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

Funder: Research Trainees Coordinating Centre; Id: http://dx.doi.org/10.13039/501100000659Funder: National Institute for Health Research; Id: http://dx.doi.org/10.13039/501100000272During 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

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

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

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

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

International comparison of liver transplant programmes:differences in indications, donor and recipient selection and outcome between Italy and UK

Comparing liver transplant (LT) programmes internationally can improve outcomes by stimulating cross-national learning. Yet, comparison of crude outcomes, by using registry data, is limited by missing data, not allowing proper risk-adjustment for donor- and recipient-related factors. The objective of this study was to compare two European LT programmes based on high-quality national longitudinal databases prospectively collected in Italy and UK respectively