Left Ventricular Assist System (LVAS)

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

Contents Introducing the HeartMate II Indications for use
Clinical experience

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

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 Continuous-flow devices have been developed to overcome the limitations of volume-displacement devices, while still providing effective hemodynamic support. These pumps continuously drain blood from the left ventricle to the ascending aorta by the action of an internal rotor. No internal valves are needed. The elimination of the blood pumping chamber required in pulsatile, volume-displacement pumps, allows for continuous flow devices to be made much smaller in size and weight, mitigating size restrictions. 60% smaller than currently approved implanted volume displacement LVADs, and weighing only 400 grams. Venting of air is not required, which allows for a significantly smaller percutaneous lead. The small size and silent operation have the potential to increase patient comfort, expedite surgical implantation, minimize infection and improved quality of life.

Key Design Features Elegant Design Two piece outflow conduit
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 The HeartMate II incorporates precision engineering, a simple design, and 30 years of clinical experience. The rotor spins on precision jeweled ruby bearings. These bearings are blood immersed, lubricated by plasma to prevent heat build up that could damage blood with the potential to cause thrombus formation. There is also the potential for significantly improved durability The percutaneous lead attaches to the external system controller that controls electronics and motor drive. Outflow graft with snap on bend relief allows direct visualization during de-airing and minimizes risk of kinking The rotor is capable of providing flow from 3 to 10 liters per minute at a speed range of 6,000 to 15,000 rpm, covering the full cardiac output of a healthy heart.

System Components Implanted Components: External Components:
Implantable titanium blood pump External Components: System Controller System Monitor Display Module Power Sources Power Module Batteries & Clips Emergency Power Pack Accessories The HeartMate I and II share many of the same components. In September, 2009 new advanced system components were released.

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 The flexible inflow conduit is designed for a wide range of patients, accommodating changes in anatomical position and allowing the inlet to remain centered in the ventricle. Both the inflow conduit and outflow elbow feature textured blood-contacting surfaces clinically proven on the HeartMate XVE to be thrombo-resistant. The flexible inflow conduit is attached to the apex of the left ventricle, and the outflow graft is attached to the ascending aorta. The HeartMate II pumps blood from the weakened left ventricle to the aorta, the main artery feeding blood to the entire body. Although HM II provides continuous flow, the pump output will vary over the cardiac cycle due to changes in LV and aortic pressure during LV diastole and systole. High afterload pressures will impede forward flow resulting in a decreased pump output.

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) Inflow conduit consists of textured titanium inlet cannula and elbow, 20 mm diameter (same as XVE) with a flex section. The flex section consists of the following layers – woven polyester graft “stented” with a titanium ring in the middle (to prevent graft collapse if high negative pressures are generated by the pump), preclotting slots above and below, encased in a silastic rubber sleeve. Flexible inflow section allows for relative movement between the native LV and LVAD. It attaches to the pump with a locking screw ring that is hand tightened. The pump capsule contains an integrated electric motor, rotor and stators which will be discussed on the next slide. Percutaneous lead is 8mm in diameter (velour portion), approximately 40 inches long, and contains 6 wires, 3 primary with a back up for each one, housed in a silastic sleeve with a polyester velour covered portion (12.5 – 13 inches from pump to end of velour) to promote tissue in-growth. At least 2 cm should exit the body to allow in-growth at the exit site and decrease the risk of exit site infection. The metal end attaches to the system controller by aligning the etched black markings. Bend relief is reinforced e-PTFE, a teflon like material. It is secured to the outflow graft with metal clips that attach above the locking screw ring (different than XVE where screw ring is on bend relief). This allows deairing closer to the pump and visualization of the black line on the graft to observe for kinking. It is available in the 4 inch standard length and a stand alone shorter 3 inch length. The outflow graft is constructed of textured titanium and 16mm woven polyester graft with an integrated locking screw ring used to attach it to the outflow elbow. Both the outflow graft and graft in the inflow conduit flex section must be pre-clotted prior to implant. A project is underway to develop pre-sealed grafts that would not require pre-clotting.

