Dynamics of the Romanian Waiting List for Liver Transplantation after Changing Organ Allocation Policy

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1 Dynamics of the Romanian Waiting List for Liver Transplantation after Changing Organ Allocation Policy Liana Gheorghe 1, Speranta Iacob 1, Razvan Iacob 1, Gabriela Smira 1, Corina Pietrareanu 1, Doina Hrehoret 2, Vlad Brasoveanu 2, Cristian Gheorghe 1, Irinel Popescu 2 1) Gastroenterology and Hepatology Center 2) General Surgery and Liver Transplantation Center, Fundeni Clinical Institute, Bucharest Romania Address for correspondence: Liana Gheorghe, MD, PhD Gastroenterology and Hepatology Center Fundeni Clinical Institute Fundeni Str , Bucharest Romania drgheorghe@xnet.ro Received: Accepted: ABSTRACT Aim: The aim of the present study was to characterize the dynamics of the Romanian waiting list (WL) for liver transplantation (LT) over two periods: vs Methods: 1,085 patients listed for LT during the time period were included in our analysis. Results: Death on the WL was significantly higher before 2008 (37% vs. 26.4%, p=0.0001) and risk of dying while on WL was 60% higher. Waiting time on the WL was 75% longer and time until LT was 102% longer before 2008 compared to the second time period (p=0.0001). After 2008, 62.3% of patients were listed for LT with Child Pugh class C compared to 22.1% before 2008 (p<0.0001). Conclusion: A significant reduction of mortality has been registered on the Romanian WL for LT after 2008, despite the increased severity of liver disease in patients listed for LT. Key words: waiting list liver transplantation mortality. INTRODUCTION Liver transplantation (LT) is the optimal therapy for acute liver failure and end-stage liver disease. Access to LT at the appropriate timing depends on a three-step process: (1) referral to a transplant center; (2) listing after careful evaluation by the transplant team; and (3) medical management, prioritization and allocation policy on the waiting list (WL). Merion et al found that post-transplant mortality was approximately one-fifth of that on the WL [1]. However, there is a wide gap between patients awaiting LT and available donor organs, requiring the prioritization of patients for each available deceased donor liver. This disparity is even higher in countries such as Romania (one single center performing LT, 2.2 donors/ million inhabitants annually, 5,890 annual liverrelated deaths) (personal communication 2010, unpublished data). The introduction of MELD in the US was associated with a 12% reduction in WL registrations, a 3.5% reduction in WL mortality, and an increase in transplantation rates distributed across all demographic and epidemiologic strata [2]. As we have previously demonstrated [3], the MELD score was found to be an excellent predictor of death within 12 months on our WL, characterized by a long waiting time. Although MELD eliminates subjective assessments and has shown accuracy for outcome prediction in patients with decompensated cirrhosis, it also has several limitations, especially lack of prediction of post-transplant survival [4-6]. It was suggested that a liver benefit score, a score that is donor- and recipient-specific and is computed as the difference between 5-year predicted posttransplant lifetime and 5-year predicted future WL lifetime, would change substantially the ordering of the waitlisted patients [6]. In this study, the waitlisted patients in the single Romanian LT Center are evaluated by assessing patient characteristics, mortality rates, waiting times, and risk factors for mortality in a program characterized by long waiting periods for LT. Another important aim was to compare two definite periods with different allocation and management policies: versus The more recent period is characterized by an increased number of LT procedures (>40/year up to 65);

2 300 Gheorghe L et al MELD score for prioritization is applied systematically, thus too early or too late referral is avoided; exception points or case-bycase review board discussion are adopted in case MELD score does not predict patient prognosis; there is an improvement in the management of non-urgent cases while on the WL in order to avoid complications/progression (prophylactic band ligation, antibiotic prophylaxis, weekly albumin infusion) and bridging therapy (chemoembolization/ radiofrequency ablation) is used whenever possible; there was an increase in the adult living-related donor procedures and also an increase of the use of marginal grafts, as well as a better recipient-donor matching in order to adopt a benefit score-based allocation system. PATIENTS AND METHODS A retrospective study was conducted gathering data from 1,085 consecutive adult patients with end-stage liver disease (2B or 3 United Network for Organ Sharing UNOS status fullfilling the minimal listing criteria Child-Pugh score of 7; or one of the following complications no matter what Child Pugh class was: variceal upper digestive bleeding, spontaneous bacterial peritonitis, hepatocellular carcinoma - HCC) listed for LT at the referral center between January 2004 and December All patients had complete data required for MELD calculation in the LT file. For prioritization to transplantation