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PROTECT II William O’Neill, Neal Kleiman, Jose Henriques, Simon Dixon, Joseph Massaro, Ioana Ghiu, Brijeshwar Maini, Suresh Mulukutla, Vladimir Dzavik,

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Presentation on theme: "PROTECT II William O’Neill, Neal Kleiman, Jose Henriques, Simon Dixon, Joseph Massaro, Ioana Ghiu, Brijeshwar Maini, Suresh Mulukutla, Vladimir Dzavik,"— Presentation transcript:

1 PROTECT II 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 1 Prospective Multicenter Randomized Trial Comparing IMPELLA to IABP in High Risk PCI: 90 Day Results 2011

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

3 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. ClinicalTrials.gov identifier: NCT Assumption: 20% Major Adverse Events (MAE) rate for Impella vs. 30% for IABP, Power=80%, alpha=5%, N=654 patients.

4 PROTECT II Trial Design IMPELLA PCI IMPELLA PCI IABP + PCI IABP + PCI Primary Endpoint = 30-day Composite MAE* rate 1:1 R 4 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% 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% 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

5 112 INVESTIGATOR SITES OPENED Principal Investigators and Clinical Research Coordinators USA, Canada, Europe 112 INVESTIGATOR SITES OPENED Principal Investigators and Clinical Research Coordinators USA, Canada, Europe DATA SAFETY MONITORING BOARD (DSMB) DATA SAFETY MONITORING BOARD (DSMB) DATA MANAGEMENT, DATA MONITORING, EVENTS ADJUDICATION, STATISTICAL ANALYSES Harvard Clinical Research Institute DATA MANAGEMENT, DATA MONITORING, EVENTS ADJUDICATION, STATISTICAL ANALYSES Harvard Clinical Research Institute ANGIO CORELAB Harvard Beth Israel Deaconess ANGIO CORELAB Harvard Beth Israel Deaconess PROTECT II Committees & Partners ECHO CORELAB Duke Clinical Research Institute ECHO CORELAB Duke Clinical Research Institute SPONSOR ABIOMED, Inc. SPONSOR ABIOMED, Inc. CLINICAL EVENTS COMMITTEE (CEC) CLINICAL EVENTS COMMITTEE (CEC) 5 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) 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 EXECUTIVE COMMITTEE William O’Neill (Chair), Magnus Ohman, Neal Kleiman, Simon Dixon, Jose Henriques

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

7 PROTECT II Enrollment & Milestones Patients Enrolled *PROTECT II DSMB Stopping rule for futility = C *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 Goal: 654 pts Interim analysis Final analysis

8 PROTECT II Study Flow 8 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. IMPELLA 30day N= day F/U, N=213 IMPELLA 30day N= day F/U, N=213 IABP 30day N= day F/U, N=210 IABP 30day N= day F/U, N=210 Per Protocol (PP) population (N=426) Intent-To-Treat (ITT) population (N=447) IMPELLA N= day F/U, N=222 IMPELLA N= day F/U, N=222 IABP N= day F/U, N=220 IABP N= day F/U, N=220 RandomizedIntent-to-TreatN=447RandomizedIntent-to-TreatN=447 Not Eligible: N= % Met Exclusion criteria 47.8% Met Exclusion criteria 30% Patient refusal, MD decision 30% Patient refusal, MD decision 13% Unknown 13% Unknown 9.2% Referred for CABG 9.2% Referred for CABG (N=12) (N=9) 1 withdrew consent post PCI (alive) 1 EF >=35% 1 Not 3VD or ULM 3 Active MI 1 Severe PVD 1 Platelets< 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 Assessed for Eligibility N=1082 N=1082

9 Baseline Characteristics Patient Characteristics IABP () (N=223)Impella () (N=224)p-value Age 67±11 68± Gender-Male 81.2%79.5% History of CHF 83.4%91.1%0.015 Current NYHA (Class III / IV)54.8%58.1% 0.5 Diabetes Mellitus50.7%52.2%0.7 Implantable Cardiac Defib. 31.1%34.8% 0.4 Prior CABG 28.7% 38.4% 0.03 LVEF24.1± ± STS Mortality score 6±76±60.8 Not Surgical Candidate64.1%63.4%0.9 Syntax score pre-PCI29±1330±

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

11 Procedural Differences Procedural Characteristics IABP(N=223)Impella(N=224)p-value Use of Heparin82.4%93.5% <0.001 IIb/IIIa Inhibitors26.1%13.5% Total Contrast Media (cc)241±114267± Rotational Atherectomy (RA)9.5%14.9% Median # of RA Passes/lesion (IQ range) 1 (1-2)3 (2-5) Median # of RA passes/pt (IQ range) 2.0 ( )5.0 ( ) Median RA time/lesion (IQ range sec) 40 (20-47)60 (40-97) RA of Left Main Artery3.1%8.0% % of SVG Treatment or RA use17.5%25.4% Total Support Time (hour)8.2± ±2.7 <0.001 Discharge from CathLab on device37.7%5.7% <