Pump Rotor and Stators Flow Inflow Stator Rotor Outflow Stator
The inlet stator, rotor and outlet stator are comprised of smooth titanuim surfaces housed within a thin walled, 12 mm diameter titanium duct that passes through the bore of the motor. The inlet and outlet stators straighten the blood flow as it enters and leaves the pump. The rotor spins on bearings. The hydrostatic, jeweled precision bearings are a ball and cup design lubricated by plasma to prevent overheating that could damage the blood cells. Outflow Bearing Inflow Bearings

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 The system controller has 2 controller boards, one for the primary system and one for complete backup system operation. It has automatic event recording and data logging capabilities. It records and stores pump parameters during all alarm conditions. In addition, the data logger can be set up to record pump parameters routinely at a preset interval from 30 minutes, 1 hour to 24 hours in 1 hour increments. This must be turned on and set up using the system monitor save data screen. It will store a total of 120 events (this includes alarms and non alarm events) then will erase the oldest and store the newest.

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) The Power Module and 14-Volt lithium-ion batteries are part of the advanced system components, referred to as “GoGear”. The new platform was developed to support a patient’s active lifestyle, providing mobility and flexibility in a safe, secure manner.

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 Batteries were characterized over a five year period to ensure optimal operation with the HeartMate system.

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

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

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

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 Although HM I and HM II share peripheral components, the pump parameters and alarms are different between the 2 systems. Display Module Provides a display of system performance (pump rate, pulsatility, flow,and alarms)

Clinical experience

Indications for Use Bridge to Transplant Destination Therapy
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 HeartMate II is the first and only continuous flow LVAD to have received FDA approval for both bridge-to-transplantation and destination therapy.

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 Youngest patients: pilot study 14 year old, pivotal trial 16 year old Oldest patient: 89 Smallest patient within a study: BSA 1.33

Clinical experience

Worldwide Clinical Experience*
More than 10,000 patients worldwide have now been implanted with the HeartMate II LVAS. 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) The clinical basis from which hypotheses regarding the HeartMate II can be derived is rapidly growing. Patients have been supported in excess of seven years. As of June 2012 *Based on clinical trial and device tracking data

Worldwide Clinical Experience
> 10,000 Patients Implanted Pilot Trial n=53 Pivotal Trial n=1315* *as treated Commercial Experience n>9000 (+114 XVEs) Bridge to Transplant n=490 Destination Therapy n=825 More than 9,000 patients have been implanted worldwide. There are published clinical data on nearly 1,400 HM II patients for both BTT and DT in the US and in Europe. With experience, the clinical data have shown improvement and have been consistently favorable. BTT Approvals DT Approvals CE Mark: Nov. 2005 CE Mark: Nov. 2005 FDA: Apr. 2008 FDA: Jan. 2010 Health Canada: May 2009 Health Canada: Nov. 2010 As of Apr 2012

Summary of BTT Outcomes
Reference Study Enrollment period n Survival to Tx, Recovery, or Ongoing Device Support at 180 Days Miller, Pagani, Russell et al NEJM 357: , 2007 HM II Pivotal Trial 3/05- 5/06 133 79% Pagani, Miller, Russell et al JACC 54: , 2009 3/05- 3/07 281 84% Starling, Naka, Boyle et al JACC 57(19): , 2011. Post Approval Study 4/08 – 8/08 169 90% John, Ann Thorac Surg 19: Post-trial Study 4/08-9/10 1496 89% Even as the device moved into the commercial environment, the outcomes have remained favorable and even showed improvement as clinical best practices became established. Pivotal trial outcomes are available in Appendix A.

BTT Actuarial Survival
Post Approval Study The analysis shown here includes outcomes from the pivotal trial, Starling post-approval study and the Ranjit John study of ~1500 commercial BTT patients. Note: The first analysis of BTT patients came from the initial cohort of patients (n=133) enrolled in the HeartMate II BTT Pivotal Trial and shows 75% survival at 6 months and 68% at one year. The second analysis done came from the initial cohort and second cohort of patients (n=281) enrolled in the HeartMate II BTT Pivotal Trial and shows 82% and 73% survival at 6- & 12- months. The post-approval study had n=169 commercial HM II BTT patients with 90% and 85% survival at 6 months and 12 months, respectively Dr. John’s study of 1496 commercial HM II BTT patients with 89% and 85% survival at 6 and 12 months; respectively a John et al.ATS 2011 b Starling et al JACC 2011 d Pagani et al JACC 2009 e Miller et al NEJM 2007

