Sixth Annual Meeting March 12, :00am to 4:00pm Crowne Plaza National Airport Arlington, VA Research Symposium INTERMACS Annual Meeting March 2012

What are the outstanding issues with VADs? Which of these can be answered by INTERMACS? Robert Kormos, MD Sixth Annual Meeting, March 12, 2012 INTERMACS Annual Meeting March 2012

How can INTERMACS help shape the Future of MCS? Where is the field today? Recap the role of INTERMACS Destination Therapy: Evolving Heart Transplantation: Also Dynamic Major Challenges to MCSD Therapy Upcoming Initiatives to Help Answer the Questions INTERMACS Annual Meeting March 2012

How can INTERMACS help shape the Future of MCS? Where is the field today? Recap the role of INTERMACS Destination Therapy: Evolving Heart Transplantation: Also Dynamic Major Challenges to MCSD Therapy Upcoming Initiatives to Help Answer the Questions INTERMACS Annual Meeting March 2012

How can INTERMACS help shape the Future of MCS? Dr. Marvin Slepian, University of Arizona INTERMACS Annual Meeting March 2012

Changing the Life Cycle of New Technology Bowling Alley Paradigm Shift 1 Paradigm Shift 2 Tornado Value Added Adjuvant functions Controls Changeable parts R and L components Wear indicators Forgettable ISHLT 2004 INTERMACS Annual Meeting March 2012

How can INTERMACS help shape the Future of MCS? Dr. Marvin Slepian, University of Arizona INTERMACS Annual Meeting March 2012

How can INTERMACS help shape the Future of MCS? Temporary Devices (include only in conjunction LVAD, BIVAD, TAHwith a durable device listed above) HeartMate II LVASAbiomed AB5000 HeartMate IPAbiomed BVS 5000 HeartMate VELevitronix Centrimag HeartMate XVETandemHeart Micromed DeBakey VAD – Child Novacor PC Novacor PCq Thoratec IVAD Thoratec PVAD Abiocor TAH Syncardia Cardiowest INTERMACS Annual Meeting March 2012

How can INTERMACS help shape the Future of MCS? Later this afternoon, Dr. Tim Baldwin will show the (miniature) pediatric devices that will be part of the PumpKiN Trial INTERMACS Annual Meeting March 2012

How can INTERMACS help shape the Future of MCS? Where is the field today? Recap the role of INTERMACS Destination Therapy : Evolving Heart Transplantation: Also Dynamic Major Challenges to MCSD Therapy Upcoming Initiatives to Help Answer the Questions INTERMACS Annual Meeting March 2012

INTERMACS Hospital Enrollment INTERMACS Annual Meeting March 2012

Pulsatile Flow Intracorporeal LVAD Pump Continuous Flow Intracorporeal LVAD Pump Implants per year Cont Intra Pump Puls Intra TAH Puls Intra Pump Puls Para Pump Pulsatile Flow Paracorporeal LVAD Pump Primary Implant Enrollment: n=5407 : June 2006 – December 2011 Pulsatile Flow Intracorporeal TAH INTERMACS Annual Meeting March 2012

Continuous Flow Intracorporeal Device n=896, deaths=112 Pulsatile Flow Paracorporeal Device, n=74, deaths=28 p (overall) < Event: Death (censored at transplant or recovery) % Survival Months after Device Implant Pulsatile Flow Intracorporeal Device, n=470, deaths=140 INTERMACS: Survival After LVAD Implant Implants: June 2006 – March 2010 INTERMACS Annual Meeting March 2012

How can INTERMACS help shape the Future of MCS? Where is the field today? Recap the role of INTERMACS Destination Therapy : Evolving Heart Transplantation: Also Dynamic Major Challenges to MCSD Therapy Upcoming Initiatives to Help Answer the Questions INTERMACS Annual Meeting March 2012

Evolution from “Transplant Ineligible” to “Transplant Alternative” Destination Therapy How can INTERMACS help shape the Future of MCS? INTERMACS Annual Meeting March 2012

. Long-Term Use of a Left Ventricular Assist Device for End-Stage Heart Failure (for the REMATCH Study Group). N Engl J Med 2001; 345: ; Nov 15, How can INTERMACS help shape the Future of MCS? INTERMACS Annual Meeting March 2012

