1. Global and Disease-Specific Health Status in Patients Undergoing Continuous-Flow Left Ventricular Assist Device Placement Kelsey Flint, MD University of Colorado School of Medicine Division of Cardiology General Cardiology Fellow

2. Survival after LVAD Survival curve for all continuous-flow LVADs in a clinical database Kirklin JHLT 2014

3. Risk Models for Survival After LVAD RV Failure ScoreMELDMELD excluding INR DTRSHMRS BilirubinXXX INRXXX Creatinine/BUNXXXXX Vasopressor useXX ASTXX AgeX AlbuminXX Center volume ≤ 15X Pulmonary artery pressureXX Platelet countX HematocritX AUC derivation0.73-- 0.890.77 AUC validation0.61-0.660.66--0.600.64 Reproduced from Levy JACC 2013

4. Health Status and Heart Failure Heart failure-specific health status is associated with death and hospitalization in patients with heart failure who were medically treated in the outpatient setting. Heidenreich JACC 2006

5. Health Status and CABG The physical component score of the SF-36 had greater impact on 6-month mortality than creatinine or smoking history Health status is also associated with mortality following cardiac surgery, such as CABG Rumsfeld JAMA 1999

6. Health Status and Outcomes After LVAD

7. Flint JHLT 2013

8. Health Status and Outcomes After LVAD Therefore we decided to further study health status in the LVAD setting: – Outside the clinical trial setting, as patients entered in to the clinical trials had uniformly very poor health status – With a generic as well as heart failure-specific health status measure – Measured before and shortly (3 months) after LVAD placement

9. Methods The INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) database is a prospective, observational registry of all FDA-approved LVADs placed at participating centers (N-158) – Health status data are collected pre-operatively and after LVAD at 3,6 and 12 months, then yearly – Hospitalization and mortality outcomes are recorded as they occur and at each follow-up period – The INTERMACS protocol was approved by each institution’s IRB, and individual patient consent was obtained when mandated by the local IRB

10. Methods – Statistics Heart failure-specific health status – KCCQ Global health status – Euroqol 5D visual analog scale (VAS) Based on the skewed distribution of health status scores towards poor health status, KCCQ and VAS scores were broken down into quartiles Inverse propensity weighting (IPW) was used to minimize bias associated with missing health status scores (40%) Kaplan-Meier method assessed the association between health status and mortality and hospitalization Incremental prognostic value of health status was assessed using IPW-weighted Cox proportional hazards – We used the variables included in the HeartMate II Risk Model (age, albumin, creatinine, INR, center volume) as the base model

11. Table 1 Overall N=3836 KCCQ Q1 N= 552 KCCQ Q2 N= 558 KCCQ Q3 N=556 KCCQ Q4 N=559 P-value Age0.292 19-20150 (3.9)12 (2.2)13 (2.3)16 (2.9)20 (3.6) 30-39242 (6.3)34 (6.2)36 (6.5) 28 (5) 40-49513 (13.4)90 (16.3)70 (12.5)65 (11.7)68 (12.2) 50-59972 (25.3)141 (25.5)131 (23.5)145 (26.1)126 (22.5) 60-691330 (34.7)189 (34.2)207 (37.1)177 (31.8)212 (37.9) 70-79597 (15.6)80 (14.5)97 (17.4)111 (20)101 (18.1) ≥ 8032 (0.8)6 (1.1)4 (0.7)6 (1.1)4 (0.7) Female807 (21)26.8%23.8%17.4%14.7%<0.001 Overall N=3836 KCCQ Q1 N= 552 KCCQ Q2 N= 558 KCCQ Q3 N=556 KCCQ Q4 N=559 P-value INTERMACS profile<0.001 1 (Critical cardiogenic shock)500 (13)66 (12)27 (4.8)23 (4.1)26 (4.7) 2 (Progressive decline)1361 (35.5)237 (42.9)197 (34.2)188 (33.8)195 (34.9) 3 (Stable but inotrope dependent)1193 (31.1)162 (29.3)201 (36)202 (36.3)213 (38.1) 4 (Resting symptoms)608 (15.8)73 (12.2)117 (21)110 (19.8)101 (18.1) 5 (Exertion intolerant)112 (2.9)7 (1.2)14 (2.5)25 (4.5)13 (2.3) 6 (Exertion limited)33 (0.9)2 (0.4)3 (0.5)5 (0.9) 7 (Advanced NYHA III)29 (0.8)5 (0.9) 3 (0.5)6 (1.1)

