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The New Era Begins HeartMate II ® Left Ventricular Assist System (LVAS)

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1 The New Era Begins HeartMate II ® Left Ventricular Assist System (LVAS)

2 2 Contents  Introducing the HeartMate II  Indications for use  Clinical experience

3 3 HeartMate II LVAS  A surgically implanted, rotary continuous-flow device in parallel with the native left ventricle – Left ventricle to ascending aorta  Percutaneous driveline  Electrically powered – Batteries & line power  Fixed speed operating mode  Home discharge

4 4 Benefits of a Rotary Device  Smaller size – 60% Smaller than HeartMate I (XVE) – 35 mm diameter – 70 mm long – 280 grams  No requirement for venting ―40% reduction in the size of percutaneous lead  Enhanced patient comfort  Silent, vibration-free operation  Ease of surgical implantation ―Standard sternotomy vs. extended midline excision ―Smaller preperitoneal pocket  Designed for extended durability

5 Key Design Features  Elegant Design – Valveless – Only one moving part, the rotor – Blood immersed bearings designed for minimization of blood damage – All motor drive and control electronics are outside of the implanted blood pump  Two piece outflow conduit  Speed range: 6,000 to 15,000 rpm  Flow range: 3 – 10 L/min

6 6 System Components  Implanted Components: – Implantable titanium blood pump  External Components: – System Controller – System Monitor – Display Module – Power Sources  Power Module  Batteries & Clips  Emergency Power Pack – Accessories

7 HeartMate II LVAS Pump  Flexible inflow conduit  Textured surfaces – Inlet cannula, inflow and outflow elbows – Thrombo-resistant  Outflow graft with bend relief  Anastomosed to LV apex and ascending aorta  Pump output varies over cardiac cycle – Follows native pulse – Afterload sensitive

8 HM II Pump External View Inflow Conduit (20 mm) Flex Section - Pre-clotted, knitted polyester graft - Titanium ring - Silastic sleeve Percutaneous lead (8 mm) Blood Pump Bend Relief Outflow Graft (14 mm)

9 9 Pump Rotor and Stators Flow Outflow Stator Inflow Stator Inflow Bearings Outflow Bearing Rotor

10 HM II System Controller Microprocessor that:  Delivers power to the pump  Controls pump speed and power  Monitors, interprets & responds to system performance  Performs diagnostic monitoring  Indicates hazard and advisory alarms  Provides complete backup system  Automatic event recording  Data logger capabilities

11 11 HeartMate II Power Sources  AC power from Power Module (PM)  DC power from a pair of 14-volt lithium-ion batteries and clips  DC power from the Emergency Power Pack (EPP)

12 12 14-Volt Lithium-Ion Batteries  Full work day of support on a single charge (10 hours per pair)  Weigh approx 1 pound each  Smart technology results in optimal charging, accurately gauges charge level and ensures battery lifespan (up to three years)  Four hour recharge for fully discharged battery

13 13 Universal Battery Charger  Rapid charging (4 hours for 4 batteries) minimizes the number of batteries required for excursions – reduces the burden of battery management  Continuous diagnostic testing and automatic calibration delivers consistent battery performance Intuitive light indicators provide readily-accessible battery status  Highly portable – 8 pounds

14 14 Power Module  Supplies AC power to HM II  Provides 30 minutes of backup power in case of AC power failure  Simple, effective light indicators and audio alarms give immediate feedback on system operation  Automobile port offers patients the added convenience of “plugging in” while in the car  Repeats alarms generated by the System Controller  Powers the System Monitor and Display Module for system programming and monitoring purposes

15 15 Emergency Power Pack  Single use battery pack enclosed in a plastic carrying case with a shoulder strap  Provides battery power to the HM II in the event of extended power outage  Approximately 12 hours of support  Must be replaced if used for a period exceeding three hours