. Long-Term Destination Therapy With the HeartMate XVE Left Ventricular Assist Device: Improved Outcomes Since the REMATCH Study. Congestive Heart Failure, 11: 133–138. How can INTERMACS help shape the Future of MCS? INTERMACS Annual Meeting March 2012

% Survival Months after Device Implant Event: Death (censored at transplant or explant recovery) : June 2006 – June 2011 Primary Continuous Flow LVADs (+/- RVADs): n= 3405* Overall Survival Bridge to Transplant Listed, n=1221, deaths=153 By initial Device Strategy Bridge to Candidacy, n=1391, deaths=247 p <.0001 *An additional 53 pts had initial device strategy of rescue therapy (n=11), recovery (n=21) and other (n=21). These patients are not included in the figure. Destination Therapy, n=740, deaths=132 Figure 10 12/14/2011 INTERMACS Annual Meeting March 2012

BTT Other* Implants per year Other BTC BTT DT DT Primary Implant Enrollment: n=5407 : June 2006 – December 2011 BTC * Other includes bridge to recovery, rescue therapy and miscellaneous. INTERMACS Annual Meeting March 2012

Pulsatile Flow Intracorporeal Pump Continuous Flow Intracorporeal Pump Implants per year Cont Intra Pump Puls Intra Pump Primary Implant Enrollment, Destination Therapy: n=1286 : June 2006 – December 2011 INTERMACS Annual Meeting March 2012

How can INTERMACS help shape the Future of MCS? Where is the field today? Recap the role of INTERMACS Destination Therapy : Evolving Heart Transplantation: Also Dynamic Major Challenges to MCSD Therapy Upcoming Initiatives to Help Answer the Questions INTERMACS Annual Meeting March 2012

Survival to 1 Year After Transplant for Adult Heart Transplants Performed Between January 1982 and June 2009, Stratified by Era of Transplant. The Registry of the International Society for Heart and Lung Transplantation-Twenty-eighth Adult Heart Transplant Report JHLT Oct;30(10): INTERMACS Annual Meeting March 2012

CTRD: Years After Transplant Status II Patient Predicted Survival of a Status II Patient Smoker No comorbid conditions Percent Survival INTERMACS Annual Meeting March 2012

CTRD: Years After Transplant Status II Patient Predicted Survival of a Status II Patient Smoker Smoker, Diabetic No comorbid conditions Percent Survival INTERMACS Annual Meeting March 2012

CTRD: Years After Transplant Status II Patient Predicted Survival of a Status II Patient Smoker Smoker, Diabetic Smoker, Diabetic, Hx of Pulmonary Vascular Disease No comorbid conditions Percent Survival INTERMACS Annual Meeting March 2012

How can INTERMACS help shape the Future of MCS? Where is the field today? Recap the role of INTERMACS Destination Therapy: Evolving Heart Transplantation: Also Dynamic Major Challenges to MCSD Therapy Upcoming Initiatives to Help Answer the Questions INTERMACS Annual Meeting March 2012

Major Challenges 1.Accurate contemporary risk-adjusted depictions of survival after cardiac transplantation 2.Risk-adjusted contemporary survival after mechanical circulatory support 3.Effective analyses that unveil the shortcomings of MCS therapy How can INTERMACS help shape the Future of MCS? INTERMACS Annual Meeting March 2012

Major Challenges 4. Find “common ground” between Cardiac Transplantation and MCS analyses that accommodate the differing patient populations in Cardiac Transplantation, Destination Therapy – Transplant Ineligible, and Destination Therapy – Transplant Alternative How can INTERMACS help shape the Future of MCS? INTERMACS Annual Meeting March 2012

Major Challenges 5. Develop analyses that are sensitive to the evolution of individual devices and device categories as we allocate device therapies. How can INTERMACS help shape the Future of MCS? INTERMACS Annual Meeting March 2012

Specific Adverse Events that challenge the long-term implementation of MCS: Early mortality and its causes Infection of driveline and pump pockets Right Ventricular Failure Pump and Outflow Graft Thrombosis Renal Dysfunction Plus Quality of Life and Functional Capacity How can INTERMACS help shape the Future of MCS? INTERMACS Annual Meeting March 2012

