Survival Analysis of Liver Transplant Patients in Canada 1997–2002

OUTCOMES

Survival Analysis of Liver Transplant Patients in Canada 1997–2002 Z. Hong, J. Wu, G. Smart, K. Kaita, S.W. Wen, S. Paton, and M. Dawood

ABSTRACT Liver transplantation is an important health care issue for Canadians. Very few studies have assessed survival and determinants of survival in liver transplant patients in Canada. Methods. We carried out an epidemiological analysis of 1 year survival and determinants of 1 year survival in liver transplant patients, using Canadian Organ Replacement Registry data (1997–2002). Survival curves were plotted by the Kaplan-Meier method. Cox proportional hazards analysis was applied to evaluate hazard ratios with different age groups, gender, ethnicity, blood groups, donor type, pretransplantation medical status, and HBV infection status. Results. A total of 1164 liver transplant patients were included in the analysis. One-year survival rate was 84.7%. Male recipients had a 21% higher risk of developing organ failure than females. Recipients over 60 years of age had a 5% lower survival probability in comparison with recipients below 20 years of age. Pacific Islanders and Aboriginals had 32% and 9% lower survival probabilities, respectively, in comparison with Caucasians. Type B blood recipients had a 12% higher survival probability, whereas type AB blood recipients had a 7% lower survival probability compared with type O blood recipients. Twenty-six live organ recipients had 40% higher survival probabilities than 1138 cadaveric organ recipients. Patients with fulminant hepatitis (status 3F) had the highest survival, while patients with fulminant failure in ICU with intubation/ventilation (status 4F) had the

From the Blood Safety Surveillance and Health Care Acquired Infection Division, Centre for Infectious Disease Prevention and Control, Public Health Agency of Canada, Ottawa, Ontario (Z.H., J.W., S.P.); Cadham Provincial Laboratory, Manitoba Health, Winnipeg, Manitoba (G.S., M.D.); Viral Hepatitis Investigative Unit, University of Manitoba, John Buhler Research Centre, Winnipeg, Manitoba (K.K.); OMNI Research Group, Department of Obstetrics and Gynecology, the Clinical Epidemiology Program, Department of Epidemiology and Community Medicine,

Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario (S.W.W.); and Department of Medical Microbiology, University of Manitoba, Basic Medical Science Building, Winnipeg, Manitoba (M.D.), Canada. Address reprint requests to Dr. Zhiyong Hong, Blood Safety Surveillance and Health Care Acquired Infection Division, Centre for Infectious Disease Prevention and Control, Public Health Agency of Canada, Ottawa, ON K1A 0L2. E-mail: zhiyong_hong@ phac-aspc.gc.ca

© 2006 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710

0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2006.08.180

Transplantation Proceedings, 38, 2951–2956 (2006)

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lowest survival. One hundred sixty-seven recipients with positive HBsAg antigen showed 10% lower survival probability than 997 cases with negative HBsAg antigen. Conclusion. In Canada, the first year survival rate is about 85%, which is comparable with other industrialized countries. Type of donor organs and recipient gender, ethnicity, ABO blood group, pretransplantation medical status, and HBV infection status had significant affects on the recipient survival.

T

HE NUMBER OF LIVER TRANSPLANTATIONS has been increasing at the Canadian centers in Vancouver, Edmonton, London, Toronto, Montreal, and Halifax, with improved patient and graft survival rates.1 However, the waiting list for transplantation continues to increase. As of December 31, 2004, there were 4004 patients awaiting an organ transplant in Canada. In 2004, 224 people died while awaiting an organ, which included 96 (43%) awaiting liver transplantation; 55 patients (25%) awaiting kidney, 33 patients (15%) awaiting bi-lung, and 26 patients (12%) awaiting a heart transplantation.2 Several factors, including recipient age, gender, ethnicity, medical status before liver transplantation, donor type, and antiviral drugs, may affect the survival of patients with liver transplantations. Liver transplantation in HBsAg-positive patients remains controversial because of the risk of recurrence of HBV infection due to graft reinfection. There is marked variability regarding the policy, about HBsAgpositive potential liver donors and the selection criteria for HBsAg-positive recipients to undergo liver transplantation. The issue is whether liver transplant recipients with hepatitis B virus infection have shorter, similar, or longer survival times compared with recipients without hepatitis B virus infection. Some investigators have observed less acute rejection among the patients undergoing liver transplantation and having hepatitis B virus markers,3,4 while other workers have reported that hepatitis B virus infection had a negative impact on recipient survival.5–7 The aim of this study was to analyze the determinants of survival among liver transplant patients in Canada, with a focused discussion of organ allocation policy for liver transplantation in hepatitis B carriers.

