Neither grants nor financial support was received for this study. The authors do not have a financial relationship with any commercial organization that produces health care products or services.
Improved Waiting-List Outcomes in Argentina After the Adoption of a Model for End-Stage Liver Disease–Based Liver Allocation Policy
Article first published online: 25 JUN 2013
© 2013 American Association for the Study of Liver Diseases
Volume 19, Issue 7, pages 711–720, July 2013
How to Cite
Cejas, N. G., Villamil, F. G., Lendoire, J. C., Tagliafichi, V., Lopez, A., Krogh, D. H., Soratti, C. A. and Bisigniano, L. (2013), Improved Waiting-List Outcomes in Argentina After the Adoption of a Model for End-Stage Liver Disease–Based Liver Allocation Policy. Liver Transpl, 19: 711–720. doi: 10.1002/lt.23665
- Issue published online: 25 JUN 2013
- Article first published online: 25 JUN 2013
- Accepted manuscript online: 15 JUN 2013 02:25AM EST
- Manuscript Accepted: 18 APR 2013
- Manuscript Received: 5 FEB 2013
In July 2005, Argentina became the first country after the United States to introduce the Model for End-Stage Liver Disease (MELD) for organ allocation. In this study, we investigated waiting-list (WL) outcomes (n = 3272) and post–liver transplantation (LT) survival in 2 consecutive periods of 5 years before and after the implementation of a MELD-based allocation policy. Data were obtained from the database of the national institute for organ allocation in Argentina. After the adoption of the MELD system, there were significant reductions in WL mortality [28.5% versus 21.9%, P < 0.001, hazard ratio (HR) = 1.57, 95% confidence interval (CI) = 1.37-1.81] and total dropout rates (38.6% versus 29.1%, P < 0.001, HR = 1.31, 95% CI = 1.16-1.48) despite significantly less LT accessibility (57.4% versus 50.7%, P < 0.001, HR = 1.53, 95% CI = 1.39-1.68). The annual number of deaths per 1000 patient-years at risk decreased from 273 in 2005 to 173 in 2010, and the number of LT procedures per 1000 patient-years at risk decreased from 564 to 422. MELD and Model for End-Stage Liver Disease–Sodium scores were excellent predictors of 3-month WL mortality with c statistics of 0.828 and 0.857, respectively (P < 0.001). No difference was observed in 1-year posttransplant survival between the 2 periods (81.1% versus 81.3%). Although patients with a MELD score > 30 had lower posttransplant survival, the global accuracy of the score for predicting outcomes was poor, as indicated by a c statistic of only 0.523. Patients with granted MELD exceptions (158 for hepatocellular carcinoma and 52 for other reasons) had significantly higher access to LT (80.4%) in comparison with nonexception patients with equivalent listing priority (MELD score = 18-25; 54.6%, P < 0.001, HR = 0.49, 95% CI = 0.40-0.61). In conclusion, the adoption of the MELD model in Argentina has resulted in improved liver organ allocation without compromising posttransplant survival. Liver Transpl 19:711–720, 2013.. © 2013 AASLD.
The adoption in the United States in 2002 of a new allocation policy based on the Model for End-Stage Liver Disease (MELD) score resulted in decreased deaths and removals from the waiting list (WL) for being too sick for liver transplantation (LT). Even though priority was given to patients with more advanced liver failure, there was no significant impact on post-LT survival.[1, 2] On July 12, 2005, Argentina became the first country after the United States to introduce the MELD score for liver allocation. It is still unclear whether the benefits of the MELD-based system in the United States, as reported by the United Network for Organ Sharing (UNOS), are reproducible in other countries. Therefore, the goal of this study was to analyze the applicability and results of LT in Argentina over the last decade before and after the adoption of a MELD-based allocation policy.
PATIENTS AND METHODS
Data from all adult patients listed for LT over the last decade in Argentina (n = 3272) were analyzed with the database of the Instituto Nacional Central Unico Coordinador de Ablación e Implante (INCUCAI), which is the national institute for organ allocation. To investigate the impact of the adoption of the MELD-based allocation policy, we selected 2 consecutive 5-year periods: era 1 or the pre-MELD era (January 01, 2000 through July 11, 2005) and era 2 or the MELD era (July 12, 2005 through December 31, 2010). WL registrations, deaths/removals, and transplant rates were compared for the 2 study periods. Post-LT survival was analyzed for 1567 of 1741 recipients (90.0%) with available follow-up at the end of the study period. The results of allocation by the MELD system were evaluated over a period of 6 complete years (from July 13, 2005 to July 12, 2011). As required, the ethical review committee of INCUCAI previously approved the study protocol.
