Predicting Major Outcomes after MCSD Implant 1 Risk Factors for Death, Transplant, and Recovery James Kirklin, MD David Naftel, PhD

James K Kirklin I have no financial disclosures (I am the Principle Investigator for the NIH contract for INTERMACS)

Predicting Major Outcomes after MCSD Implant 3 Risk Factors for Death, Transplant, and Recovery What do we have so far?

Months post implant % Survival Deaths/months Hazard (early + late) n=9359, Deaths=2280 Months% Survival 195% 1280% 2469% 36 59% 4847% Continuous Flow LVAD/BiVAD Implants: 2008 – 2013, n=9359 n at risk: Event: Death (censored at transplantation or recovery)

Months post implant % Survival Deaths/months Hazard (early + late) n=9359, Deaths=2280 Months% Survival 195% 1280% 2469% 36 59% 4847% Continuous Flow LVAD/BiVAD Implants: 2008 – 2013, n=9359 n at risk: Event: Death (censored at transplantation or recovery)

Months post implant % Survival LVAD: Continuous n=9112, Deaths=2154 BiVAD: Continuous n=260, Deaths=118 LVAD: Pulsatile n=612, Deaths=230 BiVAD: Pulsatile n=319, Deaths=123 overall p <.0001 Event: Death (censored at transplant and recovery) Figure 10 Implants: June 2006 – December 2013, n=10542 TAH: Pulsatile n=239, Deaths=59 % Survival at Pump1 yr post implant CF LVAD 81% CF Bi-VAD 57% PF LVAD 65% PF Bi-VAD 45% TAH 59% 6

Months post implant % Survival LVAD: Continuous n=9112, Deaths=2154 BiVAD: Continuous n=260, Deaths=118 LVAD: Pulsatile n=612, Deaths=230 BiVAD: Pulsatile n=319, Deaths=123 overall p <.0001 Event: Death (censored at transplant and recovery) Implants: June 2006 – December 2013, n=10542 TAH: Pulsatile n=239, Deaths=59 % Survival at Pump1 yr post implant CF LVAD 81% CF Bi-VAD 57% PF LVAD 65% PF Bi-VAD 45% TAH 59% 7

Early hazardLate hazard Risk Factors for Death Hazard Ratiop-valueHazard Ratiop-value Demographics Age (older)1.36<.0001 Female BMI (higher)1.13<.0001 Clinical Status History of Stroke INTERMACS Level 11.69<.0001 INTERMACS Level 21.44<.0001 Destination Therapy Non-Cardiac Systems Albumin (lower) Creatinine (higher) Dialysis2.37<.0001 BUN (higher)1.06< Right Heart Dysfunction Right Atrial Pressure (higher) RVAD in same operation2.45<.0001 Bilirubin (higher)1.21<.0001 Ascites Surgical Complexities History of cardiac surgery1.43<.0001 Concommitant Cardiac Surgery Adult Primary Continuous Flow LVADs and BiVADs Implants: June 2006 – December 2013, n=9372 8

Early hazardLate hazard Risk Factors for Death Hazard Ratiop-valueHazard Ratiop-value Demographics Age (older) 1.36<.0001 Female BMI (higher)1.13<.0001 Clinical Status History of Stroke INTERMACS Level 11.69<.0001 INTERMACS Level 21.44<.0001 Destination Therapy Non-Cardiac Systems Albumin (lower) Creatinine (higher) Dialysis2.37<.0001 BUN (higher)1.06< Right Heart Dysfunction Right Atrial Pressure (higher) RVAD in same operation2.45<.0001 Bilirubin (higher)1.21<.0001 Ascites Surgical Complexities History of cardiac surgery1.43<.0001 Concommitant Cardiac Surgery Adult Primary Continuous Flow LVADs and BiVADs Implants: June 2006 – December 2013, n=9372 9

Months post implant % Survival Age < 50 yrs n=2403, deaths=446 Age yrs n=4184 Deaths= 942 Age yrs n=1484, deaths=433 Overall P <.0001 Event: Death (censored at transplant and recovery) Age > 70 yrs, n=1301 deaths=451 Continuous Flow LVAD/BiVAD Implants: 2008 – 2013, n=