transplant patients was collected starting in 1997, with further data enhancements introduced in 2001.

Organ Allocation Policies in Canada Organ allocation decisions in Canada are based on the patient’s medical urgency: Status 1, patients at home; Status 1T, patients with tumors; Status 2, hospitalized patients; Status 3, patients hospitalized in ICU; Status 3F, patients with fulminant failure in ICU; Status 4, patients in ICU with intubation/ventilation; and Status 4F, patients with fulminant failure in ICU with intubation/ventilation. Urgent patients with 3F, 4 or 4F status received priority for organs. The waiting time for the urgent patients was typically in the range of 1 day to 1 week. The nonurgent patients usually waited several months and even 1 to 2 years to receive a liver transplantation.

Hepatitis B Virus Infection Markers Liver transplant recipients were grouped according to their hepatitis B virus (HBV) infectious status.8 Patients with a positive test for HBsAg antigen were defined as HBV positive; the remaining patients with any negative test were HBV negative.

Statistical Analysis Survival curves for liver transplant patients were plotted using the Kaplan-Meier method. The independent effects of age, gender, ethnicity, ABO blood group, donor type, medical status before transplantation, and hepatitis B virus infection status on the survival of liver transplant patients were estimated by Cox proportional hazards regression analysis and by a stepwise regression approach. The hazard rate ratio (HR), which was used as the effect measure, was defined as the ratio of the mortality rate in the group of patients with a given factor to the rate in those without the factor. A rate larger than 1 HR indicates a lower survival probability, whereas a rate smaller than 1 HR means a higher survival probability.

MATERIALS AND METHODS Study Population

RESULTS

The current study was based on all liver transplant patients registered by the Canadian Organ Replacement Registry (CORR) for the period January 1, 1997 to December 31, 2002. CORR is a database developed by the Canadian Institute for Health Information. There have been nine active liver transplant programs operating in nine hospitals in Canada since 1985. CORR has collected data at nine hospitals that have dialysis or regional transplant programs, organ procurement organizations, and kidney dialysis services offered at independent health facilities. Patient-level transplant data were collected retrospectively for the years 1997 to 2002 given the expanded mandate of the register. Follow-up was completed on all patients until the date of graft loss, patient death, or December 31, 2002. The database has information on more than 95% of liver transplant patients. More detailed information on

From January 1, 1997 to December 31, 2002, 1164 patients underwent liver transplantation in Canada. At the end of our observation (December 31, 2003), 986 patients remained alive, with a 1 year survival rate of 84.7%. Twenty-six patients (2.2%) received living donor organs, and 1139 patients (97.8%) received cadaveric organs. The most common indications for liver transplantation were chronic viral hepatitis followed by alcoholic cirrhosis and cholestatic liver diseases (Table 1). Distribution of other characteristics among the patient population is shown in Table 1. The 1 year survival of liver transplant patients was affected by the patient’s age group, gender, ethnicity, ABO

SURVIVAL ANALYSIS, 1997–2002

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Table 1. Reason for Liver Transplantation in Canada 1997–2002 Etiology of Liver Disease

No. of Patients (N ⫽ 1122)

Percentage (%)

Alcoholic Cirrhosis Cancers Cholestatic Liver Disease Cryptogenic Cirrhosis Hepatitis Missing Other Total

265 116 194 77 313 9 148 1122

23.62 10.34 17.29 6.86 27.90 0.80 13.19 100.00

Frequency Missing ⫽ 42. Data source: The Canadian Organ Replacement Registry database 1997–2002.