Coordinator Training Session, March 11, Device Malfunction Device malfunction denotes a failure of one or more of the components of the MCSD system which either directly causes or could potentially induce a state of inadequate circulatory support (low cardiac output state) or death. The manufacturer must confirm device failure. A failure that was iatrogenic or recipient-induced will be classified as an Iatrogenic/Recipient-Induced Failure. Device failure should be classified according to which components fails as follows: 1)Pump failure (blood contacting components of pump and any motor or other pump actuating mechanism that is housed with the blood contacting components). In the special situation of pump thrombosis, thrombus is documented to be present within the device or its conduits that result in or could potentially induce circulatory failure. 2) Non-pump failure (e.g., external pneumatic drive unit, electric power supply unit, batteries, controller, interconnect cable, compliance chamber) The Adverse Event: Device Malfunction Form is to be collected at time of event. FDA has set forth regulations regarding these events. For the purposes of submitting adverse event device malfunction information to the FDA, you must enter any device malfunction event that occurs within 72 hours of the event. INTERMACS Protocol Mar 5, 2012 INTERMACS Annual Meeting March 2012

Coordinator Training Session, March 11, INTERMACS Annual Meeting March 2012

Coordinator Training Session, March 11, INTERMACS Annual Meeting March 2012

Coordinator Training Session, March 11, Major Infection A clinical infection accompanied by pain, fever, drainage and/or leukocytosis that is treated by anti-microbial agents (non- prophylactic). A positive culture from the infected site or organ should be present unless strong clinical evidence indicates the need for treatment despite negative cultures. The general categories of infection are listed below: Localized Non-Device Infection Infection localized to any organ system or region (e.g. mediastinitis) without evidence of systemic involvement (See sepsis definition), ascertained by standard clinical methods and either associated with evidence of bacterial, viral, fungal or protozoal infection, and/or requiring empirical treatment. Percutaneous Site and/or Pocket Infection A positive culture from the skin and/or tissue surrounding the drive line or from the tissue surrounding the external housing of a pump implanted within the body, coupled with the need to treat with antimicrobial therapy when there is clinical evidence of infection such as pain, fever, drainage, or leukocytosis. Internal Pump Component, Inflow or Outflow Tract Infection Infection of blood-contacting surfaces of the LVAD documented by positive site culture. (There should be a separate data field for paracorporeal pump that describes infection at the percutaneous cannula site, e.g. Thoratec PVAD). Sepsis Evidence of systemic involvement by infection, manifested by positive blood cultures and/or hypotension. INTERMACS Protocol Mar 5, 2012 INTERMACS Annual Meeting March 2012

Continuous Intracorporeal pump, n=896, infections=265 P <.0001 Event: First Infection % Freedom from Infection Months after Device Implant Pulsatile Intracorporeal pump, n=470, infections=190 Months Continuous Pulsatile/Intra Post Implant (n=896) (n=470) 1 81%72% 3 74%59% 6 67%51% 12 61%42% 24 58%37% % Free of Infection INTERMACS: June 2006 – September 2009: Infection Study Adult Primary intracorporeal LVADs: 1366 INTERMACS Annual Meeting March 2012

Continuous intracorporeal pump, n=896, infections=77 P <.0001 Event: First pump pocket or drive line infection % Freedom from Pump pocket or Drive line Infection Months after Device Implant Pulsatile intracorporeal pump, n=470, infections=105 Months Continuous Pulsatile/Intra Post Implant (n=896) (n=470) 199%96% 3 96%87% 6 91%77% 1285%64% 24 80%62% % Free of Pump pocket or Drive line Infection INTERMACS: June 2006 – September 2009: Infection Study Adult Primary intracorporeal LVADs: 1366 INTERMACS Annual Meeting March 2012

Months after Implant % Freedom from Driveline Infection Freedom from Driveline Infection p <.0001 Continuous Flow Pump, n=2006, first DL infections=197 Pulsatile Flow Pump, n=484, first DL infections=81 Months% Freedom 1 99% 6 93% 12 81% 24 74% INTERMACS Annual Meeting March 2012