16 16 Shared HeartMate Components System Monitor  Provides data about HM II function when the patient is on tethered operation  Six screens, touch interface  The only place in the system where the fixed rate setpoint and low speed limit can be adjusted  Ability to download HM II data & view system controller event recorder  Appropriate software implemented upon system controller connection Display Module  Provides a display of system performance (pump rate, pulsatility, flow,and alarms)

17 17 Contents  Introducing the HeartMate II  Indications for use  Clinical experience

18 18 Indications for Use  Bridge to Transplant – Non-reversible left heart failure – Imminent risk of death – Candidate for cardiac transplantation  Destination Therapy — NYHA Class IIIB or IV heart failure — Optimal medical therapy 45 of last 60 days — Not candidate for cardiac transplantation  For in-patient and out-patient use

19 19 Considerations  No trial data on BSA < 1.3 m², use medical judgment  Limited data on pediatric patients (Age < 18 years)  Ability to tolerate / allergy toward anticoagulation  Social support  Acceptance of blood products  Pregnancy  Nonreversible end organ failure

20 20 Contents  Introducing the HeartMate II  Indications for use  Clinical experience

21 21 Worldwide Clinical Experience * 2-3 years = 1151 3-4 years = 428 4-5 years = 174 5-6 years = 73 6-7 years = 19 7 -8 years = 3 8-9 years = 1 (ongoing) More than 10,000 patients worldwide have now been implanted with the HeartMate II LVAS. As of June 2012 *Based on clinical trial and device tracking data

22 22 Worldwide Clinical Experience > 10,000 Patients Implanted Pilot Trial n=53 Pivotal Trial n=1315* *as treated Commercial Experience n>9000 Bridge to Transplant n=490 Destination Therapy n=825 CE Mark: Nov. 2005 FDA: Jan. 2010FDA: Apr. 2008 CE Mark: Nov. 2005 Health Canada: May 2009 BTT ApprovalsDT Approvals (+114 XVEs) Health Canada: Nov. 2010 As of Apr 2012

23 23 Summary of BTT Outcomes ReferenceStudyEnrollment period nSurvival to Tx, Recovery, or Ongoing Device Support at 180 Days Miller, Pagani, Russell et al NEJM 357:885-896, 2007 HM II Pivotal Trial 3/05- 5/0613379% Pagani, Miller, Russell et al JACC 54:312-321, 2009 HM II Pivotal Trial 3/05- 3/0728184% Starling, Naka, Boyle et al JACC 57(19): 1890-9, 2011. Post Approval Study 4/08 – 8/0816990% John, Ann Thorac Surg 19: 1406-13. 2011 Post-trial Study 4/08-9/10149689%

24 24 BTT Actuarial Survival Post Approval Study a John et al.ATS 2011 b Starling et al JACC 2011 d Pagani et al JACC 2009 e Miller et al NEJM 2007

25 Study Backgrounds Post-Approval Study 1 Initiated post-BTT approval to assess outcomes in a broader patient care environment First approved study to use INTERMACS The first 169 consecutive HM II patients enrolled in INTERMACS – Listed or likely to be listed for transplant Enrolled across 77 centers from April to August 2008 Patients followed for at least 1 year Post-trial Study 2 Assess outcomes in a broad, commercial setting 1496 commercial HM II patients enrolled in INTERMACS Enrolled across 83 centers from April 2008 to Sept 2010 – Listed or likely to be listed for transplant Patients followed for at least 1 year 25 1. Starling RC, Naka Y, Boyle AJ, et al. Results of the Post-U.S. Food and Drug Administration-Approval Study With a Continuous Flow Left Ventricular Assist Device as a Bridge to Heart Transplantation. JACC 2011; 57(19): 1890-8. 2. John R, Naka Y, et. al. Continuous Flow Left Ventricular Assist Device Outcomes in Commercial Use Compared with the Prior Clinical Trial. Ann Thorac Surg 2011; 92:1406-13.