blood group, donor type, and medical status before transplantation. Higher survival probabilities were observed among female subjects, Caucasians, type B blood, and patients transplanted with organs from living donors (Table 2). Patients with fulminant hepatitis (status 3F) had the highest survival while patients who were fulminant in the ICU with intubation/ ventilation (status 4F) had the lowest survival (Table 2). Patients displaying an HBV-marker had a lower survival

probability (80%) than patients without an HBV-marker (90%) (Fig 1). DISCUSSION

The 1 year survival rate among 1164 liver transplant patients in Canada from January 1, 1997 to December 31, 2002 was 84.7%. The survival rate is the outcome of both the general level of medical practice and nursing care during hospitalization. The survival rate of liver transplant patients in Canada were comparable to those reported in the United States and United Kingdom, 88% and 84%, respectively,9 demonstrating the competence of the Canadian publically funded health care system in caring for the most complicated disorders such as patients requiring liver transplantations. Many factors determine 1 year patient survival after liver transplantation. Donor factors include compromised liver, HLA-class I compatibilities, age, and anti-HBc-positive donor.28 Recipient factors include ethnic background, age (better results have been reported for pediatric patients),31 cause of liver failures (noncholestatic cirrhosis, hepatitis C, and hepatocellular carcinoma),30,32,34 disease severity, peri-

Table 2. Cox Proportional Hazard Analysis for 1164 Liver Transplant Patients in Canada 1997–2002 Recipient Characteristics

Age (per year increment) ABO blood grouping O A AB B Donor type Cadaveric Live Hepatitis B virus infection Negative Positive Pretransplantation medical status At home With tumor Hospitalized Hospitalized at ICU Fulminant at ICU ICU with intubated and ventilated Fulminant at ICU with intubated and ventilated Race Caucasian Aboriginal Asian Black Indian subcontinents Pacific Islanders Gender Male Female

Hazard Ratio

X2 Value

Standard Error

95% CL*

1

0.0003

0.99–1.00

0.01

.9091

1 1.02 1.07 0.88

0 0.0108 0.0233 0.0175

Reference 0.99–1.01 1.02–1.12 0.85–0.91

— 2.05 8.38 48.71

— .1526 .0038** ⬍.0001**

1 0.6

0 0.0414

Reference 0.56–0.66

— 148.07

— ⬍.0001**

1 1.1

0 0.0165

Reference 1.07–1.14

— 36

— ⬍.0001**

1 1.08 1.05 1.22 0.92 1.15 1.59

0 0.0382 0.0117 0.0229 0.0315 0.0256 0.0299

Reference 1.03–1.14 1.02–1.09 1.13–1.32 0.87–0.98 1.10–1.20 1.40–1.72

— 14.5 18.55 43.15 6.14 4.27 70.9

— ⬍.0001** ⬍.0001** ⬍.0001** .0132** .0388* ⬍.0001**

1 1.09 1.03 1.06 0.98 1.32

0 0.0252 0.0231 0.0328 0.0466 0.0646

Reference 1.04–1.15 0.98–1.08 0.99–1.12 0.89–1.07 1.17–1.51

— 12.44 1.39 2.54 0.26 19.37

— .0004** .2386 .1109 .6116 ⬍.0001**

1 0.79

0 0.0103

Reference 0.89–0.93

— 75.63

— ⬍.0001**

Source: The Canadian Organ Replacement Registry database 1997–2002. *95% CI, Wald 95% Confidence Limits. **There is significant difference in hazard ratio between specific group and reference group.

