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March 26 and April 1, 2009

Analysis and Review of Clinical and Scientific Findings of Preservation Solutions to Minimize Donor Organ Damage. March 26 and April 1, 2009. Histidine-Tryptophan-Ketoglutarate Solution Vs. University of Wisconsin Solution for Deceased Donor Liver Transplantation: Analysis of SRTR Database.

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March 26 and April 1, 2009

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  1. Analysis and Review of Clinical and Scientific Findings of Preservation Solutions to Minimize Donor Organ Damage March 26 and April 1, 2009

  2. Histidine-Tryptophan-Ketoglutarate Solution Vs. University of Wisconsin Solution for Deceased Donor Liver Transplantation: Analysis of SRTR Database John Fung, MD, PhD Chairman of the Department of General Surgery Cleveland Clinic

  3. Purpose • This analysis aims to evaluate the impact of the organ preservation solutions (OPS) ,(Histidine-Tryptophan-Ketoglutarate (HTK) vs. University of Wisconsin (UW) solution) on the outcome of adult deceased donor liver transplantation (DDLT) using the Scientific Registry of Transplant Recipient (SRTR) database.

  4. Materials and Methods Only adult first liver-only transplants from 2002-2006. We included only those for whom both flush and storage solutions were the same. Risk-unadjusted graft survival was estimated non-parametrically by the method of Kaplan and Meier, and parametrically by a multiphase hazard decomposition method

  5. Statistical Analysis • Risk factors for graft survival were determined using nonproportional, multiphase, multivariable hazard methodology. This methodology allows modeling of recipient, donor, and procedure variables in all phases of the hazard model simultaneously. Bootstrap aggregating was used for variable selection with a probability for inclusion of .001; variables appearing in at least 50% of bootstrap analyses were considered reliably statistically significant at p<.001.

  6. Patients • The data set included 20,908 patients, 17,559 (84%) with UW and 3349 (16%) with HTK solutions. Mean follow-up was 2.9 ± 1.5 years (3.0 ± 1.5 years for UW and 1.9 ± 1.0 years for HTK). We defined an early phase (EP) shortly after DDLT followed by a constant phase (CP) of hazard for graft failure.

  7. Results • Significant predictors of graft failure in the EP after DDLT include the following recipient factors: older age, race either White or Black, portal vein thrombosis, last creatinine and last MELD for the transplant (tx) candidacy, on life support just prior to tx, and previous kidney tx.

  8. Risk Factors for Graft Failure - Early Phase

  9. Risk Factors for Graft Failure - Constant Phase

  10. Results • Significant donor factors in the EP are: race other than White, donation after cardiac death (DCD) and donor risk index (DRI). OPS did not appear as a statistically significant predictor of graft failure.

  11. Results • OPS was not statistically significant (p=.06, EP; p=.2, CP). Hospital death, re-transplant rates (overall and within 14 days of initial transplant) and relisting rates (overall and within 30 days of tx) were similar (p>0.05).

  12. Patient Survival - Donor >65 • Donor Age >  65 • N=1698 UW • N=  311 HTK • p=.46  log rank test

  13. Patient Survival - Donor <65 • Donor Age <65 • N=15861 UW • N= 3038 HTK • p=.28 log rank test

  14. Patient Survival - DCD Donor • DCD Donor • N=570 UW • N=159 HTK • p=.73  log rank test

  15. Patient Survival - Non-DCD Donor • Non-DCD Donor • N=16989 UW • N=3190 HTK • p=.55  log rank test

  16. Patient Survival - DRI >2.5 • Donor DRI >2.5 • N=8663 UW • N=1682 HTK • p=.25  log rank test

  17. Patient Survival - DRI <2.5 • Donor DRI <2.5 • N=6600 UW • N=1218 HTK • p=.37  log rank test

  18. Graft Survival - Donor Age >65 • Donor Age >65 • N=1698 UW • N=  311 HTK • p=.64  log rank test

  19. Graft Survival - Donor Age <65 • Donor Age <65 • N=15861 UW • N= 3038 HTK • p=.045  log rank test

  20. Graft Survival - DCD Donor • DCD Donor • N=570 UW • N=159 HTK • p=.17  log rank test

  21. Kaplan-Meier Adult Graft Survival Primary Deceased Donor Liver Transplants 2000-2006 SRTR Includes adult, primary, liver alone transplants