26 26 Study Endpoints & Quality of Life Primary Endpoint: – Survival Secondary Endpoint – Adverse events Reported upon occurrence Quality of Life – EuroQol scale determined at baseline and 3, 6, and 12 months post-implant

27 27 Demographics, Patient Characteristics & INTERMACS Profiles 1. John R, Naka Y, et. al. Continuous Flow Left Ventricular Assist Device Outcomes in Commercial Use Compared with the Prior Clinical Trial. Ann Thorac Surg 2011; 92:1406-13. 2. Starling RC, Naka Y, Boyle AJ, et al. Results of the Post-U.S. Food and Drug Administration-Approval Study With a Continuous Flow Left Ventricular Assist Device as a Bridge to Heart Transplantation. JACC 2011; 57(19): 1890-8. CharacteristicTrial Group 1 n = 486 Post Approval Study 2 n = 169 Posttrial Group 1 n= 1496 BSA, m21.99 ± 0.272.03 ± 0.252.05 ± 0.29 IABP Use42% 33% IV Inotropes90%80% INTERMACS Profile Starling Post- Approval Study 2 n = 169 Posttrial Group 1 n= 1496 1 – critical cardiogenic shock 24%16.8% 2 – progressive decline 37%44.6% 3 – inotrope dependent 20%19.9% Profiles 4 – 718%18.7% 60+% of commercial HM II patients were in INTERMACS profiles 1 & 2 ProfileDescription 1Critical cardiogenic shock 2Progressive decline 3Stable, but inotrope dependent 4Recurrent advanced heart failure 5Exertion intolerant 6Exertion limited 7Advanced NYHA III

28 28 Adverse Events Patients in the commercial environment experienced a reduced or similar rate of adverse events in a broader patient care environment compared to clinical trial patients. Only 10% of HM II patients in a commercial setting had GI bleeding 3 Adverse EventTrial 1 n = 486Post Approval Study 2 n = 169 Posttrial Group 1 n= 1496 Stroke Ischemic Hemorrhagic Unknown 0.05 eppy 0.0 eppy 0.06 eppy 0.01 eppy 0.06 eppy 0.02 eppy Bleeding requiring surgery0.23 eppyNR0.12 eppy RVAD7%3%1% Device Replacement (through 12 months)5%NR1% 1. John R, Naka Y, et. al. Continuous Flow Left Ventricular Assist Device Outcomes in Commercial Use Compared with the Prior Clinical Trial. Ann Thorac Surg 2011; 92:1406-13. 2. Starling RC, Naka Y, Boyle AJ, et al. Results of the Post-U.S. Food and Drug Administration-Approval Study With a Continuous Flow Left Ventricular Assist Device as a Bridge to Heart Transplantation. JACC 2011; 57(19): 1890-8.

29 29 Study Outcomes Survival was 89-90% at 6-months and 85% at 12-months –The difference between commercial and trial groups was statistically significant Higher percentage of patients continuing on device support at 1 year in the posttrial group versus the trial. –45% vs. 32%, respectively SurvivalTrial 1 n = 486Post Approval Study 2 n = 169 Posttrial 1 n = 1496 6 months84%90%89% 12 months75%85% % ongoing6 months12 months Post trial 3 66%45% Trial 1 53%32% 1. John R, Naka Y, et. al. Continuous Flow Left Ventricular Assist Device Outcomes in Commercial Use Compared with the Prior Clinical Trial. Ann Thorac Surg 2011; 92:1406-13. 2. Starling RC, Naka Y, Boyle AJ, et al. Results of the Post-U.S. Food and Drug Administration-Approval Study With a Continuous Flow Left Ventricular Assist Device as a Bridge to Heart Transplantation. JACC 2011; 57(19): 1890-8.

30 30 Quality of Life Improvements seen here from the post-trial study with ~1500 patients are consistent with the improvements observed during the pivotal trial and the post- approval study John R, Naka Y, et. al. Continuous Flow Left Ventricular Assist Device Outcomes in Commercial Use Compared with the Prior Clinical Trial. Ann Thorac Surg 2011; 92:1406-13.