Liver Allocation in Argentina Before and After the Adoption of the MELD Score
Since the start of LT in 1987, Argentina has had a single national WL with no center or regional allocation. Up to the present time, LT has been performed only with brain-dead donors. Before the adoption of the MELD score in 2005, patients were listed in 1 of 3 categories:
- Emergency: fulminant hepatic failure or a need for retransplantation due to primary graft nonfunction or hepatic artery thrombosis within 7 days of the original LT procedures. These patients were given the highest priority.
- Urgency: chronic liver disease with at least 2 of the following 3 criteria: a serum creatinine level ≥ 1.7 mg/dL, a serum total bilirubin level ≥ 8 mg/dL, and a prothrombin activity level ≤ 35%. For patients with chronic cholestatic diseases, the urgency criteria were a total serum bilirubin level ≥ 20 mg/dL and a prothrombin activity level ≤ 60%.
- Elective: all patients with chronic liver disease not fulfilling the urgency criteria.
Within the urgency and elective categories, organs were allocated according to the WL time. With the adoption of the MELD-based policy, the emergency category has remained unchanged, and all other adult patients are listed by their calculated MELD scores with no minimal score required. An expert committee designed by INCUCAI reviews requests for supplemental points for pre-established MELD exceptions and for other clinical situations that, in the opinion of the transplant physicians, require allocation priority. Each reviewer is blinded to the other experts' opinions and to the LT center requesting the MELD exception. Pre-established exceptions include familial amyloidotic polyneuropathy (16 points), hepatopulmonary syndrome with a partial pressure of arterial oxygen < 60 mm Hg while breathing air (20 points), and hepatocellular carcinoma (HCC) within the Milan criteria (22 points). Explant pathology reports are requested by INCUCAI for all patients undergoing LT for HCC with supplemental MELD points in order to correlate histological tumor stages with preoperative radiological findings.
Simultaneously with the adoption of the MELD model, an Internet-based collection system, Sistema Nacional de Información de Procuración y Trasplante de la República Argentina (SINTRA), was established to capture directly from the centers all pre- and post-LT data in real time. MELD scores were recorded at registration and removal from the WL and were linked to the online registration forms through unique patient identifiers. The MELD score was calculated according to the UNOS formula. The serum bilirubin level, the international normalized ratio, and a serum creatinine level < 1.0 mg/dL were set to a value of 1.0 to preclude negative scores. The serum creatinine concentration was capped at 4.0 mg/dL. Laboratory values were regularly updated according to the MELD score at listing: every 7 days for a MELD score ≥ 20, every 30 days for a MELD score of 15 to 19, every 90 days for a MELD score of 11 to 14, and every 12 months for a MELD score < 10. The serum sodium value was prospectively collected, and the Model for End-Stage Liver Disease–Sodium (MELD-Na) was calculated with the Mayo Clinic formula. For death and LT rates, the number of events on the WL was related to the sum of waiting months for all candidates during the observation period (patient-years at risk) and was adjusted to 1000 patient-years according to UNOS.
To assess post-LT survival, data were collected with an online follow-up form to be completed by all transplant centers once a year. Additionally, the outcomes of listed and transplant patients were investigated through the Argentinean National Registry of Deaths (Registro Nacional de las Personas) to prevent an underestimation of accounted mortality. The data for patients undergoing transplantation before July 12, 2005 were retrospectively reviewed and loaded into the SINTRA database. Unfortunately, MELD scores from the pre-MELD era were not available.
Data are presented as medians and ranges. Differences between groups were tested with the χ2 test for categorical variables and with the Mann-Whitney U test for continuous variables. The WL outcomes and survival of listed and transplant patients were analyzed with the Kaplan-Meier method. Statistical significance was defined as a P value < 0.05 (2-sided test). The c statistic (equivalent to the area under the receiver operating characteristic curve) was used to assess the accuracy of MELD and MELD-Na scores in predicting 3-month WL mortality and post-LT mortality.