Study Backgrounds Post-Approval Study1 Post-trial Study2
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 Study2 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 In response to requirements set by the FDA for BTT approval, a study was initiated to assess outcomes in a broader, commercial setting. It is the first approved study to utilize the national Interagency Registry for Mechanically Assisted Circulatory Support. The first 169 consecutive HM II patients enrolled in INTERMACS that were listed or likely to be listed for transplant were included in this study. Enrollment took place across 77 centers from April to August Patients were followed for at least 1-year post-implant. The post-trial study is a retrospective review of 1496 commercial HM II patients implanted after BTT approval. Patients were implanted across 83 centers between April 2008 and Sep 2010. 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): 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:

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 The primary endpoint of the study was survival. The secondary endpoint was adverse events, reported upon occurrence. Quality of life was also captured using a determined EuroQoL scale measured at baseline pre-implant and 3,6, and 12 months post-implant.

Demographics, Patient Characteristics & INTERMACS Profiles
Trial Group1 n = 486 Post Approval Study2 n = 169 Posttrial Group1 n= 1496 BSA, m2 1.99 ± 0.27 2.03 ± 0.25 2.05 ± 0.29 IABP Use 42% 33% IV Inotropes 90% 80% INTERMACS Profile Starling Post-Approval Study n = 169 Posttrial Group1 n= 1496 1 – critical cardiogenic shock 24% 16.8% 2 – progressive decline 37% 44.6% 3 – inotrope dependent 20% 19.9% Profiles 4 – 7 18% 18.7% Profile Description 1 Critical cardiogenic shock 2 Progressive decline 3 Stable, but inotrope dependent 4 Recurrent advanced heart failure 5 Exertion intolerant 6 Exertion limited 7 Advanced NYHA III Patient populations in the post-trial study were compared to patients in the post-approval study and to patients in the BTT Pivotal Trial Data points for the pivotal trial are from the Pagani JACC 2009 paper Key Message: Patients in a commercial setting are as sick as the Pivotal trial patients 60+% of commercial HM II patients were in INTERMACS profiles 1 & 2 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: 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):

Adverse Events Adverse Event Trial1 n = 486 Post Approval Study2 n = 169 Posttrial Group n= 1496 Stroke Ischemic Hemorrhagic Unknown 0.05 eppy 0.0 eppy 0.06 eppy 0.01 eppy 0.02 eppy Bleeding requiring surgery 0.23 eppy NR 0.12 eppy RVAD 7% 3% 1% Device Replacement (through 12 months) 5% 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 bleeding3 Improvements in adverse event rates can be attributed to improvements in patient selection and patient management. 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: 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):

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 Survival Trial1 n = 486 Post Approval Study2 n = 169 Posttrial 1 n = 1496 6 months 84% 90% 89% 12 months 75% 85% 89-90% of patients were transplanted, recovered or still ongoing at 6 months post-implant. This is an improvement over the 82% survival at 6 months reported in the later experiences of the pivotal trial. In addition, patients in the commercial setting are waiting longer for a transplant than they did during the trial. % ongoing 6 months 12 months Post trial3 66% 45% Trial1 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: 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):

Quality of Life EuroQoL is the standard quality of life measurement used by the INTERMACS registyr. EuroQoL assesses global QoL of heart failure patients during circulatory support. The improvements seen here are similar to improvements demonstrated in the Minnesota Living with Heart Failure and Kansas City Cardiomyopathy Questionaires observed during the pivotal trial. See Rogers JG, et. al. Continuous flow left ventricular assist device improves functional capacity and quality of life of advanced heart failure patients. JACC. 2010; 55: 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:

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 Due to significant improvements, HeartMate II has rapidly become the gold standard in LVAD therapy. There have been over 9000 advanced heart failure patients who have received the therapy worldwide.