INTERMACS 11 Age Category AGE GROUP (yr) IMPLANT DATE PERIOD < n%n%n% %300.8 %80.3 % % % % % % % % % % %180.8 % Unspecified % TOTAL % % % June 2006 – December 2012

Early hazardLate hazard Risk Factors for Death Hazard Ratiop-valueHazard Ratiop-value Demographics Age (older)1.36<.0001 Female BMI (higher)1.13<.0001 Clinical Status History of Stroke INTERMACS Level <.0001 INTERMACS Level <.0001 Destination Therapy Non-Cardiac Systems Albumin (lower) Creatinine (higher) Dialysis2.37<.0001 BUN (higher)1.06< Right Heart Dysfunction Right Atrial Pressure (higher) RVAD in same operation2.45<.0001 Bilirubin (higher)1.21<.0001 Ascites Surgical Complexities History of cardiac surgery1.43<.0001 Concommitant Cardiac Surgery Adult Primary Continuous Flow LVADs and BiVADs Implants: June 2006 – December 2013, n=

Months post implant % Survival Level 1: n=1391 Deaths=381 Level 2: n=3601 Deaths=942 Level 3: n=2591 Deaths=544 Levels 4-7, n=1789 Deaths=405 P <.0001 Event: Death (censored at transplant and recovery) Continuous Flow LVAD/BiVAD Implants: 2008 – 2013, n=

Patient Profile at time of implant Implant Date Era TOTAL N%N%N% 1 Critical Cardiogenic Shock % % % 2 Progressive Decline % % % 3 Stable but Inotrope Dependent % % % 4 Resting Symptoms % % % 5 Exertion Intolerant842.9%1923.0%2762.9% 6 Exertion Limited491.7%791.4%1291.4% 7 Advanced NYHA Class %431.0%731.0% TOTAL % % % CF-LVAD/BiVAD Implants: January 2008 – December 2013, n=9372 Continuous Flow Devices 14

Patient Profile at time of implant Implant Date Era TOTAL N%N%N% 1 Critical Cardiogenic Shock % % % 2 Progressive Decline % % % 3 Stable but Inotrope Dependent % % % 4 Resting Symptoms % % % 5 Exertion Intolerant842.9%1923.0%2762.9% 6 Exertion Limited491.7%791.4%1291.4% 7 Advanced NYHA Class %431.0%731.0% TOTAL % % % CF-LVAD/BiVAD Implants: January 2008 – December 2013, n=9372 Continuous Flow Devices 15

Early hazardLate hazard Risk Factors for Death Hazard Ratiop-valueHazard Ratiop-value Demographics Age (older)1.36<.0001 Female BMI (higher)1.13<.0001 Clinical Status History of Stroke INTERMACS Level 11.69<.0001 INTERMACS Level 21.44<.0001 Destination Therapy Non-Cardiac Systems Albumin (lower) Creatinine (higher) Dialysis2.37<.0001 BUN (higher)1.06< Right Heart Dysfunction Right Atrial Pressure (higher) RVAD in same operation2.45<.0001 Bilirubin (higher)1.21<.0001 Ascites Surgical Complexities History of cardiac surgery1.43<.0001 Concommitant Cardiac Surgery Table 6 Adult Primary Continuous Flow LVADs and BiVADs Implants: June 2006 – December 2013, n=9372 LVAD, left ventricular assist device; BiVAD, biventricular assist device; DT, destination therapy; BTT, bridge to transplant; BMI, body mass index; BUN, blood urea nitrogen; RVAD, right ventricular assist device. 16

Months post implant % Survival DT, n= 3373 Deaths= 1027 BTT (including BTC), n= 5886 Deaths= 1218 p <.0001 Event: Death (censored at transplant and recovery) Continuous Flow LVAD/BiVAD Implants: 2008 – 2013, n=9372 BTR, n= 46 Deaths= 4 Rescue Therapy, n= 27 Deaths= 11 Other, n= 40 Deaths= 12 17

CF-LVAD/BiVAD Implants: June 2006 – December 2013, n=9372 Device Strategy at time of implant Implant Date Era TOTAL N%N%N% BTT Listed % % % BTT Likely % % % BTT Moderate % % % BTT Unlikely 822.8%218¾%3003.2% Destination Therapy % % % BTR 151.0%311.0%461.0% Rescue Therapy 100.3%170.3%270.3% Other 140.5%260.4%400.4% TOTAL % % % Continuous Flow Devices 18