  22. Graft Survival - Non-DCD Donor • Non-DCD Donor • N=16989 UW • N=3190 HTK • p=.23  log rank test

  23. Graft Survival - DRI >2.5 • Donor DRI >2.5 • N=8663 UW • N=1682 HTK • p=.053 log rank test

  24. Graft Survival - DRI <2.5 • Donor DRI <2.5 • N=6600 UW • N=1218 HTK • p=.15 log rank test

  25. Analyzing Studies • In addition to the common underlying OPTN data, SSAF files include extra ascertainment of outcomes from SSDMF, and from cross-linking of records within the OPTN data for the same person. Files are linked by a patient key so that the entire history of a particular person can be studied. The extent to which these links are made, and the specific matching process, may be different between the two sets of files.

  26. Data Fixes CMS-ESRD Feedback Monthly Transfer Person Linking Data Quality NCHS, AHA, etc Standard Analysis Files SEER Center-Specific Analyses Analytical Procedures and Products OPO- Specific Reports Annual, Biennial Reports Center- Specific Reports OPTN, ACOT Committees TAC RFI Conference Present’ns Journal Articles OPTN MPSC SRTR Information Flow SSDMF OPTN SRTR Analysis File Creation Reorganization for Research Cleaning and Validation Analysis Variables Added Data Use Agreements Public Release External Research

  27. Hopkins UNOS Analysis Used casewise deletion of missing data, i.e. threw out cases that were missing any of the predictor variables they were studying. Doing this can potentially bias the results. It means they are using only patients for whom all variables were reported - and these patients might come from centers where they are more diligent about data reporting, etc.

  28. Implications of Casewise Deletions • While they do say that data were missing for less than 4% of covariates, if the missing values were scattered over 20% of patients, then 20% of total data might have been deleted. • Example: • SRTR CIT data: 100% complete • UNOS CIT data: 86% complete

  29. Critique • Last transplant included was 2/28/08 - the paper was submitted on 7/17/08.  Assuming that it took 45 days to analyze and write the paper, then it would be safe to say that the data cutoff was 6/1/08, meaning that the last patients only had a 3 month follow-up.  However, the first recipient follow-up form required by UNOS is at 6 months and then they only release data after a 60 day period for completion, meaning that for a 6/1/08 cutoff, they only have data for transplants performed before 11/1/07. 

  30. Validation of Follow-Up Forms by Year Source: SRTR analyses, August 2003 for the 2003 OPTN/SRTR Annual Report, Figure II-4.

  31. Other Considerations • Slightly different timeframes: • is there a change in clinical practice? • is there a learning curve for new users of HTK? • Do the conclusions make sense? • Recipient age 18-34 HR 1.14 • COD - CVA, HR 1.04 (SRTR HR 1.16) • COD - DCD, HR 1.97 (SRTR HR 1.51)

  32. Does Not Fit Clinical Impressions • Cleveland Clinic DCD experience • 15 controlled DCD LTX preserved with HTK since 2005 • Heparin could not be given prior to declaration of death • Mean donor age was 38 ± 12 years • Mean WIT and CIT was 25 ± 9 min and 427 ± 97 min, respectively • No recipient developed ITBS. PNF was seen in one recipient who was salvaged with retransplantation

  33. Analysis and Review of Clinical and Scientific Findings of Preservation Solutions to Minimize Donor Organ Damage Richard S. Mangus, MD, MS Assistant Professor of Surgery and Transplant Surgeon Transplant Division, Department of Surgery Indiana University, School of Medicine March 26 and April 1, 2009

  34. Disclosure Dr. Mangus has participated in the advisory board and speaker’s bureau for Essential Pharmaceuticals in the last 12 months.