Coordinator Training Session, March 11, Neurological Dysfunction Any new, temporary or permanent, focal or global neurological deficit ascertained by a standard neurological examination (administered by a neurologist or other qualified physician and documented with appropriate diagnostic tests and consultation note). The examining physician will distinguish between a transient ischemic attack (TIA), which is fully reversible within 24 hours (and without evidence of infarction), and a stroke, which lasts longer than 24 hours (or less than 24 hours if there is evidence of infarction). The NIH Stroke Scale (for patients > 5 years old) must be re-administered at 30 and 60 days following the event to document the presence and severity of neurological deficits. Each neurological event must be subcategorized as: 1)Transient Ischemic Attack (acute event that resolves completely within 24 hours with no evidence of infarction) 2)Ischemic or Hemorrhagic Cardiovascular Accident/CVA (event that persists beyond 24 hours or less than 24 hours associated with infarction on an imaging study.) INTERMACS Protocol Mar 5, 2012 INTERMACS Annual Meeting March 2012

IMACS 3, n=172, neuro events=12 Event: First Neurological Event % Free from Neurological Events Months after Device Implant IMACS 2, n=396, neuro events=28 IMACS 1, n=172, neuro events=23 p =.08 Adult Primary Continuous Intracorporeal LVADs: 896 By INTERMACS Patient Profile Levels INTERMACS: June 2006 – September 2009: Neurological Dysfunction IMACS 4-7, n=156, neuro events=15 INTERMACS Annual Meeting March 2012

IMACS 3, n=49, neuro events=8 Event: First Neurological Event % Free from Neurological Events Months after Device Implant IMACS 2, n=197, neuro events=33 IMACS 1, n=160, neuro events=41 p =.02 Adult Primary Pulsatile Intracorporeal LVADs: 470 By INTERMACS Patient Profile Levels INTERMACS: June 2006 – September 2009: Neurological Dysfunction IMACS 4-7, n=64, neuro events=11 INTERMACS Annual Meeting March 2012

Coordinator Training Session, March 11, MAJOR BLEEDING AN EPISODE OF SUSPECTED INTERNAL OR EXTERNAL BLEEDING THAT RESULTS IN ONE OR MORE OF THE FOLLOWING: 1. Death, 2. Re-operation, 3. Hospitalization, 4. Transfusion of red blood cells If TRANSFUSION IS SELECTED, then apply the following rules: During first 7 days post implant:  Adults (≥ 50 kg): ≥ 4U packed red blood cells (PRBC) within any 24 hour period during first 7 days post implant. After 7 days post implant  Any transfusion of packed red blood cells (PRBC) after 7 days following implant with the investigator recording the number of units given. Note: Hemorrhagic stroke is considered a neurological event and not as a separate bleeding event. INTERMACS Protocol Mar 5, 2012 INTERMACS Annual Meeting March 2012

Right Heart Failure Symptoms and signs of persistent right ventricular dysfunction [central venous pressure (CVP) > 18 mmHg with a cardiac index <2.0 L/min/m 2 in the absence of elevated left atrial/pulmonary capillary wedge pressure (greater than 18 mmhg), tamponade, ventricular arrhythmias or pneumothorax] requiring RVAD implantation; or requiring inhaled nitric oxide or inotropic therapy for a duration of more than 1 week at any time after LVAD implantation. INTERMACS Protocol Oct 30, 2008 INTERMACS Annual Meeting March 2012

Coordinator Training Session, March 11, Right Heart Failure Symptoms and signs of persistent right ventricular dysfunction [central venous pressure (CVP) > 18 mmHg with a cardiac index <2.3 L/min/m2 in the absence of elevated left atrial/pulmonary capillary wedge pressure (greater than 18 mmhg), tamponade, ventricular arrhythmias or pneumothorax] requiring RVAD implantation; or requiring inhaled nitric oxide or inotropic therapy for a duration of more than 1 week at any time after LVAD implantation.” LEVEL OF RIGHT HEART FAILURE Severe RHF: RVAD Moderate RHF: Inotrope or intravenous or inhaled pulmonary vasodilator (e.g. prostaglandin E or inhaled nitric oxide) Mild RHF: Meets 2 of the 4 clinical criteria listed below  CVP > 18 mmHg or mean RA pressure > 18 mmHg  CI < 2.3 L/min/M 2 (by Swan)  Ascites or evidence of moderate to worse peripheral edema  Evidence of elevated CVP by echo (dilated VC, IVS with collapse), physical exam (signs of increased jugular venous pressure) INTERMACS Protocol Mar 5, 2012 INTERMACS Annual Meeting March 2012