Overall, 3272 adults were listed in Argentina from 2000 to 2010: 1741 (53.2%) underwent LT, 797 (24.4%) died waiting, 270 (8.3%) were removed from the WL for being too sick or medically unsuitable for liver grafting, and 464 (14.2%) remained listed at the end of the study. The number of WL registrations and the number of LT procedures performed each year progressively increased across the analyzed decade, especially after the adoption of the MELD model in mid-2005 (Table 1). There were increases in both the incidence of new registrations per year (from 8.8 to 15.6 per million population) and the incidence of LT procedures performed per year (from 3.9 to 6.9 per million population). LT accessibility (transplants/listed patients) increased from 45% in 2000 to 69% in 2005 but decreased thereafter to 44% in 2010. A similar trend was observed for the LT rate (number of transplants/1000 patient-years at risk) which was 248 in 2000, 564 in 2005, and 422 in 2010 (Table 1). The rates of deceased donors and multiorgan donors increased from 7.0 (2000) and 3.4 per million population (2002) to 14.5 and 7.4 per million population, respectively, in 2010. However, the proportion of multiorgan donors remained stable throughout the decade at approximately 50%.
|Transplants/listed patients (%)c||45||40||37||62||67||69||69||57||58||41||44|
|LT procedures/1000 patient-years t risk (n)||248||303||333||475||553||564||572||499||545||422||422|
|Incidence (per million population)d|
|Donors (per million population)|
|Time to transplant (days)e||102 (0-1229)||175 (0-1666)||169 (0-1637)||91 (0-3131)||119 (1-2020)||84 (1-2961)||55 (1-2392)||66 (1-2275)||49 (1-1719)||43 (1-2736)||70 (1-1606)|
Comparison of the Pre-MELD and MELD Eras
During the last decade, hepatitis C was the most common indication for LT (22.2%) in adults from Argentina, and it was followed by alcoholic liver disease (16.3%) and cryptogenic cirrhosis (12.4%). After implementation of the MELD-based system, there were small but significant increases in the median candidate age, proportion of males, and listings for alcoholic liver disease and metabolic causes of cirrhosis and significant decreases in the proportions of patients with cryptogenic cirrhosis, acute liver failure, primary biliary cirrhosis, and primary sclerosing cholangitis (Table 2). WL outcomes changed significantly after the adoption of the MELD system (Table 3). The number of patients listed during era 2 increased 70.4% (from 1210 to 2062), and the number of LT procedures increased 50.5% (from 695 to 1046). The disproportion between the number of WL registrations and the number of transplants performed resulted in significantly reduced LT accessibility (57.4% versus 50.7%, P < 0.001). However, after the adoption of the MELD-based policy, WL mortality decreased from 28.5% to 21.9% (P < 0.001); the WL removal rate decreased from 10.1% to 7.2% (P = 0.37); and the total WL dropout rate decreased from 38.6% to 29.1% (P < 0.001). The number of deaths per 1000 patient-years at risk steadily increased from 163 in 2000 to 273 in 2005 and subsequently declined to 173 in 2010 (Fig. 1). The median time to LT decreased from 108 days (range = 1-2736 days) in the pre-MELD era to 47 days (range = 1-1889 days) in the MELD era (P < 0.001).