both MELD score and the modified MELD score described by our group were used [7]. For patients with HCC the following criteria for listing and transplantation were used: presence of strictly intrahepatic tumors, without macrovascular invasion regardless of the Child or MELD score, any BCLC stage. For patients with HCC the MELD score was not assigned to be 20 or 24 as proposed by UNOS, but calculated as usual. Survival analysis was conducted in December 2012, 12 months after the inclusion of the last patient. The date of death while on WL, the date of the last contact with our center and the date of the LT were registered. Patients transplanted during the study interval and patients still alive at the moment of the survival analysis were considered censored cases. The followup period was the number of days from a patient s placement on the transplant WL to LT, death or withdrawal from the list (patients who were too sick to undergo LT and those who were lost to follow-up). The MELD score was calculated using serum creatinine, bilirubin and the International Normalized (Prothrombin) Ratio (INR) [8] according to the following formula currently in use by UNOS [9]: MELD score = [9.57 x loge creatinine mg/ dl x loge bilirubin mg/dl x loge INR ]. This study complies with the standards of the Declaration of Helsinki and current ethical guidelines. All patients signed an informed consent at inclusion on WL for LT. Statistical analysis Continuous data were expressed as mean ± standard deviation (SD). Categorical data were expressed as a proportion of the subjects with a specific feature and compared using a chi-square test. t-student or Wilcoxon test were used to compare continuous variables. Survival rates were computed using Kaplan-Meier methods and compared using log-rank tests. In order to identify potential predictors of patient death at 12 months, univariate and multivariate Cox s proportional hazards regression models were used. To assess the MELD score ability to correctly rank order of patients according to risk of death while on the WL, our analysis was performed by measuring the concordance (c-statistic) equivalent to the area under the receiver operating characteristic curve (ROC). The outcome assessed was the occurrence of death within 12 months while on the WL. A c-statistic between 0.8 and 0.9 indicated excellent diagnostic accuracy and a parameter with a c-statistic over 0.7 should be considered clinically useful. A logistic regression analysis was used to estimate the waiting time and the time to LT according to each studied time period. All tests were two-sided and a p value < 0.05 was considered to indicate statistical significance. RESULTS Waiting list characteristics There was a constant yearly increase of the number of patients on the WL from 2004 (71 patients) to 2011 (383 patients included). Between , 567 adult patients were present on the WL for LT and 518 between Table I lists the general characteristics for the patients in these two groups. The period comprises patients with a significantly Table I. Patients characteristics according to the two different time periods on the liver transplant waiting list at the Gastroenterology and Hepatology Center, Fundeni Clinical Institute Variable period (n=567) period (n=518) p value Age at LT (years) 46.5 ± ± Male gender 58.7% 59.6% 0.76 Mean MELD score at inclusion 14 ± ± Mean MELD at LT 17.6 ± ± LT rate (%) 22.9% 26.6% 0.15 Living Donor LT 17.7% 21.7% 0.40 Hepatocellular carcinoma 13.2% 11.7% 0.43 HCV etiology 30% 32.8% 0.31 HBV etiology 16.8% 16.1% 0.77 HBV/HDV etiology 25.4% 25% 0.89 Alcohol etiology 12% 16.7% 0.02 Cryptogenic etiology 8.3% 4.9% 0.02 Blood type OI Blood type AII Blood type BIII Blood type ABIV 28.6% 48.7% 15.6% 7.1% 32.5% 43.2% 17.3% 7% 0.31 Child-Pugh class A Child-Pugh class B Child-Pugh class C 25.7% 52.2% 22.1% 12.2% 24.6% 63.2% < Spontaneous bacterial peritonitis 13.1% 15.9% 0.17 Hepato-renal syndrome 10.9% 9.5% 0.44 Refractory ascites 26.5% 28% 0.57 Hyponatremia 20.6% 23.9% 0.19 Upper GI hemorrhage 24.2% 18.3% 0.01 Hepatic encephalopathy 31.6% 42.8%

3 Dynamics of the waiting list for liver transplantation 301 higher age and MELD score at inclusion on WL and with more advanced liver disease (Child C class). A significantly higher number of patients died while on the WL before 2008 (38% vs. 26.4%, p=0.0001). Patients included in the recent period had significantly more episodes of hepatic encephalopathy, but lower number of upper digestive hemorrhage episodes and a higher number of patients had alcoholic liver disease. Waiting time on the WL was 75% longer before 2008 compared to the period after 2008 (21.2 ± 21 vs 12.1 ± 9 months, p<0.0001). Time until LT was 102% longer during compared to (18 ± 17.6 vs 8.9 ± 7.3 months, p<0.0001). The same was true when comparing the Kaplan-Meier curves for time to LT (log rank test p<0.0001). A significantly lower percentage of patients had a MELD score <15 at inclusion on WL (42.6% vs 60%, p=0.002) and at LT (23.2% vs 33.1%, p=0.04) in the era before Also, more patients with severe disease (Child-Pugh class C) were transplanted in the period (72.5% vs 43.2%, p=0.002). Time to LT for patients with HCC was significantly shorter (10.1 vs months) after 2008, and