31 31 Discussion/Conclusions The HM II post-approval & post-trial studies demonstrate a significant improvement in survival outcomes in a broader patient care setting. Dramatic improvements in QoL, first seen during the BTT pivotal trial, continue to be observed Factors contributing to improving trends: – Improved timing of patient referral – Better patient selection – Enhanced implantation techniques – Improved post-op patient management – Increased knowledge and team training – Higher surgery volume – More dedicated coordinators and experienced patient care teams

32 32 Summary of DT Outcomes ReferenceStudyEnrollment period nOne-Year Survival Two-Year Survival Slaughter, Rogers, Milano et al N NEJM 2009;361:2241-51 HM II Pivotal Trial 3/05- 5/0713468%58% Park, S, et al Circ Heart Fail 2012. HM II Pivotal Trial 5/07- 3/0931173%63%

33 33 Improvements in DT Survival Park, S, et al Circ Heart Fail 2012. Early Trial vs Mid Trial * P value adjusted for body surface area

34 34 DT Trial CAP: Background Survival in Destination Therapy Trials 2 Background Initial HeartMate II Destination Therapy (DT) trial demonstrated significant improvements in outcomes compared to randomized patients with pulsatile LVADs 1 – 68% survival at 1 year – 58% survival at 2 years Over 500 additional DT patients have been enrolled under continued access protocol (CAP) 1 Slaughter MS, Rogers JG, Milano CA et al: Advanced heart failure treated with continuous-flow left ventricular assist device. N Engl J Med. 2009 Dec 3;361(23):2241-51. 2 Fang JC: Rise of Machines – Left Ventricular Assist Devices as Permanent Therapy for Advanced Heart Failure N Engl J Med. 2009 Dec 3;361(23):2282-84. Park, S, et al Circ Heart Fail 2012.

35 35 DT Trial CAP: Overview & Baseline Trial Overview and Baseline Characteristics Park, S, et al Circ Heart Fail 2012.

36 36 DT Trial CAP: Adverse Event Summary Improvements in Adverse Event Rates: Early to Mid Trial Stroke (events per pt-year) Infection (events per pt-year) *** Relative Risk Ratio *p<0.05 **p<0.01 * Park, S, et al Circ Heart Fail 2012.

37 37 DT Trial CAP: Functional Class Improvements 6-Minute Walk Test and NYHA Functional Class I & II Park, S, et al Circ Heart Fail 2012.

38 38 DT Trial CAP: Conclusions & Inference Source: Park SJ, AHA 2010 Trend towards improving survival – Fewer deaths from hemorrhagic stroke Significant reductions in adverse events: – Hemorrhagic stroke >50% reduction – Device related infections >35% reduction – Sepsis >25% reduction Both QoL measures (KCCQ and MLWHF) demonstrated significant improvement over baseline values What is the magnitude of absolute survival benefit with LVAD DT therapy? Conclusions 73% 63%

39 39 Appendix Appendix A: BTT Pivotal Trial Outcomes

40 40 BTT Commercial Outcomes INTERMACS Annual Report Jan 2010 – 88% Survival (n=548) Kirklin JK et al: JHLT 2010

41 41 HeartMate II Pivotal Trial  FDA approved Investigational Device Exemption (IDE) for two clinical studies: 1.Bridge to Transplantation (BTT) – patients enrolled at 33 sites —Primary cohort enrollment completed May, 2006 —Six month follow-up completed November, 2006 —Approved April, 2008 2.Destination Therapy (DT) – patients enrolled at 38 sites ―Randomized 2:1; HeartMate II vs. HeartMate I ―Primary cohort enrollment completed May, 2007 ―Two year follow-up completed May, 2009 ―Approved January, 2010