|Overall (n = 3272)||Era 1: Pre-MELD (n = 1210)||Era 2: MELD Era (n = 2062)||P Value|
|Age (years)a||50.4 (18-74)||48.6 (18-70)||50.8 (18-74)||<0.001|
|Sex: male (%)||55||51||57||<0.001|
|Primary diagnosis at listing [n (%)]|
|Hepatitis C||728 (22.2)||266 (22.0)||462 (22.4)||0.82|
|Alcoholic liver disease||534 (16.3)||169 (14.0)||365 (17.7)||0.01|
|Cryptogenic cirrhosis||407 (12.4)||190 (15.7)||217 (10.5)||<0.001|
|Acute liver failure||324 (9.9)||147 (12.1)||177 (8.6)||<0.001|
|Autoimmune hepatitis||291 (8.9)||116 (9.6)||175 (8.5)||0.32|
|Primary biliary cirrhosis||244 (7.5)||110 (9.1)||134 (6.5)||0.01|
|Metabolic cirrhosis||116 (3.5)||19 (1.6)||97 (4.7)||<0.001|
|Hepatitis B||102 (3.1)||40 (3.3)||62 (3.0)||0.71|
|Other cholestatic diseases||93 (2.8)||39 (3.2)||54 (2.6)||0.37|
|Primary sclerosing cholangitis||80 (2.4)||39 (3.2)||41 (2.0)||0.04|
|Otherb||197 (6.0)||24 (2.0)||173 (8.4)||<0.001|
|Retransplantation [n (%)]||156 (4.8)||51 (4.2)||105 (5.1)||0.29|
|Outcome||Era 1: Pre-MELD (n = 1210)||Era 2: MELD (n = 2062)||P Value||HR||95% CI|
|LT||695 (57.4)||1046 (50.7)||<0.001||1.53||1.39-1.68|
|Death||345 (28.5)||452 (21.9)||<0.001||1.57||1.37-1.81|
|Removal||122 (10.1)||148 (7.2)||0.37||1.11||0.85-1.41|
|Total dropouta||467 (38.6)||600 (29.1)||<0.001||1.31||1.16-1.48|
|Remaining on list||48 (4.0)||416 (20.2)||<0.001||6.75||5.62-8.11|
Patients with chronic liver diseases represented 84.7% (n = 1025) of all registrations in the pre-MELD era and 90.4% (n = 1864) in the MELD era. Significantly lower WL mortality [29.5% versus 22.7%, P < 0.001, hazard ratio (HR) = 1.52, 95% confidence interval (CI) = 1.35-1.72] and removal rates (9.2% versus 6.3%, P < 0.001, HR = 1.90, 95% CI = 1.37-2.63) were observed after the adoption of the MELD system, despite the decreased access to LT (61.3% versus 42.6%, P < 0.001, HR = 1.52, 95% CI = 1.35-1.72; Fig. 2). The actuarial patient survival rates 1, 3, and 5 years after LT were 81.1%, 75.5%, and 70.0%, respectively, in era 1 (n = 617) and 81.3%, 71.0%, and 65.1%, respectively, in era 2 (n = 894, P = 0.37; Fig. 3). The proportions of patients who were relisted for graft loss were similar in the 2 study periods (4.2% versus 5.1%, P = 0.29). The survival of listed patients not undergoing LT increased significantly from 79.6%, 58.5%, and 23.4% at 1 month, 1 year, and 3 years in the pre-MELD era to 83.1%, 74.1%, and 40.0%, respectively, in the MELD era (P < 0.001).
Results of the MELD Allocation Policy (July 2005 to July 2011)
After the adoption of the MELD-based allocation policy, 2539 patients were listed for LT: 2093 (82.4%) with their calculated MELD scores, 210 (8.3%) as MELD exceptions, and 236 (9.3%) in the emergency category (198 cases of acute liver failure and 38 cases of re-LT). Among the patients listed by their calculated MELD scores, the median score was 16 (range = 4-51) at registration, 26 (range = 6-47) at LT, and 25 (range = 6-50) at the time of death on the WL (data were available for 175 of 426 patients). The proportions of patients with MELD scores in the range of 21 to 30 points were 20% at listing and 42% at LT, and the proportions with MELD scores > 30 points were 7% and 31%, respectively. At the other end, MELD scores of 6 to 10 were observed in 15% at the time of listing and in only 5% at the time of LT.
Accuracy of the MELD Score for Predicting WL Mortality
For the 3-month time period following listing, 136 (6.5%) of the 2093 listed pts by calculated MELD died, 1399 (66.8%) survived, 533 (25.5%) were transplanted and 25 (1.2%) were removed of the WL. For the 1535 patients who either died or survived without LT, the MELD score was an excellent predictor of 3-month WL mortality with a c statistic of 0.828 (0.800-0.844, P < 0.001). As shown in Fig. 4, WL mortality progressively increased from 2.6% for patients with MELD scores of 6 to 10 to 26.2% for patients with scores > 30. MELD-Na, which was investigated for 72% of the 1535 patients, was also very accurate in predicting the risk of dying on the WL with a c statistic of 0.857 (0.835-0.877, P < 0.001). The superiority of MELD-Na versus MELD was, however, small. When we considered the 419 patients who died on the WL during the 6-year study period, we estimated that only 11 lives (approximately 3% of the WL deaths) could have been saved if the MELD-Na score had been used for organ allocation instead of the MELD score.
