009 IABP ↓ 30% MAE IMPELLA Log rank test, p=0.005 N=191 N=183 N=190 N=181 Per Protocol= Patients that met all incl./ excl. criteria.

  17. Practical Implications of PROTECT II

  18. PROTECT II Outcome** (PP) IABP IMPELLA p=0.038 ↓ 29% MACCE p=0.037 ↓ 38% MACCE p=0.595 N=215 N=211 N=210 N=213 N=210 N=213 In-hospital MACCE Post-Discharge MACCE Total 90 days MACCE MACCE = Death/Stroke or TIA/MI/Repeat Revascularization **Using x8ULN for biomarkers or Q-wave for Peri-procedural MI (Stone et al Circulation 2001;104:642-647) and 2xULN for Spontaneous MI (Universal MI definition)

  19. PROTECT II MACCE** Per Protocol Population, N=426 Death, Stroke, MI, Repeat revasc. IABP IMPELLA Log rank test, p=0.04 **Using x8ULN threshold for biomarkers or Q-wave for Peri-procedural MI (Stone et al Circulation 2001;104:642-647) and 2xULN threshold for biomarkers for Spontaneous MI (Universal MI definition)

  20. Conclusion • The use of Impella for hemodynamic support during high risk PCI is safe. • The superior hemodynamic support of Impella appears to have led to significant procedural differences between the two arms. • Impella arm had strong trends towards superior clinical outcomes for the entire intent-to-treat population with a significant reduction of the MAE rate in the per protocol population at 90 day follow-up. • The clinical benefit was more pronounced for patients undergoing high risk PCI without atherectomy with the Impella support. • There was a significant reduction of the MACCE rate in the per protocol population at 90 day follow-up when a more clinically relevant threshold of CK-MB release for peri-procedural MI** is considered. **Using x8ULN for biomarkers or Q-wave for Peri-procedural MI (Stone et al Circulation 2001;104:642-647) and 2xULN for Spontaneous MI (Universal MI definition)

  21. Appendix

  22. Primary Endpoint Combined Major Adverse Events • Death (all cause mortality) • Myocardial infarction (> x3 ULN in CK-MB or Troponin) • Stroke/TIA • Repeat revascularization (Any PCI/CABG post index procedure) • Need for cardiac/vascular operation or vascular operation for limb ischemia • Acute renal dysfunction • Increase in Aortic insufficiency by more than one grade • Hypotension ( SBP <90 mmHg for ≥ 5 min requiring pressor or IV fluid) • CPR or Ventricular arrhythmia requiring cardioversion • Angiographic failure

  23. PROTECT II Top 20 Enrollers

  24. PROTECT II MAE Outcome Per Protocol Patient Population Without Atherectomy (N=374) All Patients (N=426) p=0.029 p=0.003 IABP IMPELLA ↓ 30% MAE ↓ 21% MAE p=0.009 p=0.100 ↓ 30% MAE N=211 N=215 N=191 N=183 N=190 N=181 N=210 N=213 Per Protocol= Patients that met all incl./ excl. criteria.

  25. Differential Impact of CK-MB Ratios on Outcomes * Stone et al, Circulation 2001;104:642-647;

  26. Differential Impact of CK-MB Level and MI Incidence in PROTECT II With Peri-procedural MI Definition = Cardiac Biomarkers>3xULN With Peri-procedural MI Definition = Cardiac Biomarkers>8xULN** IMPELLA IABP IABP IMPELLA Log rank test, p=0.649 Log rank test, p=0.505 **8xULN (or Q-wave) is used as a relevant threshold for Peri-procedural MI (Stone et al, Circulation 2001;104:642-647). For Spontaneous MI (i.e, MI occurring after 72hours), 2xULN were used, unchanged from PROTECT II definition.

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