Presentations: Quantifying the impact of adverse events on HRQOL early after implant Patient selection and estimation of prognosis using health status measures Predicting patients at risk for poor global outcomes after DT MCS therapy INTERMACS 9 th Annual Meeting May , 2015 Quality of Life Session

Actuarial survival for primary device implant, stratified by device type. Error bars indicate ± 1 SE. Patients are censored at transplant and recovery. CF, continuous flow; LVAD, left ventricular assist device; PF, pulsatile flow; TAH, total arti... Kirklin JK, Naftel DC, Pagani FD, et al., Sixth INTERMACS annual report: A 10,000-patient database. The Journal of Heart and Lung Transplantation, 2014;33(6):555 – 564. Improvement in Survival after LVAD Implant

Actuarial survival for primary device implant, stratified by device type. Error bars indicate ± 1 SE. Patients are censored at transplant and recovery. CF, continuous flow; LVAD, left ventricular assist device; PF, pulsatile flow; TAH, total arti... Kirklin JK, Naftel DC, Pagani FD, et al., Sixth INTERMACS annual report: A 10,000-patient database. The Journal of Heart and Lung Transplantation, 2014;33(6):555 – 564. Improvement in Survival after LVAD Implant ↓ adverse events

The Time is Right … to Assess Quality of Life after LVAD Implant Since 1948, when the World Health Organization defined health as being not only the absence of disease and infirmity, but also the presence of physical, mental, and social well-being, quality of life issues have become steadily more important in health care practice and research. Testa & Simonson, NEJM, 1996

What is the Clinical Importance of Measuring QOL? Clinical Inform shared decision making Diagnosis or screening Monitoring patients in routine clinical care Evaluating benefits and risks of treatment Prognosis Quality assessment / improvement

Why Study QOL Outcomes? Research ● Determine the benefits of one treatment versus another regarding outcomes that are important to patients (e.g., HRQOL) ● Differentiate HRQOL benefits of two therapies with marginal differences in mortality or morbidity ● Estimate the burden of different diseases ● Compare impact of different diseases on functioning and well-being ● Inform relationships between QOL outcomes and clinical outcomes

INTERMACS HRQOL Abstracts and Publications Abstracts (published): 7 abstracts Articles (published): Beyond survival: Recommendations from INTERMACS for Assessing Function and Quality of Life with Mechanical Circulatory Support Grady KL, Warner Stevenson L, Pagani FD, Teuteberg J, Pamboukian SV, Birks E, Moore S, Kirklin JK. J Heart Lung Transplant Nov;31(11): Overall Quality of Life Improves to Similar Levels after Mechanical Circulatory Support Regardless of Severity of Heart Failure before Implantation Grady KL, Naftel D, Stevenson L, Dew MA, Weidner G, Pagani FD, Kirklin JK, Myers S, Baldwin T, Young J. J Heart Lung Transplant April;33 (4): Change in Health-Related Quality of Life from Before to After Destination Therapy Mechanical Circulatory Support is Similar for Older and Younger Patients: Analyses from INTERMACS Grady KL, Naftel DC, Myers S, Dew MA, Weidner G, Spertus JA, Idrissi K, Lee HB, McGee EC, Kirklin JK. J Heart Lung Transplant Feb;34(2): Articles (submitted): Age and gender differences in HRQOL and factors related to change in HRQOL from before to 6 months after LVAD implantation: Findings from INTERMACS Grady KL, Wissman S, Naftel D, Myers S, Gelijns A, Moskowitz A, Pagani F, Young J, Kirklin JK. J Heart Lung Transplant.

INTERMACS Pre-implant Data for June 2006 through March 2015 for Patients at Primary Implant EQ-5D Completion by Implant Year Implant YearCompletedNot CompletedTotal (27%)70 (73%) (30%)237 (70%) (41%)439 (59%) (45%)553 (55%) (55%)747 (45%) (53%)895 (47%) (59%)937 (41%) (57%)1190 (43%) (55%)1204 (45%) (59%)238 (41%)581 Total7529 (54%)6510 (46%)14039 INTERMACS HRQOL Data Capture across Time