P

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Fig 1. Survival curves between the group with HBV marker (P) and the group without HBV marker (XO). X-axis represents the survival time (months). Y-axis represents the survival probabilities. The group without HBV (XO) had significant higher survival probability than the group with HBV marker (P).

operative HBV replication status, extrahepatitic HBV existence status, and blood transfusion volume. Perioperative treatments included use of an antiviral agent, drug resistance, virus mutation, immunosuppressant protocol, and blood transfusion.28 Postoperative complications like early allograft dysfunction, biliary leak, or obstruction, hemorrhage, and hepatic artery thrombosis (HAT) also affect survivals of liver transplant patients.29,33 We assessed the effects of several demographic and clinical factors on the survival of liver transplant patients, observing that liver transplant recipient gender, ethnicity, ABO blood group, pretransplantation medical status, HBV infection status, and type of donor organ were associated with the recipient’s survival. Recipients over age 60 years showed significantly lower rates of survival than did recipients below 20 years of age. This result is consistent with other studies that showed recipient’s poor patient and graft survival for age ⬎65 years, donor age ⬎50 years, male sex of recipient, retransplantation, and pretransplant MELD score of ⬎25. These risk factors were operative among 1472 recipients irrespective of the year of transplantation from 1991 to 2002 in the United States.10 Malago et al also found that hospital mortality among 537 liver transplant patients significantly correlated with age over 60 years.11 In our study, female liver transplant recipients showed significantly lower rates of graft failure and death than male recipients, in agreement with those reported by other investigators.12–15 Perhaps female hormones play a role in protecting liver graft survival and increasing longevity. There were no significant differences in posttransplantation survival between Caucasians and Asians, African, or Indians from the Sub-Continents. However, Aboriginal people

in Canada displayed significantly lower survival than Caucasians. The possible explanations for this observation include poor health care infrastructures and a lower likelihood of having seen a physician among aboriginal peoples in Canada.16,23,24 A lower rate of organ transplantation among Aboriginal people could be another explanation for their lower survival rate.25 Pacific Islanders seemed to have a lowest survival probability for liver transplantation. There is a need to explore the outcomes of liver transplantation among various ethnic groups to evaluate the influence of genetic factors on survival probability. We found that liver transplant recipient ABO blood group was strongly associated with survival, results consistent with Matinlauri’s observations.17 The reason for this phenomenon is not clearly understood. We observed that patients who received living donor grafts had significantly higher survival probabilities than those who received cadaveric organs, a result in agreement with published data among pediatric patients.18 –20 In Canada, 2% to 3% of transplant patients receive livers from living donors which is far less than in the United States or Spain.21 Another interesting finding in our study was that the current priority lists established by transplant centers in Canada for organ allocation is not consistent with patient survival probabilities. We observed better survival probabilities among liver transplant patients in the following order: status 3F ⬎ status 1 ⬎ status 2 ⬎ status 1T ⬎ status 4 ⬎ status 3 ⬎ status 4F. There is an urgent need to revise the current priorities for organ allocation to improve the survival of the organ transplant patients. According to current policy, hospitalized patients, those hospitalized in an ICU,

SURVIVAL ANALYSIS, 1997–2002

or intubated and ventilated normally receive a liver transplantation within 1 week. On the other hand, patients staying at home usually have to wait for several months and even years to have a liver transplant. During 2004, 224 people died while awaiting an organ transplant. Among them 43% were awaiting a liver. Therefore, reducing the waiting time for liver transplant patients is an urgent issue that needs to be addressed in Canada. There is a need to increase the number of organs suitable for transplantation as well as to increase the number of organs available for patients staying at home awaiting transplantation. Ethical debates focusing on the fair allocation of the limited supply of organs and on ways to increase the number of organs will continue in Canada. Our results support the view that the probability of the success for liver transplantation is greater if the organ is given to more stable patients. Our data showed that the 1 year survival rate of recipients with HBV markers was lower than that of recipients without an HBV marker, with values of 80% and 90%, respectively. This result is different from recent results of the United Network for Organ Sharing database in the United States, which indicated that the outcomes after OLT for HBV were comparable with those of patients with other diagnoses.26 The reason for such a difference between Canada and the United States may be the availabilities of antiviral agents and different regimens for prophylaxis of HBV reinfection. There are several protocols to prevent hepatitis B recurrence after liver transplantation in the nine transplant centers across Canada. Some transplant centres proffered HBIG monotherapy, or treatment with 10 MIU interferon-alpha subcutaneously three times per week or 5 MIU subcutaneously daily for 16 weeks. Other transplant centers preferred lamivudine monotherapy with a regimen of 100 mg lamivudine subcutaneously daily for up to 5 years or more, until observing a partial virological response (HBeAg seroconversion). In recent years, the combination of lamivudine pretransplant followed by HBIG plus lamivudine has rapidly become the standard prophylactic treatment in several transplant centres in Canada.27 The limitations to our study are mainly related to the data. Because data collected by CORR were principally for organ allocation and not for comprehensive follow-up of recipients, the data lacked details of clinical information. The most significant limitation with respect to this analysis was that we had no information regarding posttransplant patient management, histology, and laboratory data to directly correlate a specific regimen for prophylaxis or treatment with HBV recurrence or patient outcome.22,35,36 ACKNOWLEDGMENTS Data for this study were obtained from the CORR, a data holding of the Canadian Institute for Health Information (CIHI). Information available from CORR represents the collaborative efforts and voluntary contribution of the organ procurement organization, transplant physicians, surgeons, nurses, and coordinators across Canada. Public Health Agency of Canada is indebted to this large number of individuals and The Canadian Transplantation Society