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

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

14 90 day MAE Relative Risk [95% CI] Group p-value Interaction p-value 0.79 [0.64, 0.98] [0.55, 0.89] [0.79, 1.98] [0.55, 1.28] [0.62, 1.00] [0.74, 1.66] [0.57, 0.93] [0.60, 1.32] [0.59, 0.97] Pre-Specified Sub-group Analysis (PP) 14 With Atherectomy (n=52) Without Atherectomy (n=371) STS ≥ 10 (n=70) STS < 10 (n=353) 1 st Impella/IABP Pt per site (n=116) After 1 st Impella/IABP Pt (n=307) ULM / Last conduit (n=100) 3VD (n=323) Anatomy PCI Procedure STS Mortality Score Roll in subject Overall – Per Protocol (n=423) Impella betterIABP better Per Protocol (PP)= Patients that met all incl./ excl. criteria.

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

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

17 Practical Implications of PROTECT II 17

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

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

20 20

21 21 Conclusion The use of Impella for hemodynamic support during high risk PCI is safe.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.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.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.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.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: ) and 2xULN for Spontaneous MI (Universal MI definition)

22 Appendix 22

23 Primary Endpoint Death (all cause mortality)Death (all cause mortality) Myocardial infarction (> x3 ULN in CK-MB or Troponin)Myocardial infarction (> x3 ULN in CK-MB or Troponin) Stroke/TIAStroke/TIA Repeat revascularization (Any PCI/CABG post index procedure)Repeat revascularization (Any PCI/CABG post index procedure) Need for cardiac/vascular operation or vascular operation for limb ischemiaNeed for cardiac/vascular operation or vascular operation for limb ischemia Acute renal dysfunctionAcute renal dysfunction Increase in Aortic insufficiency by more than one gradeIncrease in Aortic insufficiency by more than one grade Hypotension (  SBP <90 mmHg for ≥ 5 min requiring pressor or IV fluid)Hypotension (  SBP <90 mmHg for ≥ 5 min requiring pressor or IV fluid) CPR or Ventricular arrhythmia requiring cardioversionCPR or Ventricular arrhythmia requiring cardioversion Angiographic failureAngiographic failure Combined Major Adverse Events 23

24 PROTECT II Top 20 Enrollers 24 Site#PtsLeadersLocation University of Alabama, AL40 Dr Zoghbi / Dr Misra/ DrAqel Mount-Sinai Medical Ctr, NY 26 Dr Sharma / Dr Kini University of Miami, FL25 Dr Heldman / Dr O’Neill Columbia University, NY21 Dr Collins / Dr Moses Pinnacle Health Med Ctr, PA21Dr Maini Banner Good Sam. Med Ctr, AZ 17 Dr Pershad / Dr Byrne Methodist DeBakey, TX15Dr Kleiman VA Medical Ctr Dallas, TX14Dr Banerjee Univ. of Pittsburgh Med Ctr, PA14Dr Mulukutla Academic Med. Ctr, Amsterdam, NL 11Dr Henriques Site#PtsLeadersLocation Toronto General Hospital, CAN9Dr Dzavik Massachusetts General Hosp, MA 9Dr Palacios UT Medical School at Houston, TX 9 Dr Denktas Liberty Hosp, MO9Dr Kramer University of Rochester, NY9Dr Ling Intermountain Medical Ctr, UT 8Dr Revenaugh Emory Univ. Hosp Midtown, GA8Dr Liberman York Hospital, PA8 Dr Nicholson/ Dr Tolerico Northern Michigan Hosp, MI 8Dr Cannon Providence Hospital, MI8Dr David

25 PROTECT II MAE Outcome 25 Per Protocol Patient Population Per Protocol= Patients that met all incl./ excl. criteria. ↓ 30% MAEp=0.003N=181N=190 Without Atherectomy (N=374) p=0.009N=183N=191 ↓ 30% MAE IABP IMPELLAp=0.100N=215N=211 ↓ 21% MAEp=0.029N=213N=210 All Patients (N=426)

26 26 * Stone et al, Circulation 2001;104: ; Differential Impact of CK-MB Ratios on Outcomes

27 27 With Peri-procedural MI Definition = Cardiac Biomarkers>3xULN IMPELLA IABP Log rank test, p=0.649 **8xULN (or Q-wave) is used as a relevant threshold for Peri-procedural MI (Stone et al, Circulation 2001;104: ). For Spontaneous MI (i.e, MI occurring after 72hours), 2xULN were used, unchanged from PROTECT II definition. With Peri-procedural MI Definition = Cardiac Biomarkers>8xULN** IMPELLA IABP Log rank test, p=0.505 Differential Impact of CK-MB Level and MI Incidence in PROTECT II


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