What has INTERMACS Taught Us about Patient Outcomes with Durable MCS? James K. Kirklin, MD

Disclosure: I am Director of the Data Coordinating Center for the INTERMACS project and receive support through an Institutional Contract James K. Kirklin, MD

Circulatory Mechanical Support Circulatory Support An Harnessing Era of Disruptive Disruptive Innovation Innovation John Gibbon develops and first employs a Pump Oxygenator to perform open heart surgery May,1953

Dr. Christian Barnard World s First Human Heart Transplant Dec. 3,1967

Drs. Michael DeBakey and Denton Cooley and first artificial heart developed by Dr. Domingo Liotta used as a bridge to transplantation 1969

Mechanical Circulatory Support Harnessing Disruptive Innovation as Accepted Therapy The Hemopump designed by Richard Wampler Peer Portner Victor Poirier

Education Mechanical War Era Circulatory Cardiac SurgerySupport An Era of Disruptive Innovation 2000 2003 2005 2008 2017 2004 2006 2010 2012 2018 XVE approved for DT The NHLBI puts out an RFP for proposals to organize and run a scientific database for all durable MCS devices in the US

Education Mechanical War Era Circulatory Cardiac Surgery Support An Era of Disruptive Innovation 2000 2003 2005 2008 2017 2004 2006 2010 2012 2018 XVE approved for DT Cardiowest TAH Approved for BTT

INTERMACS Implantation of an MCSS is not a simple, time-limited treatment episode. Because of the patient s total dependence on the device and because problems can occur at any time, clinical trial subjects should be followed closely during the trials: they and other MCSS patients should be followed, through a registry, for the remainder of their lives...maintaining a registry of MCSS recipients should be considered a routine aspect of this care The committee recommends that NHLBI support long term follow up studies of an adequate sample of MCSS patients. The Artificial Heart: Prototypes Policies and Patients; Institute of Medicine Report, 1991. A vision of John Watson and the NHLBI

Mechanical Circulatory Support Harnessing Disruptive Innovation as Accepted Therapy 2000 2003 2005 2008 2017 2004 2006 2010 2012 2018 XVE approved for DT The NHLBI puts out an RFP for proposals to organize and run a scientific database for all durable MCS devices in the US Award date:june 1, 2005 Duration:5 years NHLBI Contract #HHSN268200548198C To: Univ of Alabama at Birmingham PI: James Kirklin Co PI s: DavidNaftel, Robert Kormos, Lynne W. Stevenson, Cardiowest TAH Approved for BTT

INTERMACS: A Study in Collaboration What is INTERMACS? INTERMACS is a United States national registry for patients who are receiving durable mechanical circulatory support device therapy to treat advanced heart failure. This registry was devised as a joint effort of the National Heart, Lung and Blood Institute (NHLBI), the Centers for Medicare and Medicaid Services (CMS), the Food and Drug Administration (FDA), clinicians, scientists and industry representatives. Interagency Registry for Mechanically Assisted Circulatory Support NHLBI Contract #HHSN268200548198C UNIVERSITY OF ALABAMA AT BIRMINGHAM (2006-2017)

INTERMACS PLATFORM FOR PROGRESS INTERMACS Investigators NHLBI and Federal Partners MCS Field in Rapid Evolution

Mechanical Circulatory Support Harnessing Disruptive Innovation as Accepted Therapy Disruptive Innovation Slow Pace of Progress Single cohort (center) Reports Clinical Trials Gradual Acculation of Persuasive Evidence Adoption for Indication INTERMACS Platform for Progress Platform for Collection and Analysis of Large Multi-institutional Data to Generate Believable Inferences Expansion of Technology into other Potential Populations of Benefit

Mechanical War Era Circulatory Cardiac Surgery Support Harnessing Disruptive Innovation as Accepted Therapy Era 2000 2003 2005 2008 2017 2004 2006 2010 2012 2018 XVE approved for DT The NHLBI puts out an RFP for proposals to organize and run a scientific database for all durable MCS devices in the US Cardiowest TAH Approved for BTT INTERMACS begins Data Collection