42 42  New York Heart Association Class IV heart failure symptoms  Transplant listed 1A or 1B (if 1B meet hemodynamic criteria)  On inotropic support  No severe end-organ dysfunction/failure  Ability to tolerate anticoagulant or antiplatelet therapies  No moderate to severe aortic insufficiency without plans for correction BTT Clinical Trial Entry Criteria

43 43 BTT Clinical Trial Design  Multicenter, non-blinded, non-randomized, prospective study  Primary outcomes were death, transplantation, myocardial recovery, or survival to 180 days on LVAS support.  Secondary outcomes included functional status, quality of life, 30-day and 1-year post-transplant survival

44 44 BTT Clinical Trial  Bridge to Transplant (n=281)* ―Primary Cohort  133 pts at 26 sites  Enrollment: March 2005 to May 2006 —CAP (Continued Access Protocol) Cohort  148 patients at 32 sites  Enrollment: May 2006 to April 2008 * Patients implanted with at least 18 month follow up.

45 45 HeartMate II Initial BTT Results (n=133) NEJM 2007;357:885-96.

46 46 HeartMate II BTT Long-term Results (n=281) JAAC 2009;54(4):312-21.

47 47 BTT Clinical Trial Outcomes  Primary Study Outcomes ―Transplantation ―Ongoing device support ―Recovery of ventricular function and device explantation Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

48 48 BTT Clinical Trial Outcomes  Secondary Outcomes ―Overall survival to transplantation ―Frequency of adverse events ―Functional Status (NYHA, 6 minute walk) ―Quality of Life (MLWHF, KCCS) ―Survival following transplantation (30 d and 1 yr) Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

49 49 ParameterMedian (range) (n = 281) Age (yrs)54 (15-70) Etiology43% ischemic Gender % Female24% BSA (m 2 ) All Males Females 1.99 (1.33-2.62) 2.06 (1.45-2.62) 1.68 (1.33-2.57) UNOS Status56% 1A 44% 1B Patient Demographics (n=281) Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

50 50 Baseline Data (n=281) ParameterMean ± SD (n = 281) LVEF (%)16 ± 7 LVEDD (mm)70 ± 12 CI (L/min/m 2 )2.1 ± 0.6 PCWP (mmHg)25 ± 8 Systolic BP (mmHg)98 ± 15 Creatinine (mg/dl)1.4 ± 0.5 BUN (mg/dl)30 ± 17 ALT (U/L)106 ± 278 Na (mmol/l)134 ± 5 Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

51 51 Percent of Patients (n = 281) CRT48% Intravenous inotropes90%* Two or more inotropes32% IABP45% *10% of patients were intolerant to inotropes because of ventricular arrhythmias. Baseline Data (n=281) Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

52 52 P<0.001 Cardiac Index PCWP Hemodynamic Response Pagani F, ISHLT, 2009.

53 53 Support Duration (n=281)  Median duration: 155 days (longest: 3.1 yr)  Average duration: 237 days  181 pt-years cumulative support  87% patients discharged ―78% on device support ―10% following transplant (prior to index discharge)  77% of time (140 pt-years) spent out of hospital Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

54 54 Primary Outcomes at 18 months OUTCOMEPatients (% of Total) (n = 281) Transplantation157 (56%) Ongoing Device Support58 (20.6%) Cardiac Recovery7 (2.5%) Overall222 (79%) Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

55 55 OUTCOMEPatients (% of Total) (n = 281) Expired on Device56 (20%) Device replaced with another type of LVAD3 (1%) Overall59 (21%) Unsuccessful Outcomes at 18 months Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

56 56 Competing Outcomes Analysis (n=281) Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

57 57 Kaplan-Meier Survival (n=281) Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

58 58 Post-transplant Survival  30 Days Post-Transplant —150/157 (96%)  1 Year Post-Transplant —135/157 (86%) John, ISHLT 2009

