1. Survival following VAD complications: implications for transplant priority. Todd Dardas, MD, MS May 16, 2015

2. Disclosures Funding:Funding: –American College of Cardiology/Sankyo Daiichi Career Development Grant

3. Candidate survival Wever-Pinzon, O, et. al.; Circulation 2012

4. Dardas T, et al J Am Coll Cardiol 2012

5. Status 1A exceptions Meyer D, et. al. American Journal of Transplantation 2015; 15: 44–54

6. UNOS 1A(b) justifications Unpublished data, UNOS registry

7. Tier Proposals 1.MCS with arrhythmias, non-dischargeable VAD 2.Device malfunction, IABP 3.MCS (infection, thromboembolism, other complications), LVAD 30 days, dual inotropes 4.Inotrope w/o HD monitor, stable VAD 5.Multi-organ transplants 6.Remaining candidates Meyer D, et. al. American Journal of Transplantation 2015; 15: 44–54

8. Guidance from OPTN 1.Aortic insufficiency 2.Hemolysis 3.Pump thrombosis 4.Pump-related local or systemic infection 5.Bleeding 6.Right heart failure 7.Recrudescent arrhythmias 8.Device malfunction Meyer D, et. al. American Journal of Transplantation 2015; 15: 44–54

9. OPTN infection guidance Pump-related or systemic infection with one of: Symptoms along driveline with leukocytosis AND:Symptoms along driveline with leukocytosis AND: + blood culture or + site culture Surgical debridement of the driveline AND + site cultureSurgical debridement of the driveline AND + site culture + Pump pocket culture+ Pump pocket culture Bacteremia with the same organism 4 weeks following treatmentBacteremia with the same organism 4 weeks following treatment Meyer D, et. al. American Journal of Transplantation 2015; 15: 44–54; http://www.uab.edu/medicine/intermacs/appendices-4-0/appendix-a-4-0

10. Research aims Determine mortality for complications following CF VAD placement and compare to non-MCS UNOS candidates.Determine mortality for complications following CF VAD placement and compare to non-MCS UNOS candidates. Evaluate whether subgroups within complications have distinct risks useful for ranking in the tier system.Evaluate whether subgroups within complications have distinct risks useful for ranking in the tier system.

11. Methods INTERMACS data for all primary implants of CF devices implanted between 4/2012 and 3/2014INTERMACS data for all primary implants of CF devices implanted between 4/2012 and 3/2014 DT and BTT included unless otherwise specifiedDT and BTT included unless otherwise specified Complications:Complications: –Multiple complications per time point –First and isolated complication –First infection of any number reported OPTN/UNOS registry data for patients without MCSOPTN/UNOS registry data for patients without MCS

12. Sample Complications/ interval Strategy OtherBTTBTEDTTotal 05151186299641 11622,6074,3206,01113,100 2538081,3852,0524,298 312118207342679 41244487156 51991736 601438 700404

13. Outcome Death during VAD supportDeath during VAD support Censoring at transplant or recoveryCensoring at transplant or recovery

14. Sample 4725 primary CF VAD implants4725 primary CF VAD implants 22,524 complications22,524 complications 2975 1st and isolated complications2975 1st and isolated complications No AE report n=641No AE report n=641 Final cohort: n= 3616Final cohort: n= 3616

15. Mortality following first complication N = 3616

16. Kirklin J et. al., J Heart Lung Transplant 2013

17. INTERMACS AEs Hemolysis Respiratory Failure Right Heart Failure Venous Thromboembolism Device Malfunction Wound Dehiscence Major Bleeding Arterial Non-CNS embolism Major Infection Other SAE Neurological Dysfunction Hepatic Dysfunction Cardiac Arrhythmias Hypertension Pericardial Fluid Collection Myocardial Infarction Psychiatric Episode Renal Dysfunction

18. Mortality following first AE reported Adverse Event Cumulative hazard at 90 days following report Std. err. Renal Dysfunction0.460.09 Neurological Dysfunction0.450.10 Respiratory Failure0.210.04 Device Malfunction0.210.10 Right Heart Failure0.170.04 Bleeding0.150.02 Pericardial Drainage0.120.05 Infection0.120.02 Other SAE0.100.02 Venous Thromboemb.0.080.06 Hemolysis0.070.05 Cardiac Arrhythmia0.070.01 Psychiatric Episode0.050.03 Status 1A Status 1B