Summary of DT Outcomes Reference Study Enrollment period n
One-Year Survival Two-Year Survival Slaughter, Rogers, Milano et al N NEJM 2009;361: HM II Pivotal Trial 3/05- 5/07 134 68% 58% Park, S, et al Circ Heart Fail 2012. 5/07- 3/09 311 73% 63% In addition to the 200 patients from the primary cohort, an additional 311 patients from the continued access protocol (CAP) have now completed two-year follow-up. Comparing the two cohorts, shows an improvement in one- and two-year survival. Pivotal trial data and REMATCH data is available in Appendix B

Improvements in DT Survival
Early Trial vs Mid Trial Patients enrolled in the CAP cohort have shown better results through two years, at least in-part due to improved patient management techniques. Patient demographics for early vs. mid trial cohorts showed no statistically significant differences except for body surface area and weight. The p-values in the chart have been adjusted to account for the body surface area differences. * P value adjusted for body surface area Park, S, et al Circ Heart Fail 2012.

DT Trial CAP: Background
Survival in Destination Therapy Trials2 Initial HeartMate II Destination Therapy (DT) trial demonstrated significant improvements in outcomes compared to randomized patients with pulsatile LVADs1 68% survival at 1 year 58% survival at 2 years Over 500 additional DT patients have been enrolled under continued access protocol (CAP) When compared to pulsatile-flow devices and medical therapy, the HeartMate II has shown significant improvements in outcomes. Beyond the pivotal trial enrollment, over 500 additional patients were enrolled through a 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 Dec 3;361(23): 2 Fang JC: Rise of Machines – Left Ventricular Assist Devices as Permanent Therapy for Advanced Heart Failure N Engl J Med Dec 3;361(23): Park, S, et al Circ Heart Fail 2012.

DT Trial CAP: Overview & Baseline
Trial Overview and Baseline Characteristics There were no statistically significant differences in patient baseline characteristics between the primary data cohort and the portion of DT CAP patients reviewed here. Park, S, et al Circ Heart Fail 2012.

DT Trial CAP: Adverse Event Summary
Improvements in Adverse Event Rates: Early to Mid Trial Stroke (events per pt-year) Relative Risk Ratio * Infection (events per pt-year) Adverse event rates showed significant improvements between early and mid trial cohorts. Better patient selection and patient management are only a few of the several factors that could contribute to this improvement. A relative risk ratio of 1 would indicate that AE rate was the same between the two cohorts. *p<0.05 **p<0.01 ** * Park, S, et al Circ Heart Fail 2012.

DT Trial CAP: Functional Class Improvements
6-Minute Walk Test and NYHA Functional Class I & II Functional class, as measured by improvements in NYHA Functional class showed significant improvements for both cohorts. 80% + of patients improved to Class I & II from baseline to 6 months with sustained improvements out to two years. Park, S, et al Circ Heart Fail 2012.

DT Trial CAP: Conclusions & Inference
What is the magnitude of absolute survival benefit with LVAD DT therapy? 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 73% 63% There is a trend for improving survival in DT patients. This trend can be contributed to better patient selection, improved timing for patient referral, enhanced surgical techniques, improved post-op patient management, more center experience and higher volumes, and more experienced patient care teams. Adverse event rates also saw significant reductions over the course of the trials. When compared to medical management, as reported in the REMATCH study, LVAD Destination Therapy with the HM II shows enormous improvements in survival. Source: Park SJ, AHA 2010

Appendix A: BTT Pivotal Trial Outcomes

BTT Commercial Outcomes
INTERMACS Annual Report Jan 2010 – 88% Survival (n=548) The INTERMACS registry data on HM II BTT patients shows 88% survival at 6 months across a broader cohort of patients (n=548). Kirklin JK et al: JHLT 2010

HeartMate II Pivotal Trial
FDA approved Investigational Device Exemption (IDE) for two clinical studies: 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 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 The HeartMate II Pivotal Study was an FDA-approved Pivotal trial consisting of a bridge-to-transplantation study and a randomized clinical study for destination therapy evaluation. In the bridge-to-transplantation study, 489 patients were enrolled at 33 sites from March 2005 to March The primary cohort consisted of 133 patients enrolled from march 2005 to May 2006. The randomized destination therapy study enrolled 200 patients from March 2005 to May 2007 in its primary cohort. Two year follow up was completed May Additional patients were enrolled as part of a Continued Access Protocol. Randomization of patients was ended in December, 2008, because a pre-specified interim analysis indicated superiority for the HeartMate II over the HeartMate I (XVE). This was the fastest enrolling trial featuring VADs ever. The Pivotal trial has enrolled VAD patients at a rate 9 times faster than the rate seen in REMATCH.