59 59 Patients (%) (n=281) Cause of DeathN % of deaths % of implants Sepsis1120%4% Right heart failure713%2.5% MOF59%1.8% Ischemic stroke59%1.8% Hemorrhagic stroke59%1.8% Internal components (2 thrombosis, 1 elbow disconnect, 1 graft twisted)47%1.4% External components (2 loss of power, 1 perc lead trauma)35%1.1% Other1628%6% Causes of Death (56/281) Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

60 60 Patients (n=281) Adverse Eventpts% of pts Bleeding: requiring re-exploration7226% Infection: Local non-device related8430% Sepsis4917% Device-related: percutaneous lead / (pump pocket)37 (5)13% (2%) Ventricular arrhythmias: cardioversion / defibrillation5620% Renal failure3011% Adverse Events (1 of 2) Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

61 61 Patients (n=281) Adverse Eventpts% of pts Right heart failure* (RVAD subset)53 (17)19% (6% RVAD) Perioperative stroke (day 0-2)52% Ischemic stroke (after day 2)114% Hemorrhagic stroke (after day 2)93% Other neurological events (eg, TIA, seizures, confusion, etc)218% Hemolysis114% *Use of RVAD or extended inotrope use > 14 days, or starting after 14 days Adverse Events (2 of 2) Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

62 62 HeartMate II BTT (181.0 pt yrs) HeartMate VE BTT (86.2 pt yrs) Event# EventsEvents/pt yr# EventsEvents/pt yr Risk Ratio (95% CI) Stroke250.14380.44 0.34 (0.19 - 0.59) Other non-stroke Neurologic Event 240.13580.67 0.21 (0.12 - 0.35) Bleeding requiring Surgery 820.451271.47 0.31 (0.21 - 0.45) Percutaneous Lead Infection 480.263013.49 0.09 (0.06 - 0.13) RHF requiring RVAD170.09260.30 0.31 (0.16 - 0.60) Frazier, Rose, Oz et al JTCVS 2001 Adverse Event Rate Comparison – HM II (n=281) vs HM I (n=280) Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

63 63 Serious Device Events  LVAD Replaced: n=12 (4.3%) —4 Device thrombosis (including 2 deaths*) —4 Percutaneous lead wire damage —3 Complications of surgical implantation —1 Percutaneous lead / pump pocket infection  LVAS Related Deaths n=7 (2.5%) —4 internal Components  2 Device thrombosis*  1 Outflow elbow disconnect  1 Inflow graft twisted —3 External Components / Patient-related  2 Batteries depleted or Incorrectly Replaced  1 Accidental percutaneous lead trauma  LVAD Pump Mechanical Failure: 0 Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

64 64 HeartMate II Freedom from Major Device Failure or Replacement 6 mo: 96±1% 12 mo: 93±2 % 18 mo: 92±3% Remaining at risk 281 131 72 52 Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

65 65 n= 271 235 175 128 30 + 88 166 + 168 244 + 218 285 + 235 Functional Status – 6 Minute Walk Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

66 66 59% 83%82% 0% n= 259 213 169 120 Functional Status – NYHA Class I or II 98 percent of patients were NYHA Class IV at baseline. Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

67 67 n=226 201 166 120 71 + 24 58 + 27 44 + 24 38 + 25 Better QoL Absolute Scores +18%+38%+47% % = improvement from baseline Minnesota Living with Heart Failure Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

68 68 n=224 204 165 118 31 + 26 47 + 23 57 + 21 63 + 22 Overall Summary Scores Better QoL +42%+84%+103% % = improvement from baseline Kansas City Cardiomyopathy Questionnaire Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

69 69 Observations / Conclusions  Effective hemodynamic support and improvement in functional status and quality of life  At 18 months since implant, 79 percent of patients survived to transplantation, recovery, or ongoing support.  Actuarial survival (Kaplan-Meier) for ongoing support: 72% at 18 months.  Acceptable risk profile for serious adverse events.  Validates original findings regarding efficacy and risk profile of the HM II in this patient population as a BTT, with encouraging longer term results. Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