Early hazardLate hazard Risk Factors for Death Hazard Ratiop-valueHazard Ratiop-value Demographics Age (older)1.36<.0001 Female BMI (higher)1.13<.0001 Clinical Status History of Stroke INTERMACS Level 11.69<.0001 INTERMACS Level 21.44<.0001 Destination Therapy Non-Cardiac Systems Albumin (lower) Creatinine (higher) Dialysis 2.37<.0001 BUN (higher) 1.06< Right Heart Dysfunction Right Atrial Pressure (higher) RVAD in same operation2.45<.0001 Bilirubin (higher)1.21<.0001 Ascites Surgical Complexities History of cardiac surgery1.43<.0001 Concommitant Cardiac Surgery Table 6 Adult Primary Continuous Flow LVADs and BiVADs Implants: June 2006 – December 2013, n=9372 LVAD, left ventricular assist device; BiVAD, biventricular assist device; DT, destination therapy; BTT, bridge to transplant; BMI, body mass index; BUN, blood urea nitrogen; RVAD, right ventricular assist device. 19

Months post implant % Survival Low n=8237, deaths=1862 Moderate (creat > 2 or BUN > 60) n=993, deaths=339 Severe (dialysis) n=142, deaths=71 Overall P <.0001 Event: Death (censored at transplant and recovery) Figure 14 Continuous Flow LVAD/BiVAD Implants: 2008 – 2013, n=9372 Survival by Renal Risk Factors 20

Months post implant % Survival Low n=8237, deaths=1862 Moderate (creat > 2 or BUN > 60) n=993, deaths=339 Severe (dialysis) n=142, deaths=71 Overall P <.0001 Event: Death (censored at transplant and recovery) Figure 14 Continuous Flow LVAD/BiVAD Implants: 2008 – 2013, n=9372 Survival by Renal Risk Factors 21

Adult Primary Continuous Flow LVADs & BIVADs, DT and BTT, n=4917 Implants: June 2006 – March 2012: Creatinine 22 Adult Primary Continuous Flow LVADs & BIVADs, DT and BTT, n=4917 Implants: June 2006 – March 2012: Time course of Creatinine according to pre-implant Renal Dysfunction Creatinine (mg/dL) Follow-up Time Period Severe (n=282) Moderate (n=1475) Mild/None (n=3160) * p <.05 ** p <.001 Paired comparisons to pre-implant ** *

Early hazardLate hazard Risk Factors for Death Hazard Ratiop-valueHazard Ratiop-value Demographics Age (older)1.36<.0001 Female BMI (higher)1.13<.0001 Clinical Status History of Stroke INTERMACS Level 11.69<.0001 INTERMACS Level 21.44<.0001 Destination Therapy Non-Cardiac Systems Albumin (lower) Creatinine (higher) Dialysis2.37<.0001 BUN (higher)1.06< Right Heart Dysfunction Right Atrial Pressure (higher) RVAD in same operation 2.45<.0001 Bilirubin (higher) 1.21<.0001 Ascites Surgical Complexities History of cardiac surgery1.43<.0001 Concommitant Cardiac Surgery Adult Primary Continuous Flow LVADs and BiVADs Implants: June 2006 – December 2013, n=

Months post implant % Survival Low n=6596, deaths=1481 Moderate (ascites or RAP >= 18 or Bilirubin >= 2) n=2516, deaths=690 Severe (BiVAD) n=260, deaths=120 Overall P <.0001 Event: Death (censored at transplant and recovery) Continuous Flow LVAD/BiVAD Implants: 2008 – 2013, n=9372 Survival by Right Heart Failure Risk Factors 24

Early hazardLate hazard Risk Factors for Death Hazard Ratiop-valueHazard Ratiop-value Demographics Age (older)1.36<.0001 Female BMI (higher)1.13<.0001 Clinical Status History of Stroke INTERMACS Level 11.69<.0001 INTERMACS Level 21.44<.0001 Destination Therapy Non-Cardiac Systems Albumin (lower) Creatinine (higher) Dialysis2.37<.0001 BUN (higher)1.06< Right Heart Dysfunction Right Atrial Pressure (higher) RVAD in same operation 2.45<.0001 Bilirubin (higher) 1.21<.0001 Ascites Surgical Complexities History of cardiac surgery1.43<.0001 Concommitant Cardiac Surgery Adult Primary Continuous Flow LVADs and BiVADs Implants: June 2006 – December 2013, n=