Mechanical War Era Circulatory Cardiac Surgery Support Harnessing Disruptive Innovation as Accepted Therapy Era 2000 2003 2005 2008 2017 2004 2006 2010 2012 2018 XVE approved for DT HMII approved for BTT The NHLBI puts out an RFP for proposals to organize and run a scientific database for all durable MCS devices in the US Cardiowest TAH Approved for BTT INTERMACS begins Data Collection

Mechanical War Era Circulatory Cardiac Surgery Support Harnessing Disruptive Innovation as Accepted Therapy Era 2000 2003 2005 2008 2017 2004 2006 2010 2012 2018 XVE approved for DT HMII approved for BTT HMII - DT The NHLBI puts out an RFP for proposals to organize and run a scientific database for all durable MCS devices in the US Cardiowest TAH Approved for BTT INTERMACS begins Data Collection

Mechanical War Era Circulatory Cardiac Surgery Support Harnessing Disruptive Innovation as Accepted Therapy Era 2000 2003 2005 2008 2017 2004 2006 2010 2012 2018 XVE approved for DT HMII approved for BTT HMII - DT The NHLBI puts out an RFP for proposals to organize and run a scientific database for all durable MCS devices in the US HVAD approved for BTT Cardiowest TAH Approved for BTT INTERMACS begins Data Collection

Mechanical War Era Circulatory Cardiac Surgery Support Harnessing Disruptive Innovation as Accepted Therapy Era 2000 2003 2005 2008 2017 2004 2006 2010 2012 2018 XVE approved for DT HMII approved for BTT HMII - DT The NHLBI puts out an RFP for proposals to organize and run a scientific database for all durable MCS devices in the US HVAD approved for BTT HVAD - DT Cardiowest TAH Approved for BTT INTERMACS begins Data Collection

Mechanical War Era Circulatory Cardiac Surgery Support Harnessing Disruptive Innovation as Accepted Therapy Era 2000 2003 2005 2008 2017 2004 2006 2010 2012 2018 XVE approved for DT HMII approved for BTT HMII - DT HM3 approved The NHLBI puts out an RFP for proposals to organize and run a scientific database for all durable MCS devices in the US HVAD approved for BTT HVAD - DT Cardiowest TAH Approved for BTT INTERMACS begins Data Collection

Goals of the Registry Facilitate the refinement of patient selection to maximize outcomes with current and new device options. Identify predictors of good outcomes as well as risk factors for adverse events after device implantation. Develop consensus best practice guidelines to improve clinical management by reducing short and long term complications of MCSD therapy. Utilize Registry information to guide improvements in technology, particularly as next generation devices evolve. Guide clinical testing and approval of new devices. INTERMACS A Platform for Progress after Innovation which quantified the challenges and benefits of this technology over the past decade

INTERMACS A Platform for Progress after Innovation > 60 Publications in the last 5 years 21

A Platform for Progress after Innovation Numerous Impact publications Crystalizing Risk Factors and Outcomes Frailty R H Failure Infection Device Exchange Destination Therapy] QOL Ambulatory HF Concomitant Surgery TR, MR Bridge to Candidacy Stroke Renal Failure Risk Factors for mortality Optimize Patient Selection Evaluate Strategies to Reduce Adverse Events 22

Modern Mission of INTERMACS Science Identify trends in real world experience that may reflect evolution of outcomes with changing management.

Implants per year 3500 3000 2500 2000 1500 1000 500 Implants: June 2006 December 2016, n=18987 Continuous Flow Intracorporeal LVAD Pump - Axial Continuous Flow Intracorporeal LVAD Pump - Centrifugal Pulsatile Flow Intracorporeal TAH Pulsatile Flow Intracorporeal LVAD Pump Pulsatile Flow Paracorporeal LVAD Pump % Survival Months % Survival 1 95% 12 81% 24 70% 36 59% 48 49% 0 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