12. Table 1, continued Overall N=3836 KCCQ Q1 N= 552 KCCQ Q2 N= 558 KCCQ Q3 N=556 KCCQ Q4 N=559 P-value Device strategy0.110 Bridge to transplant 788 (20.5)97 (17.6)112 (20.1)102 (18.3)141 (25.2) Bridge to decision1,329 (34.6)169 (30.6)178 (32)183 (32.9)167 (29.9) Destination therapy 1,694 (44.2%)282 (51.1)266 (47.7)269 (48.4)248 (44.4) Other25 (0.7)4 (0.7)2 (0.4) 3 (0.6) Dialysis within 48 hrs 40 (1)9 (1.6)1 (0.2) 2 (0.4)0.005 Mechanical ventilation 210 (5.5)20 (3.6)10 (1.8) 12 (2.1)0.127 IABP918 (23.9)146 (26.4)89 (15.9)86 (15.5)71 (12.7)<0.001 Inotropes3097 (80.7)461 (83.5%)449 (80.5)429 (77)446 (79.8)0.116 Creatinine (mg/dl)1.4 ± 0.6 1.4 ± 0.81.4 ± 0.6 0.880 Hemoglobin (g/dl)11.4 ± 2.111.2 ± 2.111.6 ± 2.011.8 ± 2.011.8 ±2.1<0.001 Sodium (mmol/L)135.0 ± 4.7134.1 ± 4.9134.9 ± 4.8135.3 ± 4.3135.5 ± 4.1<0.001 Albumin (g/dl)3.4 ± 0.73.4 ± 0.63.5 ± 0.73.5 ± 0.63.6 ± 0.6<0.001 INR1.3 ± 0.41.3 ± 0.51.3 ± 0.41.3 ± 0.51.3 ± 0.30.165

13. Baseline and 3-month Health Status and Survival Only 3-month KCCQ was associated with 2-year mortality

14. Baseline and 3-month Health Status and Rehospitalization 3-month KCCQ and VAS score quartiles were associated with 24-month rehospitalizaiton rate

15. Incremental Prognostic Value of Baseline and 3-month Health Status C-statistic (base clinical score only) C-statistic (base clinical + health status measure) C-statistic (base clinical score only) C-statistic (base clinical + health status measure) Outcome: 24-month mortality Outcome: 24-month rehospitalization Baseline KCCQ (N=2225) 0.600.610.510.50 Baseline EQ-5D VAS (N=2205) 0.60 0.510.52 3-month KCCQ (N=2060) 0.600.660.520.55 3-month EQ-5D VAS (N=2005) 0.590.600.520.54 Base clinical score was comprised of the variables included in the HeartMate II Risk Score (Cowger JACC 2013) – age, albumin, creatinine, center volume, INR

16. Limitations Nearly 40% of patients were missing health status data, introducing significant selection bias – We attempted to account for this bias using IPW We were not able to characterize causes of death and hospitalization. This information would be useful as device-related complications leading to death or rehospitalization would not be expected to correlate with patient-reported outcomes.

17. Clinical Implications Very poor pre-operative health status should not preclude LVAD implantation 3-month KCCQ score was associated with long-term mortality, therefore serial assessments of heart failure-specific health status may help inform prognosis and goals of care discussions

18. Implications for Future Study 24-month rehospitalization is poorly predicted by the HeartMate II Risk Score or health status – Further study is needed to better characterize, and eventually predict rehospitalization in this population beyond the existing single-center descriptions 24-month mortality is moderately-well predicted by the HeartMate II Risk Score and health status – Further study is needed to further characterize patient, device and institution-related factors associated with mortality

19. Summary Pre-operative heart failure-specific and global health status are not predictive of mortality or rehospitalization after LVAD – Poor health status does not necessarily preclude LVAD 3-month KCCQ adds incremental prognostic value to an established risk model for predicting 24- month mortality after LVAD – Serial health status measurements after LVAD may be clinically useful

20. Thank you! INTERMACS DAAP Kathy Grady MAHI for analytic support and guidance – John Spertus, MD – Fengming Tang, MS Mentors and colleagues – Larry Allen, MD, MHS – Timothy Fendler, MD

21. Questions?

22. Reference slides

23. Reference material Survival after DT HMII during the the clinical trial vs. post-approval

24. Reference material Retrospective study examining the predictive value of the HMII Risk Score in all patients implanted with a CF-LVAD at Columbia University Medical Center from 3/2004 to 9/2012 (N=201). The HMII RS had a c-stat of 0.56 for the outcome of 90-day mortality in the Columbia population Thomas JHLT 2014

25. Reference The HMII RS was validated at Barnes-Jewish Hospital in 269 consecutive patients receiving the HMII (June 2005 – June 2013). The HMII RS had a c-stat of 0.70 for 90-day mortality Adamo JACC HF 2015

26. Reference ArticlePopulationHealth Status Measure Result Soto Circ 20041516 patients in the EPHESUS trial KCCQKCCQ 1 month after MI complicated by HF was associated with 1-year mortality and hospitalization Kosiborod Circ 2007 1358 patients in the EPHESUS trial KCCQChange in KCCQ from 1 to 3 months after MI complicated by HF was associated with long-term all-cause mortality and rehospitalization Kato Circ J 2011 114 outpatients with HF MLWHFWorse health status was associated with increased risk of cardiac death or hospitalization for HF and all-cause mortality Konstam Am J Card 1996 6797 patients in the SOLVD trial HRQOL measure created from established sources HRQOL was associated with subsequent mortality and HF hospitalizations Additional studies examining the prognostic value of health status in medically treated patients with heart failure.