INTERMACS Pre-implant Data for June 2006 through March 2015 for Patients at Primary Implant EQ-5D Completion (with non-completion reasons) by Implant Year Implant YearCompleted Not completed - reason other than too sick Not completed – too sick Total (27%)21 (22%)49 (51%) (30%)79 (23%)158 (47%) (41%)208 (28%)231 (31%) (45%)304 (30%)249 (25%) (55%)449 (27%)298 (18%) (53%)531 (28%)364 (19%) (59%)613 (27%)324 (14%) (57%)807 (29%)383 (14%) (55%)726 (27%)478 (18%) (59%)141 (24%)97 (17%)581 Total7529 (54%)3879 (27%)2631 (19%)14039 INTERMACS HRQOL Data Capture across Time

Grady KL, Wissman S, Naftel D, Myers S, Gelijns A, Moskowitz A, Pagani F, Young J, Kirklin JK I will not discuss off label use and/or investigational use of drugs/devices. Quantifying the Impact of Adverse Events on Health-Related Quality of Life Early after Implant

Background –Risk factors for poor HRQOL after LVAD implant are unknown –Understanding risk factors May inform selection criteria for device implant Reinforce the ongoing need to improve device technology, in order to reduce rates of adverse events Purpose –Identify pre and post implant factors related to change in overall HRQOL from before to 6 months after LVAD implantation –Rationale for 6month post implant time period Patients are adjusting to “life on a device” while potentially dealing with early post implant adverse events

Pool: Adult primary CFLVADs implanted Jun 2006 – Mar 2013 (follow-up thru March 2014) N=7353 Pre-implant patients, n=7353 Patients with completed* pre-implant EQ-5D VAS n=5640 (77%) Patients with both completed* pre-implant and 6 month post implant EQ-5D VAS n= 2748 (37% of total cohort) 6 month post implant patients, n=5931 patients with completed* 6 month EQ-5D VAS n=3353 (57%) Study Cohort, n=7353 (from 133 sites) METHODS *completed includes patients who filled out the EQ-5D and also those patients captured as ‘too sick’. ‘Too sick’ patients were assigned 0 for the VAS and ‘extreme problems’ for the 3 physical dimensions of Mobility, Self Care and Usual Activities

Pool: Adult primary CFLVADs implanted Jun 2006 – Mar 2013 (follow-up thru March 2014) N=7353 (133 sites) Pre-implant patients, n=7353 Patients with completed* pre-implant EQ-5D VAS n=5640 (77%) Patients with both completed* pre-implant and 6 month post implant EQ-5D VAS n= 2748 (37% of total cohort) 6 month post implant patients, n=5931 patients with completed* 6 month EQ-5D VAS n=3353 (57%) Study Cohort, n=7353 *completed includes patients who filled out the EQ-5D and also those patients captured as ‘too sick’. ‘Too sick’ patients were assigned 0 for the VAS and ‘extreme problems’ for the 3 physical dimensions of Mobility, Self Care and Usual Activities

METHODS (cont.) Procedures Approval from all INTERMACS site IRBs Written consent from patients Patients completed a self-report HRQOL survey pre- implant and post-implant at 3 and 6 months Medical records data collected per INTERMACS protocols HRQOL instrument EQ – 5D – 3L Survey – Generic, self-report health profile – HRQOL items: 1 VAS scale (health status) and 5 questions – If incomplete EQ-5D reason is “too sick”, VAS is assigned 0 – Reliable and valid & norms in multiple populations Statistics Pearson correlations and multiple regression analyses

Mobility I have no problems in walking about  I have some problems in walking about  I am confined to bed  Self-Care I have no problems with self-care  I have some problems washing or dressing myself  I am unable to wash or dress myself  Usual Activities ( e.g. work, study, housework, family or leisure activities) I have no problems with performing my usual activities  I have some problems with performing my usual activities  I am unable to perform my usual activities  Pain/Discomfort I have no pain or discomfort  I have moderate pain or discomfort  I have extreme pain or discomfort  Anxiety/Depression I am not anxious or depressed  I am moderately anxious or depressed  I am extremely anxious or depressed  EQ-5D-3L Health Questionnaire English version for the U.S. HRQOL Instrument

RESULTS RESULTS Characteristics of CF LVAD Patients Pre-implant Pre-implant LVAD with EQ-5D data (n=5640) Pre-implant LVAD w/out EQ-5D data (n=1713)p-value Age at implant (mean yr+ SD) Male (%) Race (% white) Married at implant (%) >HS education (%) INTERMACS profile at implant (%) < < <