the chance of being transplanted if HCC was present was higher (HR=2.95 in the period vs HR=1.72 in the period ). Living-related LT was performed in 27.2% of patients with HCC after 2008 and in 24% before this year. Also, MELD score at LT for patients with HCC was similar in the two periods (15.8±4.1 vs 15.9±3.8, p=0.92). After 2008, MELD score at WL inclusion was similar in patients with HCC and without HCC (p=0.08), but at LT it was significantly lower in patients with HCC (15.9±3.8 vs 18.0±3.9, p=0.008). MELD score at both inclusion on the WL and at LT was significantly lower in patients with HCC compared to those without HCC (p value =0.01 for both) in the first period ( ). Survival analysis The overall mortality rate while on the WL at 1, 3 and 5 years was 25%, 46.3% and 57.3%, respectively (Fig. 1). Median survival was 47.7 months. After excluding patients lost to follow-up, the mortality rate while on the WL at 1, 3 and 5 years was 31.4%, 54.1% and 63.5%, respectively, and the median survival was 30.9 months (analysis performed on 856 patients). Although there were no statistically significant differences between the two analyzed periods in 6 months, 1-year- and 2-years mortality rates (p=0.77), the risk of dying was 60% higher during compared to (OR=1.61, logistic regression analysis). Initial MELD score, etiology of liver disease, as well as the complications of liver cirrhosis (HCC, spontaneous bacterial peritonitis, refractory ascites, hyponatremia, hepatic encephalopathy, upper variceal bleeding, hepatorenal syndrome) were evaluated as potential predictors of death while on the WL using the univariate Cox regression analysis. The results of the analysis are shown in Table II. Table II. Univariate survival Cox model. Predictors of death while on the waiting list for liver transplantation Variable HR p value Presence of HCC at inclusion HCV etiology HBV etiology HBV+HDV etiology Alcohol etiology Initial MELD score 2.93 < Spontaneous bacterial peritonitis 2.82 < Hepatorenal syndrome 4.16 < Upper GI hemorrhage 1.68 < Hepatic encephalopathy 2.77 < Refractory ascites 3.40 < Hyponatremia 3.19 < In the multivariate survival analysis performed by the Cox Proportional Hazards Model, the following factors were found to be independent predictors of death on our WL: initial MELD score (p <0.0001, HR = 1.13), refractory ascites (p <0.0001, HR = 3.54), hepatorenal syndrome (p <0.0001, HR = 1.72), hepatic encephalopathy (p = 0.002, HR = 1.44), upper gastro-intestinal hemorrhage (p = , HR = 1.50) and the presence of HCC at inclusion on the WL (p = 0.002, HR = 1.58). MELD score at inclusion on WL was investigated as a predictor of death on the WL based on the c-statistic (ROC curve) according to the two analyzed time periods. Initial MELD score was found to be a good clinical indicator for prediction of 12 month mortality on the WL in the time frame between (c-statistic=0.72, Fig. 2), while for the period it had no clinical usefulness in predicting death on our WL (AUROC=0.62). A cut-off MELD score >16 at inclusion on WL had a sensitivity of 60.6%, a specificity of 74.1%, a positive predictive value 44.2% and a negative predictive value of 85.3% for predicting 12 month mortality on the Romanian WL during the period. DISCUSSION Fig. 1. Kaplan Meier curve for overall mortality on the waiting list for liver transplantation (n=1,085 patients) Disease severity at the time of listing has been demonstrated as an important predictor of WL death [10]. There is abundant evidence suggesting that the MELD allocation system improved the outcome of patients with or without HCC on the list [11, 12]. As we have previously demonstrated [3, 13], the MELD score at inclusion on the WL was found to be a good predictor of death within 12 months on our WL. This finding remained true in the new cohort of patients as well, but only for the

4 302 Gheorghe L et al Fig. 2. ROC curve for initial MELD score as a predictor of death on our waiting list for liver transplantation during more recent period, probably associated with the shorter period on the WL until LT or death after 2008 and to the fact that too early referral (MELD <10) was restricted. That is why the variation of MELD score during the last three months is superior to baseline MELD [13] in predicting the negative outcome in programs with small numbers of annual LT (< 40/ year) and characterized by a long waiting time (approximately 22 months before 2008; 102% longer time for LT compared to the period after 2008 when the annual number of LT increased). In concordance with US, Europe, but also Brazil (a LT Program similar to ours), there was a shorter time to LT for patients with HCC, although they had a rather low MELD score at LT after changing the policy of liver allocation [14, 15]. In correlation with the new allocation policy, there was a concomitant expansion of the number of donors. In Romania, the increase of LT for patients with HCC was due to the allocation of marginal livers to these patients who usually had a low MELD score ( 14). Marginal donor is defined according to the DRI (donor risk index) and associated macrovesicular steatosis >20% [16, 17]. Our policy is to use grafts with an increased donor risk index preferentially for