  35. Systematic assessment of data quality Study types: Expert opinion Non-experimental studies (questionnaire) Observational studies (retrospective analysis) Non-randomized parallel cohort studies (prospective) Randomized, blinded, prospective trial (RCTs) Systematic review and meta-analysis of randomized trials Issues: CONFOUNDING Relevance Timeliness Accuracy Comparability Timeliness Reproducibility Bias Incomplete data Assessment of Scientific Research

  36. Randomized, controlled trials (RCTs) • Kidney 1 European, 3-year follow-up 1998, n = 650 transplants, Deceased donors • Pancreas 1 European 2009, n=68 transplants • Liver 3 European 1994 (n=60) – Deceased donors 2003 (n=30) – Living donors 2005 (n=40) – Deceased donors 38

  37. Kidney preservation Transplants: HTK 332, UW 312 DGF: Need for dialysis 2 or more times during first 7-days post-transplant Flush volume: HTK 5 – 6 L UW 1 – 2 L EC 4 L 39

  38. Kidney preservation de Boer, et al, Transpl Proc, 1999; 31: 2065 40

  39. Kidney preservation 41 de Boer, et al, Transpl Proc, 1999; 31: 2065

  40. Kidney preservation 42 Lynch RJ, et al. AJT 2008; 8:567-73

  41. Kidney preservation Post-transplant kidney graft survival Living Donor: HTK n=475 UW n=475 Deceased donor: HTK n=317 UW n=317 Lynch RJ, et al. AJT 2008; 8:567-73 43

  42. Pancreas preservation Transplants: 68 transplants over 18 months at 4 centers Outcomes: 6-month graft survival – NO DIFFERENCE Graft function – NO DIFFERENCE Fasting BG C-peptide level HbA1c Insulin requirement Flush volume: HTK 5 – 8 L n=41 UW 3 L n=67 44

  43. Pancreas preservation Figure 1. No insulin requirement Figure 2. Serum amylase level Figure 3. Serum lipase level 45

  44. Pancreas preservation Figure 4. C-peptide level Figure 5. Units exogenous insulin Figure 6. HbA1c 46

  45. Pancreas preservation Indiana University, 2003 to 2007 N = 310 HTK 262, UW 48 Simultaneous, retrospective 1-year graft survival – 91% (U.S. 79-86%) 47

  46. Pancreas preservation • ISSUES: Graft pancreatitis Alonso D, et al. Increased pancreatitis in allografts flushed with histidine-tryptophan-ketoglutarate solution: a cautionary tale. AJT 2008; 8: 1942-45. • Overall rate of graft pancreatitis 28/97 (29%) • Two centers, retrospective, low volume (HTK 16, UW 81) Flush volume • 10 L likely too much and may cause pancreas graft injury from edema (related to low viscosity and high volume flush) • Indiana University – 3000-4000cc routinely no graft pancreatitis graft thombosis rate 3-4% 48

  47. Liver preservation • 3 Randomized Studies: • 1. Erhard J, et al. Comparison of HTK versus UW for organ preservation in human liver transplantation: A prospective, randomized study. Transplant International 1994; 7: 177-81. • 60 deceased donor liver transplants (HTK n=30 and UW n=30) • No difference in early and late graft survival, even for 7 donor livers with cold ischemia time >15 hrs • More late biliary complications in UW group. • Higher initial transaminases in HTK group. • 2. Testa G, et al. HTK versus UW in living donor liver transplantation: results of a prospective study. Liver Transplantation 2003; 9(8): 822-26. • 30 consecutive living donor right lobe transplants flushed alternately with HTK (n=16) or UW (n=14) • Patients were randomly allocated based upon timing of transplantation • 1-year post-transplant, there is no difference in graft and patient survival, liver enzymes and complications • 3. Nardo B, et al. Preliminary results of a clinical randomized study comparing Celsior and HTK solutions in liver preservation for transplantation. Transpl Proc 2005; 37:320-2. • European randomized trial comparing Celsior and HTK. • No difference in initial function or survival up to 1-year post-transplant. 49

  48. Liver preservation 50

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