27. Reference ArticlePopulationHealth Status Measure Result Curtis Medical Care 2002 1,778 patients undergoing CABG under usual care SF-36Worse PCS score was associated with increased in-hospital mortality and prolonged length of stay Lindsay Heart 2001 183 patients undergoing CABG SF-36Worse pre-operative health status was associated with angina 10 months post-CABG Koch Circ 20076,305 patients who underwent CABG Duke Activity Status Index Worse pre-operative and 6 or 12 month post-operative DASI were associated with long-term mortality Additional studies examining the prognostic value of health status in patients undergoing CABG.

28. Continuous-Flow LVAD There are continuous-flow LVAD’s approved by the FDA – the HeartMate II and the Heartware Blood is propelled from the LV to the aorta by a pump with a rotor that rotates in response to the electromotive forces of the motor. HeartMate II is an axial-flow pump – cylindrical rotor with helical blades, causing blood to accelerate in the direction of the rotor’s axis Heartware is a centrifugal-flow pump – rotors are shaped to accelerate blood circumferentially (towards the outer rim of the pump). Unlike the HeartMate II, the Heartware has no mechanical bearings or points of contact between the impeller and the pump housing

29. Quantifying and Qualifying Morbidity in LVAD Candidates Heart failure-specific health status, as measured by the KCCQ, may help capture LVAD-responsive frailty, which likely does not influence outcomes post- LVAD because LVAD-responsive components of a patient’s condition should be largely reversed. Flint Circ HF 2012

30. Methods – Health Status Measures Kansas City Cardiomyopathy Questionnaire (KCCQ) – Measures heart failure-specific health status in 5 domains: physical limitation, heart failure symptoms, social limitation, self-efficacy, health-related quality of life – Answers to questions are converted into a scale of 0-100, with higher scores indicating worse health status Euroqol 5-Dimensions (EQ-5D) – Measures global health status with the EQ-5D index and the visual analog scale (VAS) – The EQ-5D index is weighted to societal-based utilities to calculate quality adjusted life years – The VAS asks patients to indicate on a 100mm line how they would rate their overall health from 0-100, with 0 being the worst health imaginable

31. Patients in the INTERMACS Registry N=11,162 Enrolled prior to mandatory health status reporting N=5,854 Did not receive continuous-flow LVAD N=1,472 Continuous-flow LVAD N=9,690 Eligible for analysis: N=3,836 Baseline KCCQ N=2,225 Baseline VAS N=2,205 3-month KCCQ N=2,060 3-month VAS N=2,005 Missing: N=1,611 29% too sick, 29% enrolled too late N=1,631 33% too sick, 33% enrolled too late N=1,776 63% coordinator too busy, 32% unspecified N=1,831 48% coordinator too busy; 21% unspecified Methods: Final patient cohort selection

32. Results Quartile 1Quartile 2Quartile 3Quartile 4Total KCCQ score, pre-operative 14.3 (9.6, 18.2)28.1 (25.3, 31.5)41.1 (37.5, 45.6)63.8 (56.3, 74.5)34.6 (21.4, 50.5) VAS score, pre-operative 10.0 (5.0, 20.0)30.5 (30.0, 40.0)50.0 (50.0, 60.0)75.0 (70.0, 84.0)43.0 (25.0, 65.0) KCCQ score, 3-month 43.4 (34.8, 49.0)62.2 (58.3, 65.6)76.0 (72.9, 79.2)89.6 (85.7, 93.8)69.3 (54.2, 82.3) VAS score, 3 month 40.0 (9.0, 50.0)70.0 (62.0, 70.0)80.0 (75.0, 80.0)90.0 (88.0, 95.0)75.0 (60.0, 85.0) Median (IQR) of the health status scores in each quartile range

33. Results

34. Discussion Pre-operative heart failure-specific and global health status were not associated with 24- month mortality or rehospitalization following LVAD placement 3-month KCCQ score was associated with 24-month mortality, and added incremental prognostic value when added to a previously validated base clinical model (Heartmate II Risk Model) 3-month KCCQ and VAS scores were associated with 24- month rehospitalization but did not add prognostic value to the Heartmate II Risk Model In general, the predictive value of the Heartmate II Risk Model and health status were moderate for the outcome of mortality, and poor for the outcome of hospitalization

35. Discussion LVAD is a significant intervention aimed at reversing the hemodynamic effects of advanced heart failure – Unlike medical management of heart failure or CABG, LVAD may potentially reverse the adverse effects of heart failure – Therefore, pre-operative health status may no longer be relevant

36. Discussion Heart failure-specific health status may reflect LVAD- responsive frailty. Therefore low heart failure-specific health status by 3 months after LVAD (when most patients will have recovered from surgery) portends a poor prognosis by signifying lack of the expected benefit from the device. Flint Circ HF 2012