National time trends in mortality and graft survival following liver transplantation from circulatory death or brainstem death donors.

BACKGROUND: Despite high waiting list mortality rates, concern still exists on the appropriateness of using livers donated after circulatory death (DCD). We compared mortality and graft loss in recipients of livers donated after circulatory or brainstem death (DBD) across two successive time periods. METHODS: Observational multinational data from the United Kingdom and Ireland were partitioned into two time periods (2008-2011 and 2012-2016). Cox regression methods were used to estimate hazard ratios (HRs) comparing the impact of periods on post-transplant mortality and graft failure. RESULTS: A total of 1176 DCD recipients and 3749 DBD recipients were included. Three-year patient mortality rates decreased markedly from 19.6 per cent in time period 1 to 10.4 per cent in time period 2 (adjusted HR 0.43, 95 per cent c.i. 0.30 to 0.62; P < 0.001) for DCD recipients but only decreased from 12.8 to 11.3 per cent (adjusted HR 0.96, 95 per cent c.i. 0.78 to 1.19; P = 0.732) in DBD recipients (P for interaction = 0.001). No time period-specific improvements in 3-year graft failure were observed for DCD (adjusted HR 0.80, 95% c.i. 0.61 to 1.05; P = 0.116) or DBD recipients (adjusted HR 0.95, 95% c.i. 0.79 to 1.14; P = 0.607). A slight increase in retransplantation rates occurred between time period 1 and 2 in those who received a DCD liver (from 7.3 to 11.8 per cent; P = 0.042), but there was no change in those receiving a DBD liver (from 4.9 to 4.5 per cent; P = 0.365). In time period 2, no difference in mortality rates between those receiving a DCD liver and those receiving a DBD liver was observed (adjusted HR 0.78, 95% c.i. 0.56 to 1.09; P = 0.142). CONCLUSION: Mortality rates more than halved in recipients of a DCD liver over a decade and eventually compared similarly to mortality rates in recipients of a DBD liver. Regions with high waiting list mortality may mitigate this by use of DCD livers.

Transforming health systems to reduce health inequalities.

Never before in history have we had the data to track such a rapid increase in inequalities. With changes imminent in healthcare and public health organisational landscape in England and health inequalities high on the policy agenda, we have an opportunity to redouble efforts to reduce inequalities. In this article, we argue that health inequalities need re-framing to encompass the breadth of disadvantage and difference between healthcare and health outcome inequalities. Second, there needs to be a focus on long-term organisational change to ensure equity is considered in all decisions. Third, actions need to prioritise the fundamental redistribution of resources, funding, workforce, services and power. Reducing inequalities can involve unpopular and difficult decisions. Physicians have a particular role in society and can support evidenced-based change across practice and the system at large. If we do not act now, then when?

Trials & Tribulations of Liver Transplantation- are trials now prohibitive without surrogate endpoints?

During the past 5 decades, liver transplantation has moved from its pioneering days where success was measured in days to a point where it is viewed as a routine part of medical care. Despite this progress, there are still significant unmet needs and outstanding questions that need addressing in clinical trials to improve outcomes for patients. The traditional endpoint for trials in liver transplantation has been 1-year patient survival, but with rates now approaching 95%, this endpoint now poses a number of significant financial and logistical barriers to conducting trials because of the large numbers of participants required to demonstrate only an incremental improvement. Here, we suggest the following solutions to this challenge: adoption of validated surrogate endpoints; bigger and better collaborative multiarm, multiphase studies; recognition by funders and institutions that work on larger collaborative research projects is potentially more important than smaller, self-led bodies of work; ringfenced areas of research within trial frameworks where individuals can take a lead; and fair funding structures using both industry and public sector money across national and international borders.

The Impact of Performance Status on Length of Hospital Stay and Clinical Complications Following Liver Transplantation.

BACKGROUND: Impaired pretransplant performance status (PS) is associated with chronic liver disease (CLD). We studied its impact on hospital length of stay (LOS), complications, and readmissions in the first year after liver transplantation. METHODS: The Standard National Liver Transplant Registry was linked to a hospital administrative dataset, and all first-time liver transplant recipients with CLD aged ≥18 years in England were identified. A modified 3-level Eastern Cooperative Oncology Group score was used to assess PS. Linear- and logistic-fixed effect regression models were used to estimate the effect of specific posttransplant complications and readmissions in the first year after transplantation. RESULTS: Six thousand nine hundred sixty-eight recipients were included. Impaired PS was associated with an increased LOS in the initial posttransplant period (comparing ECOG 1-3, adjusted difference 7.2 d; 95% confidence [CI], 4.8-9.6; P < 0.001) and in time spent on the ITU (adjusted difference 1.2 d; 95% CI, 0.4-2.0; P < 0.001). There was no significant association between ECOG status and total LOS of later admissions (adjusted difference, 2.5 d; 95% CI, -0.4-5.5; P = 0.23). Those with a poorer ECOG status had an increased incidence of renal failure (odds ratio, 1.5; 95% CI, 1.1-2.0; P = 0.004) and infection (odds ratio, 1.2; 95% CI, 1.1-1.4; P = 0.02) but not an increased incidence of readmission (odds ratio, 1.2; 95% CI, 0.9-1.5; P = 0.13). CONCLUSIONS: In liver transplant recipients with CLD, impaired pretransplant PS is associated with prolonged LOS in the immediate posttransplant period but not with LOS of later admissions in the first year after transplantation. Impaired PS increased the risk of renal failure and infection.

Assessing the Impact of Suboptimal Donor Characteristics on Mortality After Liver Transplantation: A Time-dependent Analysis Comparing HCC With Non-HCC Patients.