Tricuspid Repair Following VAD Implantation in INTERMACS Howard Song, MD, PhD Co-authors James Mudd, MD; Jill Gelow, MD, MPH; Christopher Chien, MD; Fred Tibayan, MD; Kathryn Hollifield, BSN, RN; David Naftel, PhD; and James Kirklin, MD "This project has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN C" 26 04/04/2014

INTERMACS: June 2006 – March 2013: TVR Adult Destination Therapy CF primary LVAD/BiVAD, n= Phase of Hazard Early Constant Risk Factors for DeathHazard ratio p-valueHazardratiop-value Age (years) 1.58 <.0001 BMI (higher) Not Married Hx of CABG BUN (higher) Total Bilirubin (higher) Creatinine (higher) Ventilator INTERMACS Level INTERMACS Level Bi-VAD 5.05 <.0001 Tricuspid Regurgitation 1.35*.009 * Represents the increased risk for 1 level increase in TV Regurgitation

So, is the real risk factor the procedure or the condition? 28

Months post implant Event: Death with a device in place (censored at transplant and recovery % Survival Concomitant Tricuspid Surgery n deaths None Repair Overall p =.83 INTERMACS: June 2006 – March 2013: TVR Adult Destination Therapy CF primary LVAD/BiVAD, n= Tricuspid Regurg Echo at pre-implant: Moderate/Severe, n=989

No TV Procedure, n=757 TV Repair, n= 215 % Moderate/Severe Tricuspid Regurgitation INTERMACS: June 2006 – March 2013: TVR Moderate/Severe Tricuspid Regurgitation over time by TV Repair vs. No TVR Procedure, n=989 n=757 n=136 n=215 n=50 n=88 n=75 n=46 n=31 n=12 n=21 n=8 n=17 n=9 n=3 Note: N’s represent the number of Moderate/Severe Tricuspid Regurg

Months post implant % Freedom from Exchange Era 2: N=6311, events=522 Era 1: n=2800, Events=273 Continuous Flow LVAD Implants: 2008 – 2013, n=9111 Event: Time to 1 st Exchange p < Pump Thrombosis

Figure 20 Months post implant % Survival Operation 1: N=8565, deaths=2039 Operation 2: n=734, Deaths=242 Continuous Flow LVAD/BiVAD Implants: 2008 – 2013, n=9372 Event: Death (censored at transplant and recovery) p <.0001 Operation 3: n=73, Deaths=29 32

Education War Era Cardiac Surgery These stratified actuarial depictions are very useful, but… They have limited value for predicting outcomes for an individual patient. The stratified actuarial method forces conditions like..”assuming he/she does not receive a heart transplant”, or..”assuming there is not explant for recovery” Ideally, INTERMACS could provide software or website applications that allow the physician to provide the patient with the most useful predictions of the chances of various outcomes occurring to him/her. 33

Education War Era Cardiac Surgery Predictive modeling for outcome events based on initial implant strategy The goal is useful predictions of the likelihood (probability) of a specific patient (with his/her individual risk profile) experiencing a given outcome depending on the initial implant strategy. The basic methodology utilizes multivariable hazard function analyses on the competing outcomes platform. The basic strategies are BTT, BTC, DT, and BTR. The outcome event of interest are Transplant, Alive on device, Explant for recovery, and death. David Naftel will review our initial steps in this process. 34

Months after Implant Proportion of Patients Dead 12% Alive (device in place) 50% Transplanted 37% Recovery 1% BTT: Listed CFLVAD implants , n=1309 Outcome % at 1 year 35 Continuous Flow LVAD/BiVAD Implants: 2008 – 2013, n=9372 Figure 6

Months after Implant Proportion of Patients Dead 15% Alive (device in place) 64% Transplanted 20% Recovery 1% Outcome % at 1 year 36 Continuous Flow LVAD/BiVAD Implants: 2008 – 2013, n=9372 BTC CFLVAD implants , n=2205 Figure 7