Implants June 2006 March 2015: TAH Survival Outcomes All adult patients implanted From June 2006 through March 2015 N=15194 patients 16467implants TAH N= 359 (2%) 3 patients have a 2 nd TAH implanted (n=362 TAH implants) % Survival TAH Implants: June 2006 March 2015, n=359 By Total Center Experience % Survival post implant at: Total Center Experience pts deaths 3 mths 6 mths 12 mths 11+ implants (n=8 hospitals) 222 54 80% 72% 69% 10 implants (n=36 hospitals) 137 66 62% 50% 36% (note: last death at 22 months) P <.0001 Event: Death (censored at transplant or device exchange) Total Artificial Heart (TAH): Survival Outcomes, Risk Factors, Adverse Events F. Arabia 1, I. Gregoric 2, V. Kasirajan 3, J. D. Moriguchi 4, D. C. Naftel 5, S. L. Myers 5, J. K. Kirklin 5. Months post Implant 26

Implants June 2006 March 2015: TAH Survival Outcomes Higher Early Rate of Transplantation for TAH Patients Proportion of Patients N=3473, Primary CFLVAD BTT: listed for transplant Alive (device in place) 71% Transplanted 20% Dead 8% Recovery 1% CFLVAD BTT Transplanted Alive (on a device) Dead Recovery N=359, TAH Alive (device in place) 27% Transplanted 46% Dead 27% TAH Months after Implant 27

Survival after LVAD implantation for ACHD vs. non-achd patients N=16,182 Total Patients in INTERMACS Database Hepatic dysfunction Early Late ACHD (n=126) 100 pt/mo 5.6 0.88 1.6 0.2 Non-ACHD (n=16,056) 100 pt/mo P value <0.01 <0.01 Non-ACHD: n=16,056 ACHD: n=126 Cardiac Arrhythmia Early Late Infection Early Late Renal dysfunction Early Late 10.2 2.1 19.8 6.2 10.5 1.1 11.2 1.0 16.9 4.0 4.2 0.4 0.618 <0.01 0.2 <0.01 <0.01 <0.01 Utilization and Outcomes of Ventricular Assist Device Support in Adult Congenital Heart Disease: An Analysis of INTERMACS Respiratory failure Early Late Neurological dysfunction Early Late 15.2 2.0 5.6 1.5 8.0 0.5 4.6 1.2 <0.01 <0.01 0.43 0.387 C. J. VanderPluym, et al ISHLT,2016

Modern Mission of INTERMACS Science Identify trends in real world experience that may reflect evolution of outcomes with changing management. Discern truths about outcomes and risk factors when single institution experience remains small or isolated. Illuminate areas of controversy that require large datasets for useful analyses

INTERMACS: HMII Pump Investigation Implants: April 2008 June 2014, n=11123 Follow-up: Thru September 2014 Expanded Scale Primary Implants, n=9808 % Freedom from Pump Thrombosis % Freedom from pump thrombosis at Implant year 6 mths 12 mths 36 mths 48 mths 2008 99% 97% 92% 89% 2009 98% 97% 91% 88% 2010 98% 96% 89% 86% 2011 96% 93% 86% --- 2012 93% 90% --- --- 2013 93% 90% --- --- 2014 (thru Jun) 95% --- --- --- Event: pump thrombosis removal, transplant or death due to thrombus Year of Implant 2008 2009 2010 2011 2014 2012 2013 Months post implant 30

Intermacs Role in Device Approval HMII post-market approval study Heartware Lateral Thoracotomy Trial Advisory role in Berlin Heart Pivotol Trial Advisory role in Syncardia Freedom Driver approval process

Specific Adverse Events that challenge the long-term implementation of MCS Early mortality and its causes Stroke Infection of driveline and pump pockets Right Ventricular Failure Pump malfunction/ Thrombosis Renal Dysfunction GI bleeding Continuous Flow LVAD/BiVAD Implants: 2008 2016, n=17633 Instantaneous Death Rate (Hazard) for selected causes Deaths/Month Months post implant Cause of Death Infection RHF Neurological Device Malfunction MSOF Neurological MSOF Infection Device Malfunction RHF

Continuous Flow LVAD/BiVAD Implants: 2008 2016, n=17633 Cumulative Death Rate (Hazard) for selected causes Cumulative Hazard Cause of Death Infection RHF Neurological Device Malfunction MSOF 2017 Neurological MSOF Infection Device Malfunction RHF Months post implant

Education War Era Cardiac Surgery Predicting Survival and Quality of Life Demographics Clinical factors Surgical details Device factors Adverse Events Survival Time 0 3 months Pre-implant Risk Factors