BTT Clinical Trial Entry Criteria
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 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 The clinical study had a separate, independent Data Safety Monitoring Board and a separate, independent Clinical Events Committee that adjudicated all deaths and adverse events. The study incorporated a “gatekeeper” to ensure adherence to inclusion and exclusion criteria.

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 The clinical data presented here are based on the first 281 patients enrolled in the BTT study, all of whom have 18 month follow up. The first 133 patients were enrolled as part of the primary cohort – 6 month outcomes on these patients were published in the New England Journal in 2007. This larger cohort with 281 patients was published in the Journal of the American College of Cardiology in 2009. * Patients implanted with at least 18 month follow up.

HeartMate II Initial BTT Results (n=133)
The initial results with the primary cohort (n=133) with 6 month follow up were published in the New England Journal of Medicine in 2007. We now present on the primary cohort and the first portion of the continued access protocol (CAP) cohort (n=281) with 18 month follow up. These data were published in the Journal of the American College of Cardiology in 2009. Figure 1. Components of the Continuous-Flow Left Ventricular Assist Device (LVAD). The inflow cannula is inserted into the apex of the left ventricle, and the outflow cannula is anastomosed to the ascending aorta. Blood exits through the left ventricular apex and into the left ventricular assist device, which pumps throughout cardiac diastole and systole into the ascending aorta, with the rotor being the only moving part. The left ventricular assist device pump is placed within the abdominal wall or peritoneal cavity. A percutaneous lead carries the electrical cable to an electronic controller and battery packs, which are worn on a belt and shoulder holster, respectively. NEJM 2007;357:

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

BTT Clinical Trial Outcomes
Primary Study Outcomes Transplantation Ongoing device support Recovery of ventricular function and device explantation Three outcomes were considered a success – support to cardiac transplantation by 18 months, ongoing with device support at 18 months or recovery of sufficient ventricular function such that device support was no longer required with subsequent device explantation by 18 months. Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

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.

Patient Demographics (n=281)
Parameter Median (range) (n = 281) Age (yrs) 54 (15-70) Etiology 43% ischemic Gender % Female 24% BSA (m2) All Males Females 1.99 ( ) 2.06 ( ) 1.68 ( ) UNOS Status 56% 1A 44% 1B The median age of study participants was 54 years. The etiology of the heart failure was ischemic disease in 43% with a majority of other patients suffering from idiopathic cardiomyopathy, reflecting a typical cardiac transplantation population. 24% of the study participants were female representing an approximate 2 fold increase in number of female study participants compared to previously reported device trials due to the small size of the device. The median BSA was 1.99. Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

Baseline Data (n=281) Parameter Mean ± SD (n = 281) LVEF (%) 16 ± 7
LVEDD (mm) 70 ± 12 CI (L/min/m2) 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 Baseline characteristics of the study cohort were consistent with a markedly ill group of patients with decompensated heart failure. Left ventricular ejection fraction was 16%. Cardiac index was 2.1 L/min/m2 and the pulmonary capillary wedge pressure was 25 mmHg on inotrope support. There was moderate renal and hepatic dysfunction present and the serum sodium of the study cohort was 132 mg/dl. Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

Baseline Data (n=281) Percent of Patients (n = 281) CRT 48%
Intravenous inotropes 90%* Two or more inotropes 32% IABP 45% Importantly, 48% of patients failed resynchronization therapy and 90% of patients were on inotropic therapy. The 10% of patients not on inotropic therapy were intolerant due to life threatening ventricular arrhythmias. 45% of patients were supported by an intra-aortic balloon pump at the time of implant. *10% of patients were intolerant to inotropes because of ventricular arrhythmias. Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

Hemodynamic Response Cardiac Index PCWP P<0.001 P<0.001
24 hours following device implantation there was a significant increase in cardiac index and significant decrease in pulmonary capillary wedge pressure. Pagani F, ISHLT, 2009.

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.