BACKGROUND: Patients who receive a liver transplant for hepatocellular carcinoma (HCC) often receive poorer-quality livers. Tumor recurrence also has a negative effect on posttransplant outcomes. We compared mortality of HCC and non-HCC recipients in different posttransplant time periods (epochs) to separate the impact of these different risk factors on short-term and longer-term posttransplant survival. METHODS: We identified a population-based cohort of first-time liver transplant recipients (aged ≥16 years) between 2008 and 2016 in the United Kingdom. We used Cox regression to estimate hazard ratios (HRs) comparing posttransplant mortality between HCC and non-HCC patients in 3 posttransplant epochs: 0 to 90 days, 90 days to 2 years, and 2 to 5 years, with adjustment first for recipient and later also for donor characteristics. RESULTS: One thousand two hundred seventy HCC and 3657 non-HCC transplant recipients were included. Five-year posttransplant survival was 74.5% (95% confidence interval [CI] 71.2%-77.5%) in HCC patients and 84.6% (83.0%-86.1%) in non-HCC patients. With adjustment for recipient characteristics only, mortality of HCC patients was lower but not statistically significantly different in the first 90 days (HR, 0.76; 95% CI, 0.53-1.09; P = 0.11), but significantly higher thereafter (90 days to 2 years: HR, 1.99; 95% CI, 1.48-2.66; P < 0.001; 2 to 5 years HR, 1.77; 95% CI, 1.30-2.42; P < 0.001). Further adjustment for donor characteristics had little impact on these results. CONCLUSIONS: HCC recipients have poorer 5-year posttransplant survival than non-HCC recipients, most likely because of tumor recurrence. The more frequent use of poorer-quality donor organs for HCC does not explain this difference.

Implications of changing the minimal survival benefit in liver transplantation.

The limited availability of livers donated by deceased donors for transplantation means that not everyone who might benefit from the procedure can receive a graft, so any selection and allocation system must have clearly defined goals. The United Kingdom, in common with many other countries, has adopted a minimum benefit criterion of a greater than 50% probability of survival 5 years after transplantation. We investigated the impact of changing this minimum benefit criterion on a case mix of listed patients. The analysis was based on 5330 adult elective patients who underwent transplantation with livers from donation after brain death donors between January 1994 and December 2007. We examined the impact of balancing the number of registrations on the list with the number of available donor livers while allowing a 10% mortality rate and found that this would require a survival threshold of at least 74% at 5 years. According to historical data, the application of this more stringent criterion would significantly reduce the eligibility of older and nonwhite patients and patients with hepatocellular carcinoma or hepatitis C virus infections. Thus, if such undesirable restrictions on access to liver transplantation are to be avoided, we must consider alternative strategies such as the acceptance of higher transplant list mortality.

Functional status of patients before liver transplantation as a predictor of posttransplant mortality.

BACKGROUND: Risk models for mortality after liver transplantation have poor predictive ability. We examined whether the performance of these risk models can be improved by including information about patients' functional status (i.e., their ability to carry out activities of daily living) in addition to conventional clinical risk factors. METHODS: The UK and Ireland Liver Transplant Audit has data on all liver transplantations carried out in both countries since 1994. We examined the association of functional status measures taken immediately before transplantation on a 5-point scale (modified version of the Eastern Cooperative Oncology Group performance status) and mortality 90 days after transplantation. Logistic regression was used to adjust for other risk factors. RESULTS: Posttransplant mortality increased from 5.3% in patients able to carry out normal activity without restriction (functional status 1) to 24.8% in patients completely reliant on nursing and medical care (functional status 5; P for trend 0.003). This association remained after adjustment for conventional risk factors (adjusted P for trend 0.003). Adjusted odds ratios with functional status 3 (the most frequent functional status) as baseline category were 0.60 (95% confidence interval 0.29-1.25) for functional status 1, 0.70 (0.50-0.97) for functional status 2, 1.00 (0.71-1.41) for functional status 4, and 1.85 (1.07-3.19) for functional status 5. CONCLUSIONS: Considering a patient's functional status or more general measures of a patient's health status before transplantation in addition to conventional clinical factors may help to improve our ability to predict posttransplant survival.

Pretransplant MELD score and post liver transplantation survival in the UK and Ireland.

It has been shown that the model for end-stage liver disease (MELD) score is an accurate predictor of survival in patients with liver disease without transplantation. Four recent studies carried out in the United States have demonstrated that the MELD score obtained immediately prior to transplantation is also associated with post-transplant patient survival. Our aim was to evaluate how accurately the MELD score predicts 90-day post-transplant survival in adult patients with chronic liver disease in the UK and Ireland. The UK and Ireland Liver Transplant Audit has data on all liver transplants since 1994. We studied survival of 3838 adult patients after first elective liver transplantation according to United Network for Organ Sharing categories of their MELD scores (< or = 10, 11-18, 19-24, 25-35, > or =36). The overall survival at 90-days was 90.2%. The 90-day survival varied according to the United Network for Organ Sharing MELD categories (92.6%, 91.9%, 89.7%, 89.7%, and 70.8%, respectively; P < 0.01). Therefore, only those patients with a MELD score of 36 or higher (3% of the patients) had a survival that was markedly lower than the rest. As a consequence, the ability of the MELD score to discriminate between patients who were dead or alive was poor (c-statistic 0.58). Re-estimating the coefficients in the MELD regression model, even allowing for nonlinear relationships, did not improve its discriminatory ability. In conclusion, in the UK and Ireland the MELD score is significantly associated with post-transplant survival, but its predictive ability is poor. These results are in agreement with results found in the United States. Therefore, the most appropriate system to support patient selection for transplantation will be one that combines a pretransplant survival model (e.g., MELD score) with a properly developed post-transplant survival model.