70 70 Appendix Appendix B: DT Pivotal Trial Outcomes

71 71 HeartMate II Pivotal Trial  FDA approved Investigational Device Exemption (IDE) for two clinical studies: 1.Bridge to Transplantation (BTT) – patients enrolled at 33 sites —Primary cohort enrollment completed May, 2006 —Six month follow-up completed November, 2006 —Approved April, 2008 2.Destination Therapy (DT) – patients enrolled at 38 sites ―Randomized 2:1; HeartMate II vs. HeartMate I ―Primary cohort enrollment completed May, 2007 ―Two year follow-up completed May, 2009 ―Approved January, 2010

72 72 Improving DT Outcomes Two Center (Advocate Christ-Duke) Results Slaughter, Milano, Blue et al ISHLT 2010

73 73 History of DT – REMATCH Trial NEJM 2001;345(20):1435-43.

74 74 History of DT – REMATCH Trial  Randomized clinical trial – optimal medical therapy vs. pulsatile flow LVAD  Non-transplant candidates (n=129) – EF ≤ 25%, – peak VO2 < 12 ml/kg/min, – or continuous infusion inotropes  FDA approval for HM I (XVE) as destination therapy NEJM 2001;345(20):1435-43.

75 75 HeartMate II DT Results (n=200) NEJM 2009;361(23):2241-51.

76 76 Comparison of HM I (XVE) and HM II HM IHM II Weight (gm)1250280 Volume (ml)45063 NoiseAudibleSilent Moving partsManyOne Maximal flow (l/min)* 10 Clinical Durability (yr) 1.5Est. > 5 * at mean pressure=100 mm Hg HM II with controller and batteries HM I HM II

77 77  LVEF ≤ 25%  Peak VO2 < 14 ml/kg/min (or 50% age/sex predicted)  And either —NYHA Class IIIB or IV heart failure symptoms despite optimal medical therapy for at least 45 of prior 60 days or —Dependence on IV inotropes for at least 14 days, or —Dependence on an IABP for at least 7 days  Not a candidate for transplantation  No irreversible renal, pulmonary or hepatic dysfunction or active infection HM II DT Clinical Trial Entry Criteria NEJM 2009;361(23):2241-51.

78 78 DT Clinical Trial Design  Multicenter, non-blinded, randomized, prospective study  200 patients randomized 2:1 (HeartMate II: HeartMate I (XVE))  Primary composite end-point (Intention-to-Treat): – Survival at 2 years without disabling stroke (Rankin score > 3) or re-operation to replace or repair the device  Secondary endpoints (As-Treated): – Actuarial survival – Functional status: NYHA class, 6 minute walk distance – Quality of Life: Minnesota Living with Heart Failure and Kansas City Cardiomyopathy Questionnaires – Adverse Events NEJM 2009;361(23):2241-51.

79 79 DT Clinical Trial Design Met entry criteria and enrolled in primary study cohort (n=200); March 2005 – May 2007 Randomized 2:1 Allocation Follow-up Analysis Allocated to CF LVAD (n=134) Received allocated LVAD (n=130) Failed to receive allocation (n=4) Not implanted (n=3) Implanted with PF LVAD (n=1) Lost to follow-up (n=0) Discontinued Intervention (n=19, 14%) Transplant (n=17), Explanted (n=1) Withdrew (n=1) Analyzed (n=134 ITT; n=133 AT) Excluded from analysis: Primary endpoint (ITT; n=0) Secondary endpoints (AT; n=23) Did not received allocated device (n=4) After discontinuation of intervention (n=19) Allocated with PF LVAD (n=66) Received allocated device (n=58) Failed to receive allocation (n=8) Not implanted (n=5) Implanted with CF LVAD (n=3) Lost to Follow-up (n=0) Discontinued Intervention (n=32, 49%) Transplant (n=9), Explanted (n=5) Device failure and replacement with CF LVAD (n=18) Analyzed (n=66 ITT; 59 AT) Excluded from analysis: Primary endpoint (ITT; n=0) Secondary endpoint (AT; n=40) Did not receive allocated device (n=8) After discontinuation of intervention (n=32)