Primary Outcomes at 18 months
Patients (% of Total) (n = 281) Transplantation 157 (56%) Ongoing Device Support 58 (20.6%) Cardiac Recovery 7 (2.5%) Overall 222 (79%) Positive outcomes were achieved in 79% of patients by 18 months with the majority of patients undergoing cardiac transplantation. A significant number of patients were still ongoing on support at 18 months, underscoring the device’s ability to support patients for longer periods prior to cardiac transplantation. A small proportion of the successes were attributed to cardiac recovery with subsequent device explantation. Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

Unsuccessful Outcomes at 18 months
Patients (% of Total) (n = 281) Expired on Device 56 (20%) Device replaced with another type of LVAD 3 (1%) Overall 59 (21%) The majority of unsuccessful outcomes by 18 months were due to death with a small number of patients transferred to another type of LVAD. Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

Competing Outcomes Analysis (n=281)
The majority of transplants occurred within the first 8 months with the number of deaths moderating significantly in the 12 to 18 month timeframe. Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

Kaplan-Meier Survival (n=281)
Kaplan-Meier analysis estimates survival during support as 73 percent at 12 months and 72 percent at 18 months. Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

Post-transplant Survival
30 Days Post-Transplant 150/157 (96%) 1 Year Post-Transplant 135/157 (86%) Impressively post-transplant survival has been in line with post-transplant survival of patients bridged to transplant with a device. John, ISHLT 2009

Causes of Death (56/281) Patients (%) (n=281) Cause of Death N % of
deaths implants Sepsis 11 20% 4% Right heart failure 7 13% 2.5% MOF 5 9% 1.8% Ischemic stroke Hemorrhagic stroke Internal components (2 thrombosis, 1 elbow disconnect, 1 graft twisted) 4 7% 1.4% External components (2 loss of power, 1 perc lead trauma) 3 5% 1.1% Other 16 28% 6% The causes of death in the clinical study were adjudicated by the clinical events committee. The most frequent cause of death was sepsis followed by ischemic stroke, multi-organ failure, hemorrhagic stroke, right heart failure, and others. The causes of death were consistent with previously reported clinical studies with LVAD therapy. Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

Adverse Events (1 of 2) Patients (n=281) Adverse Event pts % of pts
Bleeding: requiring re-exploration 72 26% Infection: Local non-device related 84 30% Sepsis 49 17% Device-related: percutaneous lead / (pump pocket) 37 (5) 13% (2%) Ventricular arrhythmias: cardioversion / defibrillation 56 20% Renal failure 30 11% The most frequent adverse events were bleeding requiring re-exploration and infection. Other adverse events included ventricular arrhythmias, renal failure, right heart failure (next slide), and stroke (next slide). Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

Adverse Events (2 of 2) Patients (n=281) Adverse Event pts % of pts
Right heart failure* (RVAD subset) 53 (17) 19% (6% RVAD) Perioperative stroke (day 0-2) 5 2% Ischemic stroke (after day 2) 11 4% Hemorrhagic stroke (after day 2) 9 3% Other neurological events (eg, TIA, seizures, confusion, etc) 21 8% Hemolysis *Use of RVAD or extended inotrope use > 14 days, or starting after 14 days Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

Adverse Event Rate Comparison – HM II (n=281) vs HM I (n=280)
HeartMate II BTT (181.0 pt yrs) HeartMate VE BTT (86.2 pt yrs) Event # Events Events/pt yr Risk Ratio (95% CI) Stroke 25 0.14 38 0.44 0.34 ( ) Other non-stroke Neurologic Event 24 0.13 58 0.67 0.21 ( ) Bleeding requiring Surgery 82 0.45 127 1.47 0.31 ( ) Percutaneous Lead Infection 48 0.26 301 3.49 0.09 ( ) RHF requiring RVAD 17 26 0.30 ( ) A historical comparison to the HeartMate I BTT trial shows a comparative improvement with respect to adverse events. Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009. Frazier, Rose, Oz et al JTCVS 2001

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.

