Survival following VAD Survival following VAD complications: implications for complications: implications for

transplant priority.transplant priority.

Todd Dardas, MD, MSTodd Dardas, MD, MS

May 16, 2015May 16, 2015

DisclosuresDisclosures

• Funding: Funding: – American College of Cardiology/Sankyo American College of Cardiology/Sankyo

Daiichi Career Development GrantDaiichi Career Development Grant

Candidate survivalCandidate survival

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

Dardas T, et al J Am Coll Cardiol 2012

Status 1A exceptionsStatus 1A exceptions

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

UNOS 1A(b) justificationsUNOS 1A(b) justifications

Unpublished data, UNOS registry

Tier ProposalsTier Proposals1.1. MCS with arrhythmiasMCS with arrhythmias, non-dischargeable , non-dischargeable

VADVAD

2.2. Device malfunctionDevice malfunction, IABP , IABP

3.3. MCS (infection, thromboembolism, other MCS (infection, thromboembolism, other complications), LVAD 30 days, dual complications), LVAD 30 days, dual inotropes inotropes

4.4. Inotrope w/o HD monitor, stable VADInotrope w/o HD monitor, stable VAD

5.5. Multi-organ transplantsMulti-organ transplants

6.6. Remaining candidatesRemaining candidates

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

Guidance from OPTNGuidance from OPTN

1.1. Aortic insufficiencyAortic insufficiency2.2. HemolysisHemolysis3.3. Pump thrombosisPump thrombosis4.4. Pump-related local or systemic infectionPump-related local or systemic infection5.5. BleedingBleeding6.6. Right heart failureRight heart failure7.7. Recrudescent arrhythmiasRecrudescent arrhythmias8.8. Device malfunctionDevice malfunction

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

OPTN infection guidanceOPTN infection guidancePump-related or systemic infection with one of:Pump-related or systemic infection with one of:•Symptoms along driveline with leukocytosis AND:Symptoms along driveline with leukocytosis AND:

+ blood culture or+ blood culture or

+ site culture+ site culture•Surgical debridement of the driveline AND + site Surgical debridement of the driveline AND + site cultureculture•+ Pump pocket culture+ Pump pocket culture•Bacteremia with the same organism 4 weeks Bacteremia with the same organism 4 weeks following treatmentfollowing 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

Research aimsResearch aims

• Determine mortality for complications Determine mortality for complications following CF VAD placement and compare following CF VAD placement and compare to non-MCS UNOS candidates.to non-MCS UNOS candidates.

• Evaluate whether subgroups within Evaluate whether subgroups within complications have distinct risks useful for complications have distinct risks useful for ranking in the tier system.ranking in the tier system.

MethodsMethods• INTERMACS data for all primary implants of CF INTERMACS data for all primary implants of CF

devices implanted between 4/2012 and 3/2014devices 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 pointMultiple complications per time point– First and isolated complicationFirst and isolated complication– First infection of any number reportedFirst infection of any number reported

• OPTN/UNOS registry data for patients without OPTN/UNOS registry data for patients without MCSMCS

SampleSample

Complications/ interval

Strategy

Other BTT BTE DT Total

0 5 151 186 299 641

1 162 2,607 4,320 6,011 13,100

2 53 808 1,385 2,052 4,298

3 12 118 207 342 679

4 1 24 44 87 156

5 1 9 9 17 36

6 0 1 4 3 8

7 0 0 4 0 4

OutcomeOutcome

• Death during VAD supportDeath during VAD support

• Censoring at transplant or recoveryCensoring at transplant or recovery

SampleSample

• 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

Mortality following first complicationMortality following first complication

N = 3616

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

INTERMACS AEsINTERMACS 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 reportedMortality following first AE reportedAdverse Event

Cumulative hazard at 90 days following report

Std. err.