older candidates (>50 years of age) with moderate disease severity (with low MELD scores 14), with HCC and without hepatitis C. The matching of donor with recipient is an important issue in our allocation policy that has proved to be safe with no early graft dysfunction and no decreased 1-year survival rates. Living-related LT increased although it was not statistically significant, through the efforts of the hepatology team to increase awareness of the family members of the recipients regarding this procedure and the related benefits and complications. In parallel, an intensive educational and emotional television campaign has successfully expanded the deceased donor pool with a concomitant decrease of mortality on the WL. We have observed that transplants were performed more in patients with higher MELD scores in the second period than in the first period, in accordance with all the data from the literature which compared the MELD era to the pre-meld era [15, 18-20]. There was an increase in the number of Child-Pugh C patients included on the WL and transplanted during the second period and a decrease in the number of Child-Pugh A and B patients. This distribution reflects the increased number of more severe cirrhotic patients transplanted in the period. A similar distribution was noticed in Brazil [15], but here the difference was related to an increase in the number of patients with Child A cirrhosis and associated HCC as well. The reported overall mortality rates of patients on a WL for LT vary from 10% to 24%, or even up to 31% [20-22]. In the present study, the mortality rates remained high even after the change of allocation policy. However, a significant reduction of mortality has been registered on the Romanian WL for LT after 2008, despite the increased severity of liver disease in patients listed for LT. This is related to the increased number of donors (deceased and living), as well as to the use of extended criteria donor (ECD) grafts in patients with HCC outside the Milan criteria (11.2% were marginal grafts compared to 2% before 2009) (personal unpublished data). In addition, time to LT for HCC recipients decreased significantly in the second period, similar to what happened in the MELD period in other regions due to allocation of exceptional points [19]. It was noted that countries with very low donation rates are under much higher pressure to use grafts from ECD than others. There are contradictory results regarding the use of these grafts and of the MELD allocation system in relation to the short-time survival after LT (Italy/Switzerland vs Germany) [11, 19, 23]. In this study, survival after LT was not analyzed, but a recent article by our group (submitted for publication) failed to show a worsening survival rate following LT (1 year overall survival of 83.5% in HCC recipients). Indices for predicting survival are essential for assessing the prognosis of patients with cirrhosis and their priority for LT. In many countries, the waiting times for LT exceed one year [3, 24, 25]. A diagnosis of HCC, serum hyponatremia, the Child-Pugh status, and the MELD score were significant prognostic indices for patients waiting for LT both before and after the introduction of the MELD scoring system in Brazil [26]. Our analysis revealed the following independent risk factors for death on the WL: baseline MELD score, refractory ascites, hepatorenal syndrome, hepatic encephalopathy, upper gastro-intestinal hemorrhage and presence of HCC at inclusion on WL, factors that are similar to those reported above and reflect the severity of cirrhosis and their related complications. Although hyponatremia was significant also in our study in the univariate analysis, this was not an independent factor for death on our WL. This is related to the fact that hyponatremia is linked to refractory ascites and hepatorenal syndrome. Identifying risk factors for mortality in patients on a long-term WL for LT might facilitate clinical decisions at centers with similar waiting lists. CONCLUSION A significant reduction of mortality has been registered on the Romanian WL for LT after 2008, despite the increased severity of liver disease in patients listed for LT. In addition,

5 Dynamics of the waiting list for liver transplantation 303 time to LT was significantly shorter in patients listed for LT after 2008 due to continuous efforts to increase the donor pool (higher number of deceased donors, increasing use of living and marginal donors). In order to improve survival in LT candidates, our Center adopted the new MELD-oriented policy for allocation, prioritization, and a better management of complications arising during the long waiting time accompanied by methods to expand the donor pool such as the use of ECD, live-donor and split-liver transplants. Conflicts of interest: None to declare. Acknowledgement: The work has been supported by the research grant PCE 125/2011. Authors contributions: L.G. initiated the study, enrolled patients, wrote and edited the paper, and approved the final version. S.I. enrolled patients, collected data, analyzed the results, provided tables, figures, performed statistical analysis, wrote and edited the paper. 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