Kaplan-Meier Survival: Device Type INTERMACS Annual Meeting March 2012

Pre-Implant Patient Profile LVAD (n=1440) Bi-VAD (n=206) 1 Critical Cardiogenic Shock 380 (26%) 112 (54% 2 Progressive Decline 612 (43%) 78 (38%) 3 Stable but Inotrope dependent 226 (16%) 9 (4%) 4 Recurrent Advanced HF 150 (10%) 4 (2%) 5 Exertion Intolerant 27 (2%) 1 (1%) 6 Exertion Limited 22 (1%) 2 (1%) 7 Advanced NYHA Class III 23 (2%) 0 (0%) Total 1440 (100%) 216 (100%) p <.0001 * Total Artificial Heart devices (TAH) are excluded from this table Adult Primary Implants, n=1706 INTERMACS: June 2006 – September 2009: Bi-VAD Study INTERMACS Annual Meeting March 2012

RA Pressure LVAD (n=1440) Bi-VAD (n=206) < (33%) 18 (13%) (47%) 72 (53%) (17%) 44 (32%) ( 3%) 3 (2%) Total 841 (100%) 137 (100%) Missing 599/1440 (42%) 69/206 (33%) Implant dates: June 2006 – September 2009: Bi-VAD Study All Adult Primary LVADs and BIVADs: n=1646 INTERMACS Annual Meeting March 2012

Coordinator Training Session, March 11, Hemolysis A plasma-free hemoglobin value that is greater than 40 mg/dl, in association with clinical signs associated with hemolysis (e.g., anemia, low hematocrit, hyperbilirubinemia) occurring after the first 72 hours post-implant. Hemolysis related to documented non-device-related causes (e.g. transfusion or drug) is excluded from this definition. INTERMACS Protocol Mar 5, 2012 INTERMACS Annual Meeting March 2012

How can INTERMACS help shape the Future of MCS? Where is the field today? Recap the role of INTERMACS Destination Therapy: Evolving Heart Transplantation: Also Dynamic Major Challenges to MCSD Therapy Upcoming Initiatives to Help Answer the Questions INTERMACS Annual Meeting March 2012

MedaMACS  To provide parallel information about medical outcomes for survival, function, and quality of life  within INTERMACS profiles 4-7  to help refine patient selection in the crucial range of ambulatory HF  where the greatest benefit of VAD is anticipated. INTERMACS Annual Meeting March 2012

INTERMACS Annual Meeting March 2012

REVIVE-IT  This is a randomized trial of the Heartware Ventricular Assist System (VAS) versus the best medical therapy in patients with advanced heart failure and whose illness is not severe enough to qualify for transplant or permanent left ventricular assist device (LVAD) therapy based on current guidelines INTERMACS Annual Meeting March 2012

Coordinator Training Session: March 11, 2012 pediMACS Launch Status 52  pediMACS will follow the structure of INTERMACS  A few important changes from INTERMACS:  Pediatric patients (< 19 yrs. at time of implant)  Includes both durable and temporary support MCSDs  Modifications of AE definitions  Possible expansion of quality of life instruments INTERMACS Annual Meeting March 2012

IMACS Overview - General ISHLT Mechanically Assisted Circulatory Support (IMACS) Registry International registry to enroll and follow patients receiving durable MCSDs in all countries and hospitals wishing to participate TASK: Create, implement, and analyze a registry with high standards for complete enrollment of patients and complete and accurate submission of data GOAL: Allow participating centers to engage in outcomes research about MCSDs INTERMACS Annual Meeting March 2012

Mission Statement ISHLT Mechanically Assisted Circulatory Support (IMACS) Registry The specific mission of IMACS is the promotion of scientific investigations and publications based on analyses of this multinational database, providing the opportunity for an international array of authors to collaborate in Registry investigations, presentations, and publications. INTERMACS Annual Meeting March 2012