Months Post Implant Proportion of Patients Pre-implant 88% 77% 60% 4% 0% 8% 11% 12% 0% 22% 17% 1% MCS Competing Outcomes Depiction & Rates of EQ-5D Completion after implant Alive (device in place) Txpl Dead Recovery April 2008 – March 2013 **completed forms includes patients who filled out the EQ-5D and also those patients captured as ‘too sick’ to complete the EQ-5D. ‘Too sick’ patients were assigned a value of 0 for the VAS and ‘extreme problems’ for the 3 physical dimensions of Mobility, Self Care and Usual Activities 100%

VAS Scores pre and post implant & change in VAS scores over time Pre-implant 6 months VAS (n=5640**) (n=3353**) 0 – (48.1%) 404 (12.1%) 26 – (28.2%) 347 (10.3%) 51 – (16.1%) 974 (29.0%) 76 – (7.6%) 1628 (48.6%) Total5640 (100%) 3353 (100%) Change in VAS (n=2748*) n % Increase > % 11 – % 1 – % Decrease (or no change) 0 – % 11 – % > % * Only includes paired data (patients with both pre and post 6 months completed EQ-5D) ** completed forms includes patients who filled out the EQ-5D and also those patients captured as ‘too sick’ to complete the EQ-5D. ‘Too sick’ patients were assigned a value of 0 for the VAS.

Factors Associated with Change in HRQOL Pre-implant – 6 months post implant Risk Factors Estimates (SE)p value Pre-implant conditions INTERMACS Level (1.6)0.002 BTT: Listed -3.7 (1.2)0.002 Pre COPD -5.1 (1.8)0.005 Alcohol abuse -4.1 (1.7)0.02 Pre-implant VAS Score (0.02) < Clinical Course BTT: Unlikely at 6 months -9.6 (2.9) BTT: Mod likely at 6 months -4.8 (1.9)0.01 NYHA 4 at 6 months-15.2 (2.9) < Events within first 6 months Renal Dysfunction -5.3 (2.5)0.03 Respiratory Failure -4.8 (1.8)0.007 Neurological Dysfunction -5.5 (1.9) Infection -2.8 (1.1)0.01 Intercept = 64.2, R 2 = 41.3%, n=2748 HRQOL=health-related quality of life; INTERMACS=interagency Registry for Mechanically Assisted Circulatory Support; BTT=bridge to transplant; COPD=chronic obstructive pulmonary disease; VAS=visual analog scale Negative coefficients indicate the decrement in change The Intercept indicates the amount of change (improvement) for a patient with no ‘risk factors’

Prediction of VAS at 6 months post implant, n=2748 Level 1 Pre-implant: Critical Cardiogenic Shock (n=337) Visual Analog Score (VAS) Time Course Level 1 Events during 1 st 6 months Renal Respiratory Neuro Infection No No No No Yes No No Yes Yes No Yes Yes Yes Yes Yes Yes Predictions of post implant VAS score by pre implant INTERMACS Profile

Prediction of VAS at 6 months post implant, n=2748 Level 2 Pre-implant: Progressive Decline (n=1119) Predictions of post implant VAS score by pre implant INTERMACS Profile Visual Analog Score (VAS) Time Course Level 2 Events during 1 st 6 months Renal Respiratory Neuro Infection No No No No Yes No No Yes Yes No Yes Yes Yes Yes Yes Yes

Prediction of VAS at 6 months post implant, n=2748 Level 3 Pre-implant: Stable but Inotrope Dependent (n=819) Predictions of post implant VAS score by pre implant INTERMACS Profile Visual Analog Score (VAS) Time Course Level 3 Events during 1 st 6 months Renal Respiratory Neuro Infection No No No No Yes No No Yes Yes No Yes Yes Yes Yes Yes Yes

Predictions of VAS at 6 months post implant, n=2748 Levels Pre-implant (n=473) Predictions of post implant VAS score by pre implant INTERMACS Profile Visual Analog Score (VAS) Time Course Levels 4-7 Events during 1 st 6 months Renal Respiratory Neuro Infection No No No No Yes No No Yes Yes No Yes Yes Yes Yes Yes Yes

CONCLUSIONS Patients who are the sickest have the greatest opportunity for major improvement in HRQOL after implant Patients with co-morbidities that prevent listing for HT may have limited HRQOL improvement Adverse events have a detrimental impact on HRQOL at 6 months after implant

IMPLICATIONS These findings support the ongoing need to – evaluate co-morbid risks before implant – continue to improve device technology to enhance post implant HRQOL