Liver Transplant Outcomes in the United States : Effect of Preservation Solution DKFC Symposium July 16, 2012 John Fung, MD, PhD Cleveland Clinic Disclosure:

Liver Transplant Outcomes in the United States : Effect of Preservation

Solution

DKFC SymposiumJuly 16, 2012

John Fung, MD, PhD

Cleveland Clinic

Disclosure: I have been a past consultant for both Dupont and Odyssey

Recent Retrospective Database Reviews

Theme of 3 studies: These results suggest that the increasing use of HTK for abdominal organ preservation should be reexamined

Liver Preservation

Liver Preservation

Indiana University, 2001 to 2008

All adult, deceased donor

n=1013 HTK 632, UW 381

Simultaneous, retrospective

Liver Preservation

Post-liver transplant serum total bilirubin, n=1013

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Days post-transplant

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UW

Post-liver transplant serum ALT, n=1013

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UW

Indiana University, 2001 to 2008

All adult, deceased donorSimultaneous, retrospective

n=1013 HTK 632 UW 381 Serum ALT

Serum Bilirubin

Using the SRTR Database

• Only adult first liver-only transplants from 2002-2008 were included and only for those whom flush and storage solutions were the same

• All patients had minimum one year follow up• 25,616 patients, 20,901 (82%) with UW and

4,715 (18%) with HTK• Mean follow-up: 2.7 ± 1.7 years (2.9 ± 1.7 for

UW and 1.8 ± 1.1 for HTK)

Statistical Analysis

• Three comparisons:• Unadjusted graft survival• Bootstrapping hazard modeling using risk

factors for graft survival determined using non-proportional, multiphase, multivariable hazard methodology with >100 clinically relevant recipient, donor, and procedure variables

• Propensity-matched comparison for 50 most important variables

Bootstrapping• A random sample of patients is drawn from the original

data - patients are drawn one at a time, with replacement, until a new dataset of the same size has been created

• When the new dataset has been created, the stepwise regression technique is run again to see what significant predictors it finds and the process is repeated multiple times

• The bootstrap percentage is the percent of runs in which the variable appeared, so the higher the percentage, the more certain is the impact of that variable - those appearing in >50% of runs were considered reliably statistically significant at p<0.001

Adjusting for Multiple Tests

No. of independent tests 2 5 10 20 50

Probability of one or more p < 0.05 by chance

10% 23% 40% 64% 92%

To keep alpha = 0.05

accept as significant only p less than

0.025 0.010 0.005 0.002 0.001

Use p = 0.05 / no. of tests

Results

• Validation of reported significant recipient factors of graft failure in the early and later phases after DDLT

• OPS did not appear as a statistically significant predictor of graft failure – hospital death, re-transplant rates and

relisting rates were not different

UW n = 20,901 HTK n = 4,715 PS: p = 0.90 log rank test

GS: p = 0.60 

Unadjusted Patient and Graft Survival - HTK vs UWAdult LTX from 2002-2008

7,883 UW 10,484 UW1,826 HTK 2,314 HTK

DRI < 2.5 p = 0.20 log rank test DRI >2.5: p = 0.20 

Unadjusted Patient and Graft Survival - HTK vs UWAdult LTX from 2002-2008: By DRI - 2.5

14,053 UW 6,119 UW3,279 HTK 1,177 HTK

CIT < 8 hr p = 0.70 log rank test CIT >8 hr: p = 0.50 

Unadjusted Patient and Graft Survival - HTK vs UWAdult LTX from 2002-2008: By CIT - 8 hrs (non-DCD)

19,082 UW 1,090 UW4,253 HTK 203 HTK

CIT < 12 hr p = 0.80 log rank test CIT >12 hr: p = 0.60 

Unadjusted Patient and Graft Survival - HTK vs UWAdult LTX from 2002-2008: By CIT - 12 hrs (non-DCD)

Risk Factor P Bootstrap %

Early hazard phase

Older recipient age (years) <.0001 96

Recipient race White or Black <.0001 69

Recipient portal vein thrombosis <.0001 99

Recipient previous abdominal surgery <.0001 67

Candidate last creatinine (used for MELD) <.0001 96

Candidate last MELD <.0001 76

Recipient on life support just prior to tx <.0001 100

Recipient previous kidney transplant <.0001 87

Donor race non-White <.0001 89

Donor donation after cardiac death <.0001 100

Donor risk index <.0001 58

Risk Factors for Graft Failure - Early Phase

Risk Factors for Graft Failure - Constant Phase

Risk Factor P Bootstrap %

Late hazard phase

African American recipient <.0001 98

Recipient primary diagnosis for tumors <.0001 94

Recipient hepatitis C virus <.0001 100

Donor age (years) <.0001 100

Donor history of diabetes <.0001 70

Limitations of the Hopkins UNOS Analysis

• Used case-wise deletion of missing data, i.e. used only patients for whom all variables were reported - the actual number of cases deleted not provided

• Last case included was 2/28/08 - the paper was submitted on 7/17/08.  Allowing a minimum of 45 days to analyze and write the paper, the latest data cutoff was 6/1/08. Using UNOS timelines for a 6/1/08 cutoff, there would only have been data for transplants performed before 11/1/07 

Unadjusted 1-year Graft Survival Rates by Year of Transplant

Year     UW Survival Curve    HTK Survival Curve

N    1-yr survival N   1-yr survival p

2002   3684    83.5%    65     81.5% .86

2003   3889    82.9%        183    78.1%     .083

2004    3687    83.6%         535  80.6%     .067

2005    3247    82.2%         1167    81.8%     .88

2006    3052    83.6%          1398    84.1%     .71

2007    3083    84.5%     1274    87.6%    .20

Liver Transplant Graft SurvivalSRTR Data, 2000-2010, N=55110, Age 18+

By Years and Preservation Solution: 2001-2005 vs 2006-2010 and UW vs HTKSRTR Data, 2000-2010, N=55110, Age 18+

By Years and Preservation Solution: 2001-2005 vs 2006-2010 and UW vs HTK

HTK 2006-10

UW 2006-10

UW 2000-5HTK 2000-5

Liver Transplant Patient SurvivalSRTR Data, 2000-2010, N=55110, Age 18+

By Years and Preservation Solution: 2001-2005 vs 2006-2010 and UW vs HTKSRTR Data, 2000-2010, N=55110, Age 18+

By Years and Preservation Solution: 2001-2005 vs 2006-2010 and UW vs HTK

HTK 2006-10UW 2006-10

UW 2000-5HTK 2000-5

Comparing HTK Users - 2010 UNOS Report - ADDLT

Center Patient Survival Graft Survival

United States 88.5 84.7

Methodist - Memphis

92.1 (+1.0) 87.4 (+0.5)

University of Indiana

90.0 (+0.7) 87.4 (+1.5)

Cleveland Clinic 91.6 (+1.7) 87.9 (+1.3)

Comparing UW Users – 2010 UNOS Report - ADDLT

Center Patient Survival Graft Survival

Johns Hopkins 75.6 (-13.9) 69.7 (-14.2)

MUSC 87.5 (-1.1) 85.0 (-2.4)

Univ. Pennsylvania

86.7 (-2.1) 84.8 (-1.1)

Univ. Wisconsin 90.0 (+4.4) 85.2 9(+3.7)

Conclusions

• Discrepancies between published reports and clinical experience:– Flawed analysis– Learning curve– Changing practices

• Excellent outcomes can be obtained with either solution