Continuous Flow LVAD/BiVAD Implants: 2008 2016, n=17633 Early hazard Late hazard Pre-implant Risk Factors for Death Hazard Ratio p-value Hazard Ratio p-value Demographics Age 2 (older) 1.41 <.0001 1.16.<.0001 Female 1.47 <.0001 BMI (higher) 1.02 <.0001 Blood Type Not O 0.88.002 White race 1.20.0003 Clinical Status ICD 1.34.001 1.29 <.0001 INTERMACS Profile 1 1.98 <.0001 INTERMACS Profile 2 1.59 <.0001 Preimplant Risk Factors Intervention within 48 hours IABP 1.19.0004 Destination Therapy 1.22 <.0001 Non-Cardiac Systems Peripheral Vascular Disease 1.28.004 Pre-COPD 1.27.001 Albumin (lower) 0.80 <.0001 Creatinine (higher) 1.12 <.0001 Dialysis 3.29 <.0001 BUN (higher) (10 unit increase) 1.07 <.0001 1.05 <.0001 Right Heart Dysfunction RVAD in same operation 3.76 <.0001 Bilirubin (higher) (5 unit increase) 1.28 <.0001 Surgical Complexities History of cardiac surgery 1.31.004 History of CABG 1.38.001 Concommitant Cardiac Surgery 1.53 <.0001 Quality of Life Pre Implant Too Sick to complete EQ5D 1.65 <.0001 Worse Self Care Score (pre-implant) 1.25 <.0001

Education War Era Cardiac Surgery Predicting Survival and Quality of Life Demographics Clinical factors Surgical details Adverse Events Survival and QoL Implant Pre-implant Risk Factors 3 months (new time 0) Risk Factors resulting from Adverse Events

Continuous Flow LVAD/BiVAD Implants: 2008 2016, n=17633 Risk Factors for Death in Patients who were alive at 3 months postimplant (n=14,887) Constant Phase of Hazard Risk Factors Hazard ratio P-value Pre-implant Age (older) 1 1.09 <.0001 Race: white 1.32 <.0001 Device strategy: Destination Therapy 1.18.0003 ICD prior to implant 1.22.0005 Note the relative Dominance of post- Implant events over pre-implant risk factors Clinical Events during 3 months Number of strokes 1.4 <.0001 Number of respiratory failures 1.16.0003 Number of infections 1.16 <.0001 Number of device malfunctions 1.30 <.0001 Days in acute care 1.01 <.0001 Clinical Condition at 3 months BUN (higher) 1.01 <.0001 Creatinine (higher) 1.12 <.0001 Albumin (lower) 0.97 <.0001 LDH (higher) 1.00 <.0001 Ascites 1.73.003 Peripheral Edema 1.30.0008 Inotropes 1.70 <.0001 Warfarin (non-use) 0.74 <.0001 Impact of Adverse Events on Survival Quality of Life/Neurocognitive Visual Analog Scale (lower) 2 0.93 <.0001 Mobility problems 1.31 <.0001 Trail making test (higher) 3 1.07 <.0001 40

Education War Era Cardiac Surgery Predicting Survival and Quality of Life Demographics Clinical factors Surgical details Adverse Events Survival and QoL Implant Pre-implant Risk Factors 3 months New Time 0 Risk Factors resulting from Adverse Events

Profile 2 Pt Continuous Flow LVAD/BiVAD Implants: 2008 2016, n=17633 Survival path based only on pre-implant risk factors Clinical Course During 1 st 3mths Good, uneventful % Survival Clinical Course In the current state of MCS technology, with the isolated exception of right heart failure, better risk status at implant provides limited or no protection against serious adverse events. Stroke Stroke, Infection, Inotropes Months post implant

Education War Era Cardiac Surgery Timeline of the MCS Evolution 2010 2014 2025 2006 2008 2012 2018 2020 2030 Era of Device Development, Understanding AEs, and Refining Optimal Populations

Education War Era Cardiac Surgery Timeline of the MCS Evolution 2010 2014 2025 2006 2008 2012 2018 2020 2030 Era of Devicement Development Era of Adverse Event Neutralization and Novel Devices Opportunity to Facilitate Extension of MCS to Ambulatory Advanced Heart Failure through INTERMACS studies