19. 1 st Infection AE N= 4632

20. Adjusting for initial device strategy VariablesHazard ratioP-value AE infection3.1<0.0001 DTRef BTT0.58<0.0001 BTE0.67<0.0001 Other strategy0.970.92

21. Comparison to OPTN Status Status 1A Status 1B

22. Infection Definition OPTN One of: Symptoms along driveline with leukocytosis AND:Symptoms along driveline with leukocytosis AND: + blood culture+ blood culture + site culture+ site culture Surgical debridement AND + site cultureSurgical debridement AND + site culture + pump pocket culture+ pump pocket culture Bacteremia 4 wks s/p treatmentBacteremia 4 wks s/p treatment INTERMACS Localized non-deviceLocalized non-device Driveline or pump pocketDriveline or pump pocket SepsisSepsis Internal pump componentInternal pump component Meyer D, et. al. American Journal of Transplantation 2015; 15: 44–54; http://www.uab.edu/medicine/intermacs/appendices-4-0/appendix-a-4-0

23. INTERMACS subgroups All p-values <0.01 vs. No infection AE

24. Adjusted for initial device strategy VariableHazard ratioP-value Infection AE No Inf. AE reportedRef Localized, non-VAD3.2<0.0001 Perc. lead/pocket1.9<0.0001 Device component8.50.003 Sepsis3.8<0.0001 Strategy DTRef BTT0.58<0.0001 BTE0.68<0.0001 Other0.950.86

25. INTERMACS AEs & OPTN status Status 1A Status 1B Driveline vs. No inf. AE p=0.13 All other p-values <0.01

26. Tier Proposals 1.MCS with arrhythmias, non-dischargeable VAD 2.MCS sepsis OR pump pocket/internal device infection OR localized infection, IABP 3.MCS driveline infection, thromboembolism, LVAD 30 days, dual inotropes 4.Inotrope w/o HD monitor, stable VAD Meyer D, et. al. American Journal of Transplantation 2015; 15: 44–54

27. Considerations How should continued eligibility be weighted in priority decisions?How should continued eligibility be weighted in priority decisions?

28. Changing device strategy Teuteberg J, et. al. J Am Coll Cardiol HF 2013

29. BTT vs DT: 90-day mortality AE typeBTTDTDT - BTT Bleeding0.120.180.06 Cardiac Arrhythmia0.010.120.11 Infection0.140.12-0.02 Neurological Dysfunction0.220.590.37 Other SAE0.020.160.13 Psychiatric Episode0.070.00-0.07 Renal Dysfunction0.240.550.30 Respiratory Failure0.230.280.05 Right Heart Failure0.080.230.15

30. Considerations How many subgroups should be identified and analyzed?How many subgroups should be identified and analyzed?

31. Stratified complications? Yes InfectionsInfections Right heart failureRight heart failure BleedingBleeding HemolysisHemolysis No Device malfunctionDevice malfunction Maybe Ventricular arrhythmiasVentricular arrhythmias ThrombosisThrombosis Aortic regurg.Aortic regurg.

32. Conclusions Subgroups of patients within broad complication types may warrant further characterization and stratification by INTERMACS definitions

33. Susan MeyerSusan Meyer Frank PaganiFrank Pagani Kent ShivelyKent Shively

34. Mortality following first AE reported Adverse Event Cumulative hazard at 90 days following report Std. err.At riskDeaths Renal Dysfunction0.460.095330 Neurological Dysfunction0.450.105624 Respiratory Failure0.210.049522 Device Malfunction0.210.10385 Right Heart Failure0.170.0417029 Bleeding0.150.0236755 Pericardial Drainage0.120.05466 Infection0.120.0223825 Other SAE0.100.0222422 Venous Thromboemb.0.080.06232 Hemolysis0.070.05332 Cardiac Arrhythmia0.070.0129122 Psychiatric Episode0.050.03412

35. Risk of first AE relative to Status 1A/B Status 1A Status 1B