Post-LT Survival of Patients Listed by MELD Scores
Seven hundred sixty-two of 872 transplant patients (87.4%) had available follow-up, and the 1-year post-LT survival rates for patients with MELD scores at transplant of 6 to 10 (n = 19), of 11 to 20 (n = 163), of 21 to 30 (n = 313), and >30 (n = 267) were 82.9%, 84.5%, 84.4%, and 73.5%, respectively. As shown in Fig. 5, patients with a MELD score > 30 had a significantly lower survival rate than patients with a score ≤ 30 (73.5% versus 84.4%, P < 0.001). However, the MELD score was a poor overall predictor of post-LT survival with a c statistic of only 0.523 (95% CI = 0.489-0.557, P = 0.51).
Two hundred ten of the 292 requests for supplemental MELD points (71.9%) were accepted by the review committee (158 of 164 requests for HCC, 7 of 7 requests for familial amyloidotic polyneuropathy, 12 of 12 requests for hepatopulmonary syndrome, and 33 of 109 special requests). In comparison with patients listed with a calculated MELD score of 22 (n = 60), HCC candidates given 22 supplemental points (n = 158) had significantly lower WL mortality (28.3% versus 7.0%, P < 0.001, HR = 0.17, 95% CI = 0.07-0.43), fewer removals from the WL (6.7% versus 3.8%, P = 0.02, HR = 0.26, 95% CI = 0.05-1.50), and higher LT accessibility, although the difference was not significant (56.7% versus 83.5%, P = 0.83, HR = 1.04, 95% CI = 0.72-1.51). The median time from a MELD-driven upgrade to LT in patients with HCC was only 47 days (range = 1-528 days). Among the 133 patients who underwent LT for HCC, 55.7% received a deceased donor within 90 days of being listed, and 89% received one within 180 days. An analysis of the explanted liver was available for 131 of the 133 patients (98.5%) undergoing transplantation for HCC. Pathological examinations showed no evidence of tumors in 12 cases (9.2%), stage T1 HCC in 7 cases (5.34%), stage T2 HCC in 83 cases (63.4%), and stage T3 HCC in 29 cases (22.1%). Therefore, the accuracy of pre-LT staging of HCC by imaging was only 63% (70% for those with confirmed cancer on histology). Among the 52 patients with non-HCC MELD exceptions, 76.9% underwent transplantation, 12.1% died, 4% were removed from the WL, and 7% remained listed. The median time to LT was 62 days (range = 2-1171 days). Candidates with MELD exceptions (n = 210) were exaggeratedly advantaged in comparison with the 548 patients with an equivalent allocation priority at listing (MELD range = 18-25); this was reflected by significantly greater access to LT (80.4% versus 54.6%, P < 0.001, HR = 0.49, 95% CI = 0.40-0.61) and lower (although not significantly so) WL mortality (12.1% versus 21.8%, P = 0.08, HR = 1.58, 95% CI = 1.01-2.46) and total dropout rates (11.7% versus 29.4%, P = 0.36, HR = 1.21, 95% CI = 0.82-1.76).
The adoption of the MELD model in Argentina in 2005 resulted in improved liver organ allocation, as indicated by statistically significant decreases in WL death and dropout rates and in the time interval to LT with deceased donors. These benefits occurred in a scenario of a progressive disproportion between the number of patients listed and the number of available organs and thus reflect the accuracy of the MELD model in identifying and prioritizing the candidates most in need of LT. After the introduction of the MELD score in the United States, the absolute number of WL registrations decreased, and LT accessibility increased and reached a peak in 2006 (Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients 2009 Official Report Tables 1.7, 9.1a, and 9.1b). Most likely, the reduction of new registrations in the United States was due to the exclusion of the WL time from the liver allocation policy, which de-emphasized the need for early listing.[2, 8] In contrast, the WL size in Argentina increased 70.4% during the MELD era without a parallel increase in the liver donor pool, and this resulted in a significant decrease in LT accessibility. Although LT has been available in Argentina for more than 2 decades, it is likely that the WL size will continue to grow in forthcoming years because of medical education and improvements in the health system allowing better accessibility to the procedure. Despite the decreased LT accessibility, the adoption of the MELD-based allocation policy in Argentina was associated with a significant drop in the overall WL mortality and in the rate of deaths per year per 1000 patients at risk (from 273 to 173). Similar data were reported in the United States with a decrease from 156 in 2001 to 122 in 2006 (Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients 2009 Official Report Table 9.3).