2955 for its success. The CORR Board and Advisory Committee, composed of volunteers from CORR’s many stakeholder groups, have provided invaluable guidance to the registry during its evolution and enhancement. The authors acknowledge the technical assistance of Dr Naisu Zhu, Ms. Kim Badovinac, and Dr Lilyanna Trpeski from CIHI.

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2956 21. Delmonico FL, Sheehy E, Marks WH, et al: Organ donation and utilization in the United States, 2004. Am J Transplant 542:862, 2005 22. Habib S, Berk B, Chang CC, et al: MELD and prédiction of post-liver transplantation survival. Liver Transpl 123:440, 2006 23. Shah BR, Gunraj N, Hux JE: Markers of access to and quality primary care for aboriginal people in Ontario, Canada. Am J Public Health 935:798, 2003 24. Wardman D, Clement K, Quantz D: Access and utilization of health service by British Columbia’s rural Aboriginal population. Int J Health Care Qual Assur Inc Leadersh Health Serv 182–3: xxvi, 2005 25. Newbold KB: Problems in search of solutions: health and Canada aboriginals. J Community Health 231:59, 1998 26. Kim WR, Poterucha JJ, Kremers WK, et al: Outcome of liver transplantation for hepatitis B in the United States. Liver Transpl 108:968, 2004 27. Sherman M, Bain V, Villeneuve JP, et al: The management of chronic viral hepatitis: a Canadian consensus conference 2004. Can J Infect Dis Med Microbiol 156:313, 2004 28. Wu LM, Xu X, Zheng SS: Hepatitis B virus reinfection after liver transplantation: related risk factors and perspective. Hepatobiliary Pancreat Dis Int 44:502, 2005

HONG, WU, SMART ET AL 29. Varotti G, Grazi GL, Vetronea G, et al: Causes of early acute graft failure after liver transplantation: analysis of a 17-year single-centre experience. Clin Transplant 194:492, 2005 30. Schlenker C, Trotter J: Recurrent hepatitis C following liver transplantation: a review of factors associated with graft injury. Minerva Gastroenterol Dietol 522:175, 2006 31. Pompili M, Mirante VG, Rapaccini GL, et al: Liver transplantation. Ann Ital Med Int 191:20, 2004 32. Vivarelli M, Cucchetti A, Piscaglia F, et al: Analysis of risk factors for tumor recurence after liver, transplantation for hepatocellular carcinoma: key role of immunosuppression. Liver Transpl 115:497, 2005 33. Gunsar F, Rolando N, Pastacaldi S, et al: Late hepatic artery thrombosis after orthotopic liver transplantation. Liver Transpl 96: 605, 2003 34. Roche B, Samuel D: Aspects of hepatitis C virus infection relating to liver transplantation. Eur J Gastroenterol Hepatol 184: 313, 2006 35. Neff GW, O’Brien CB, Nery J, et al: Outcomes in liver transplant recipients with hepatitis B virus: resistence and recurrence patterns from a large transplant centre over the last decade. Liver Transpl 10:1372, 2004 36. Samuel D: Management of hepatitis B in liver transplantation patients. Semin Liver Dis 24(suppl 1):55, 2004