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

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

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

Dardas T, et al J Am Coll Cardiol 2012

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

UNOS 1A(b) justifications Unpublished data, UNOS registry

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

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

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;

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.

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

Sample Complications/ interval Strategy OtherBTTBTEDTTotal ,6074,3206,01113, ,3852,0524,

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

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

Mortality following first complication N = 3616

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

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

Mortality following first AE reported Adverse Event Cumulative hazard at 90 days following report Std. err. Renal Dysfunction Neurological Dysfunction Respiratory Failure Device Malfunction Right Heart Failure Bleeding Pericardial Drainage Infection Other SAE Venous Thromboemb Hemolysis Cardiac Arrhythmia Psychiatric Episode Status 1A Status 1B

1 st Infection AE N= 4632

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

Comparison to OPTN Status Status 1A Status 1B

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;

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

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

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

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

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

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

BTT vs DT: 90-day mortality AE typeBTTDTDT - BTT Bleeding Cardiac Arrhythmia Infection Neurological Dysfunction Other SAE Psychiatric Episode Renal Dysfunction Respiratory Failure Right Heart Failure

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

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

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

Susan MeyerSusan Meyer Frank PaganiFrank Pagani Kent ShivelyKent Shively

Mortality following first AE reported Adverse Event Cumulative hazard at 90 days following report Std. err.At riskDeaths Renal Dysfunction Neurological Dysfunction Respiratory Failure Device Malfunction Right Heart Failure Bleeding Pericardial Drainage Infection Other SAE Venous Thromboemb Hemolysis Cardiac Arrhythmia Psychiatric Episode

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