HeartMate II Freedom from Major Device Failure or Replacement
6 mo: 96±1% 12 mo: 93±2% 18 mo: 92±3% Freedom from major device failure or replacement was noted to be 92 percent at 18 months, demonstrating a significant improvement in durability in comparison to pulsatile devices. Remaining at risk Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

Functional Status – 6 Minute Walk
Patients exhibited a significant improvement in six-minute walk over baseline – with the mean walk distance equating to more than 3 (US) football fields. n= Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

Functional Status – NYHA Class I or II
98 percent of patients were NYHA Class IV at baseline. 83% 82% 59% Patients also exhibited a significant improvement in functional status with more than 80 percent improving from Class IV at baseline to Class I or II at 6 months. 0% n= Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

Minnesota Living with Heart Failure
Absolute Scores Significant quality of life improvements were also demonstrated in terms of both the Minnesota Living with Heart Failure Questionnaire… Better QoL +18% +38% +47% n= % = improvement from baseline Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

Kansas City Cardiomyopathy Questionnaire
Overall Summary Scores Better QoL … and the Kansas City Cardiomyopathy questionnaire. +42% +84% +103% n= % = improvement from baseline Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

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.

Appendix B: DT Pivotal Trial Outcomes

HeartMate II Pivotal Trial
FDA approved Investigational Device Exemption (IDE) for two clinical studies: 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 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 The HeartMate II Pivotal Study was an FDA-approved Pivotal trial consisting of a bridge-to-transplantation study and a randomized clinical study for destination therapy evaluation. In the bridge-to-transplantation study, 489 patients were enrolled at 33 sites from March 2005 to March The primary cohort consisted of 133 patients enrolled from march 2005 to May 2006. The randomized destination therapy study enrolled 200 patients from March 2005 to May 2007 in its primary cohort. Two year follow up was completed May Additional patients were enrolled as part of a Continued Access Protocol. Randomization of patients was ended in December, 2008, because a pre-specified interim analysis indicated superiority for the HeartMate II over the HeartMate I (XVE). This was the fastest enrolling trial featuring VADs ever. The Pivotal trial has enrolled VAD patients at a rate 9 times faster than the rate seen in REMATCH.

Slaughter, Milano, Blue et al ISHLT 2010
Improving DT Outcomes Two Center (Advocate Christ-Duke) Results Improvements in survival with experience were also seen with the top two enrollers in the DT trial (Advocate Christ and Duke), which experienced one-year survival of 85%. Two-year follow had not been completed as of the time of this analysis. Slaughter, Milano, Blue et al ISHLT 2010

History of DT – REMATCH Trial
The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) is the only randomized trial of optimal medical therapy and mechanical circulatory support (MCS). The HeartMate I (XVE) was approved for destination therapy as a result of the positive outcomes that were demonstrated in the trial. The trial is widely regarded as being a positive step forward for MCS and as a good proof of concept. There were a number of challenges with the HM I technology that were noted, however primarily related to durability – the average device requires exchange at 18 months. NEJM 2001;345(20):

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 The HeartMate I (XVE) demonstrated superiority in terms of survival at both one and two years over medical therapy. NEJM 2001;345(20):

HeartMate II DT Results (n=200)
The results of the HeartMate II DT Pivotal Trial were published in The New England Journal of Medicine in Nov The publication features the primary cohort of 200 patients of randomized HeartMate II and HeartMate I (XVE) patients. HeartMate XVE was selected as the control arm due to it establishing superiority in the REMATCH trial. NEJM 2009;361(23):

Comparison of HM I (XVE) and HM II
HM II with controller and batteries HM I HM II Weight (gm) 1250 280 Volume (ml) 450 63 Noise Audible Silent Moving parts Many One Maximal flow (l/min)* 10 Clinical Durability (yr) 1.5 Est. > 5 HM I HM II From a design perspective, HeartMate II has a number of advantages over HeartMate I (XVE), including weight, volume, noise, durability and design elegance. * at mean pressure=100 mm Hg

HM II DT Clinical Trial Entry Criteria
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 Entry criteria were very similar to the REMATCH trial. NEJM 2009;361(23):

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 The clinical study had a separate, independent Data Safety Monitoring Board and a separate, independent Clinical Events Committee that adjudicated all deaths and adverse events. The study incorporated a “gatekeeper” to ensure adherence to inclusion and exclusion criteria. NEJM 2009;361(23):

DT Clinical Trial Design
Met entry criteria and enrolled in primary study cohort (n=200); March 2005 – May 2007 Randomized 2:1 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) 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) Allocation 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) Lost to follow-up (n=0) Discontinued Intervention (n=19, 14%) Transplant (n=17), Explanted (n=1) Withdrew (n=1) The as treated cohort differed a small amount from the intent to treat cohort because of a small number of patients lost after randomization, but before implantation and patients who were not able to receive their randomized device due to body habitus or insurance issues. The study incorporated a “gatekeeper” to ensure adherence to inclusion and exclusion criteria. Follow-up 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) 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) Analysis