80 80 Baseline Characteristics Characteristic CF LVAD (HM II) (n=134) PF LVAD (HM I) (n=66)p Age (yrs)62 ± 1263 ± 120.81 Female19%8%0.04 BSA (m 2 )2.0 ± 0.32.1 ± 0.30.54 Ischemic Etiology66%68%0.75 Prior stroke16%17%0.84 Contraindications to TX Age Obesity Pulmonary Hypertension Diabetes Renal dysfunction Non-compliance/ social issues Recent history of cancer 37% 14% 10% 9% 8% 7% 36% 8% 3% 12% 6% 9% 12% NEJM 2009;361(23):2241-51.

81 81 Baseline Characteristics Characteristic CF LVAD (n=134) PF LVAD (n=66)p LVEF (%)17.0 ± 5.516.8 ± 5.40.81 Central venous pressure (mmHg)13 ± 613 ± 80.67 PCWP (mmHg)24 ± 824 ± 90.82 Cardiac Index (l/min/m2)2.0 ± 0.62.1 ± 0.60.36 Serum sodium (mmol/L)134.7 ± 4.3133.9 ± 6.00.31 Serum creatinine (mg/dL)1.6 ± 0.61.8 ± 0.70.08 Concomitant therapies Inotropic agents CRT ICD IABP Mechanical ventilation 77% 63% 83% 22% 7% 83% 59% 79% 23% 9% 0.36 0.64 0.56 1.00 0.57 DT Risk Score high/very high 10.4 ± 5.4 18 % 9.9 ± 4.7 8 % 0.78 0.06 NEJM 2009;361(23):2241-51.

82 82 Primary Endpoint Survival at 24 months, free from disabling stroke or re-operation for device replacement (intention-to-treat) Primary Composite Endpoint (% of Patients) P<0.001 62/134 (46%) 7/66 (11%) NEJM 2009;361(23):2241-51.

83 83 Actuarial Survival NEJM 2009;361(23):2241-51.

84 84 Actuarial Survival vs REMATCH NEJM 2009;361(23):2241-51.NEJM 2001;345(20):1435-43.

85 85 Adverse Events NEJM 2009;361(23):2241-51.

86 86 Leading Causes of Death CAUSE OF DEATH HeartMate II (N=133) XVE (n=59) Hemorrhagic stroke12 (9%)6 (10%) Right Heart Failure6 (5%)5 (8%) Sepsis5 (4%)3 (5%) External Power Interruption5 (4%)0 (0%) Respiratory Failure4 (3%)1 (2%) Cardiac Arrest4 (3%)1 (2%) Bleeding4 (3%)0 (0%) Multisystem Organ Failure2 (2%)4 (7%) Pocket Infection0 (0%)3 (5%) Device Thrombosis2 (2%)0 (0%) Device Failure3 (2%)2 (3%) Ischemic Stroke1 (1%)3 (5%) NEJM 2009;361(23):2241-51.

87 87 Functional Status NEJM 2009;361(23):2241-51.

88 88 Quality of Life NEJM 2009;361(23):2241-51.

89 89 Summary and Conclusions Advanced heart failure patients failing optimal therapies have a poor prognosis The HeartMate II continuous flow LVAD significantly increases survival, free of disabling stroke and re- operation to replace or repair the device at 2 years Greater than 2 fold improvement in survival at 2 years compared to the XVE LVAD Continuous flow LVADs were associated with a reduction in clinically meaningful adverse event rates NEJM 2009;361(23):2241-51.

90 90 Summary and Conclusions Continuous flow LVAD patients experienced early and sustained improvement in exercise capacity, functional class and quality of life Results support the use of continuous flow LVAD therapy for long term support in advanced heart failure patients NEJM 2009;361(23):2241-51.


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