Renal Dysfunction 0.46 0.09 Neurological Dysfunction 0.45 0.10 Respiratory Failure 0.21 0.04 Device Malfunction 0.21 0.10 Right Heart Failure 0.17 0.04 Bleeding 0.15 0.02 Pericardial Drainage 0.12 0.05 Infection 0.12 0.02 Other SAE 0.10 0.02 Venous Thromboemb. 0.08 0.06 Hemolysis 0.07 0.05 Cardiac Arrhythmia 0.07 0.01 Psychiatric Episode 0.05 0.03

Status 1A

Status 1B

11stst Infection AE Infection AE

N= 4632

Adjusting for initial device strategyAdjusting for initial device strategy

Variables Hazard ratio P-value

AE infection 3.1 <0.0001

DT Ref

BTT 0.58 <0.0001

BTE 0.67 <0.0001

Other strategy 0.97 0.92

Comparison to OPTN StatusComparison to OPTN Status

Status 1A

Status 1B

Infection DefinitionInfection DefinitionOPTNOPTN

One of:One of:•Symptoms along driveline Symptoms along driveline with leukocytosis AND:with leukocytosis AND:

• + blood culture+ blood culture• + site culture+ site culture

•Surgical debridement AND Surgical debridement AND + site culture+ site culture•+ pump pocket culture+ pump pocket culture•Bacteremia 4 wks s/p Bacteremia 4 wks s/p treatmenttreatment

INTERMACSINTERMACS

•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

INTERMACS subgroupsINTERMACS subgroups

All p-values <0.01 vs. No infection AE

Adjusted for initial device strategyAdjusted for initial device strategy

Variable Hazard ratio P-value

Infection AE

No Inf. AE reported Ref

Localized, non-VAD 3.2 <0.0001

Perc. lead/pocket 1.9 <0.0001

Device component 8.5 0.003

Sepsis 3.8 <0.0001

Strategy

DT Ref

BTT 0.58 <0.0001

BTE 0.68 <0.0001

Other 0.95 0.86

INTERMACS AEs & OPTN statusINTERMACS AEs & OPTN status

Status 1A

Status 1B

Driveline vs. No inf. AE p=0.13All other p-values <0.01

Tier ProposalsTier Proposals1.1. MCS with arrhythmiasMCS with arrhythmias, non-dischargeable , non-dischargeable

VADVAD

2.2. MCS sepsis OR pump pocket/internal device MCS sepsis OR pump pocket/internal device infection OR localized infectioninfection OR localized infection, IABP , IABP

3.3. MCS driveline infectionMCS driveline infection, thromboembolism, , thromboembolism, LVAD 30 days, dual inotropes LVAD 30 days, dual inotropes

4.4. Inotrope w/o HD monitor, stable VADInotrope w/o HD monitor, stable VADMeyer D, et. al. American Journal of Transplantation 2015; 15: 44–54

ConsiderationsConsiderations

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

Changing device strategyChanging device strategy

Teuteberg J, et. al. J Am Coll Cardiol HF 2013

BTT vs DT: 90-day mortalityBTT vs DT: 90-day mortalityAE type BTT DT DT - BTT

Bleeding 0.12 0.18 0.06

Cardiac Arrhythmia 0.01 0.12 0.11

Infection 0.14 0.12 -0.02

Neurological Dysfunction 0.22 0.59 0.37

Other SAE 0.02 0.16 0.13

Psychiatric Episode 0.07 0.00 -0.07

Renal Dysfunction 0.24 0.55 0.30

Respiratory Failure 0.23 0.28 0.05

Right Heart Failure 0.08 0.23 0.15

ConsiderationsConsiderations

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

Stratified complications?Stratified complications?

YesYes• InfectionsInfections• Right heart Right heart

failurefailure• BleedingBleeding• HemolysisHemolysis

NoNo• Device Device

malfunctionmalfunction

MaybeMaybe• Ventricular Ventricular

arrhythmiasarrhythmias• ThrombosisThrombosis• Aortic regurg.Aortic regurg.

ConclusionsConclusions

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

• Susan MeyerSusan Meyer

• Frank PaganiFrank Pagani

• Kent ShivelyKent Shively

Mortality following first AE reportedMortality following first AE reportedAdverse Event

Cumulative hazard at 90 days following report

Std. err. At risk Deaths

Renal Dysfunction 0.46 0.09 53 30 Neurological Dysfunction 0.45 0.10 56 24 Respiratory Failure 0.21 0.04 95 22 Device Malfunction 0.21 0.10 38 5 Right Heart Failure 0.17 0.04 170 29 Bleeding 0.15 0.02 367 55 Pericardial Drainage 0.12 0.05 46 6 Infection 0.12 0.02 238 25 Other SAE 0.10 0.02 224 22 Venous Thromboemb. 0.08 0.06 23 2 Hemolysis 0.07 0.05 33 2 Cardiac Arrhythmia 0.07 0.01 291 22 Psychiatric Episode 0.05 0.03 41 2

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

Status 1A

Status 1B