In this study, which included all consecutive adult patients registered in a single national WL, the MELD score was an excellent predictor of 3-month mortality with a c statistic of 0.828, which is almost identical to the value of 0.83 reported by Wiesner et al.[1, 4] in their analysis of the UNOS database and the value of 0.89 reported by Ruf et al. for a single center in Argentina. Our results also confirm the prognostic value of the MELD-Na score, which was originally reported for our country by Ruf et al. However, in agreement with the US data, the modest prognostic superiority of MELD-Na versus MELD does not justify at present its universal adoption for liver organ allocation.[5, 11-13]
McCormack et al., using the same database used for this study, reported that allocation by the MELD score in Argentina (2005-2009) resulted in increased WL mortality and that patients with a score < 10 had a 4-fold increased risk of death. Most likely, these findings resulted from underestimations of death rates due to incomplete center reports and especially due to the fact that the electronic system automatically converts MELD scores that are not renewed in a timely manner to a value of 6. In the present study, all pre- and post-LT deaths were confirmed through the national death registry in order to minimize missing or incorrectly reported data. In addition, a one-by-one case revision showed that true calculated MELD scores at the time of WL deaths were available for only 41% of patients (175/426). Not surprisingly, we found that the median MELD score at the time of WL death was similar to the median score at the time of LT (25 versus 26). As shown in Fig. 4 and in agreement with previous studies, the 3-month WL mortality rate among patients with MELD scores < 10 was negligible, and the rate progressively increased in parallel with the scores.[1, 4, 9, 10] Even though MELD scores from era 1 were not available, because of the smaller gap between listed and transplant patients, it is likely that before 2005, organs were allocated to candidates with less severe liver failure. Although MELD-based organ allocation in Argentina did not have a deleterious effect on outcomes, post-LT survival was significantly lower for patients with scores > 30, as suggested by Weismüller et al. However, as previously reported, MELD was a poor global predictor of survival with a c statistic of only 0.523.[16-21] Most likely, the outcome after LT depends not only on the severity of chronic liver disease but also on other factors such as the quality of donors, intraoperative events, and acute or chronic comorbidities.
Lastly, patients who received supplemental MELD points, 75% of whom had HCC, had significantly greater access to LT and lower risks of WL mortality and dropout. Although this situation should be changed in order to maximize equity and justice, MELD exceptions in Argentina accounted for only 8.3% of listed patients. Massie et al. recently showed that over an 8-year period in the United States, 21.4% of listed patients received supplemental MELD points (15.2% for HCC and 6.2% for other conditions). An analysis of the explanted livers of HCC patients with MELD exceptions showed that 63% of the patients were correctly diagnosed and staged preoperatively. Although this figure appears better than the value of 45% reported by Wiesner et al. in the United States, additional efforts should be made to improve the accuracy of the pre-LT radiological diagnosis and staging of HCC.
In conclusion, the adoption of a MELD-based allocation policy in a country with a single national WL—Argentina—resulted in a significant improvement in liver organ allocation. The benefits of the MELD score appear to be even higher than those in the United States because of the continuous increase in the number of list registrations in our region unparalleled by a concomitant expansion of the deceased donor pool. Consequently, the major goal for LT in Argentina should be to improve organ procurement and increase the number of multiorgan donors while remaining under a MELD-based allocation system.
The authors thank all the LT centers that provided data to the SINTRA database of INCUCAI.
- 6U.S. Department of Health and Human Services. Technical Notes and Analytic Methods, 2009. Deaths and death rates on the waiting list. http://optn.transplant.hrsa.gov/ar2009/Tech_Notes_AR_CD.htm#6. Accessed April 2013.
Instituto Nacional Central Unico Coordinador de Ablación e Implante
Model for End-Stage Liver Disease
Model for End-Stage Liver Disease–Sodium
Sistema Nacional de Información de Procuración y Trasplante de la República Argentina
United Network for Organ Sharing