Baseline Characteristics
CF LVAD (HM II) (n=134) PF LVAD (HM I) (n=66) p Age (yrs) 62 ± 12 63 ± 12 0.81 Female 19% 8% 0.04 BSA (m2) 2.0 ± 0.3 2.1 ± 0.3 0.54 Ischemic Etiology 66% 68% 0.75 Prior stroke 16% 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% 7% 36% 3% 12% 6% Patients in both arms of the trial were similar in terms of baseline characteristics. Enrolled patients reflect a severely ill heart failure population with a number of co-morbidities. NEJM 2009;361(23):

Baseline Characteristics
CF LVAD (n=134) PF LVAD (n=66) p LVEF (%) 17.0 ± 5.5 16.8 ± 5.4 0.81 Central venous pressure (mmHg) 13 ± 6 13 ± 8 0.67 PCWP (mmHg) 24 ± 8 24 ± 9 0.82 Cardiac Index (l/min/m2) 2.0 ± 0.6 2.1 ± 0.6 0.36 Serum sodium (mmol/L) 134.7 ± 4.3 133.9 ± 6.0 0.31 Serum creatinine (mg/dL) 1.6 ± 0.6 1.8 ± 0.7 0.08 Concomitant therapies Inotropic agents CRT ICD IABP Mechanical ventilation 77% 63% 83% 22% 7% 59% 79% 23% 9% 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 Patients in both arms of the trial were similar in terms of baseline characteristics. Enrolled patients reflect a severely ill heart failure population with a number of co-morbidities. NEJM 2009;361(23):

Primary Endpoint Survival at 24 months, free from disabling stroke
or re-operation for device replacement (intention-to-treat) Primary Composite Endpoint (% of Patients) 62/134 (46%) P<0.001 7/66 (11%) HeartMate II demonstrated a 4 fold improvement over HeartMate I (XVE) in terms of the primary endpoint on an intent-to-treat basis. In particular, HeartMate II demonstrated superiority in terms of need to re-operate to replace the device and mortality before two years. The study incorporated a “gatekeeper” to ensure adherence to inclusion and exclusion criteria. NEJM 2009;361(23):

Actuarial Survival Under the as-treated analysis, HeartMate II demonstrated a survival of 68% at one year and 58% at two years. HeartMate I (XVE) demonstrated similar survival to the outcomes with HeartMate I (XVE) in REMATCH. NEJM 2009;361(23):

Actuarial Survival vs REMATCH
A historical comparison shows an impressive improvement in survival with MCS. NEJM 2009;361(23): NEJM 2001;345(20):

Adverse Events There were reductions in most major adverse events and a reduction in the rate of rehospitalizations in comparison to HeartMate I (XVE). HeartMate II was shown to have an ischemic stroke rate comparable to end-stage heart failure without device support. NEJM 2009;361(23):

Leading Causes of Death
CAUSE OF DEATH HeartMate II (N=133) XVE (n=59) Hemorrhagic stroke 12 (9%) 6 (10%) Right Heart Failure 6 (5%) 5 (8%) Sepsis 5 (4%) 3 (5%) External Power Interruption 0 (0%) Respiratory Failure 4 (3%) 1 (2%) Cardiac Arrest Bleeding Multisystem Organ Failure 2 (2%) 4 (7%) Pocket Infection Device Thrombosis Device Failure 3 (2%) 2 (3%) Ischemic Stroke 1 (1%) Leading cause of death for both HeartMate II and HeartMate I (XVE) was hemorrhagic stroke. NEJM 2009;361(23):

Functional Status Impressive improvement was demonstrated and sustained in terms of functional capacity, with 80 percent of patients improving to Class I or II at 24 months. 6-Minute walk test doubled from 182 to 372 over the two year time period. NEJM 2009;361(23):

Quality of Life Patients also experienced impressive improvements in terms of quality of life as shown through both Minnesota Living with Heart Failure and Kansas City Cardiomyopathy. NEJM 2009;361(23):

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):

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):

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