Robert Smith MD Medical Director, Adult Liver Transplant Program Department of Gastroenterology and Hepatology Geisinger Medical Center Danville, PA

Robert Smith MD Medical Director, Adult Liver Transplant Program Department of Gastroenterology and Hepatology Geisinger Medical Center Danville, PA

Disclosures: Pharmaceutical Speaker Bureau Participant for: Salix Vertex Genentech *This talk contains no discussion of Pharmacologic agents

> 18,000 people are UNOS listed for orthotropic liver transplant (OLTX) Donor pool has remained flat at 6000 organs/year Approximately 1/3 of patients on the wait list die there or are de-listed Only 150 non-pediatric living related donor transplants are done nationally Approximately 600 OLTX are done annually in PA (10%)

1973: Dr. Starzl performs the first successful liver transplantation 1982: Medicare approves liver transplantation as a nonexperimental reimbursable treatment for end stage liver disease (transplant programs blossomed ) 1987: To formalize sold organ allocation the US Government established the OPTN (organ procurement and transplantation network)

Initially Informal: sickest patient first wait time on list a factor Increasing demand for organs and lack of standardization led to a CTP-based scoring and listing system

Calculator: Child Pugh classification for severity of liver disease Encephalopathy None (1 point) Grade 1: Altered mood/confusion (2 points) Grade 2: Inappropriate behavior, impending stupor, somnolence (2 points) Grade 3: Markedly confused, stuporous but arousable (3 points) Grade 4: comatose/unresponsive (3 points) Ascites Absent (1 point) Slight (2 points) Moderate (3 points) Bilirubin < 2 mg/dl (1 point) 2-3 mg/dl (2 points) > 3 mg/dl (3 points) Albumin > 3.5 g/dl (1 point) 2.8-3.5 g/dl (2 points) < 2.8 g/dl (3 points) (cont d)

Prothrombin time prolongation Less than 4 seconds above control/inr < 1.7 (1 point) 4-6 seconds above control/inr 1.7-2.3 (2 points) More than 6 seconds above control/inr > 2.3 (3 points) Total Criteria Point Count: 0 Child Pugh Score Interpretation 5-6 points: Child class A 7-9 points: Child class B 10-15 points: Child class C

Status 1: FHF, Primary Graft Non-Function, etc. essentially same today Status 2A: CTP >10, not expected to live 7 days (in ICU) Status 2B: CTP >10, expected to live > 7 days Status 3: CTP >7 (minimal listing criteria) Criteria were very subjective and major component determining allocation was wait time

In 1998 HHS stated a new allocation methodology based on scientifically validated medical criteria, deemphasizing wait time, needed to be developed and implemented

OPTN response was to us an existent model known as the Mayo End-Stage Liver Disease Model, now Model For End-Stage Liver Disease, or the MELD Score (originally predicted 3 month survival post- TIPS)

MELD = (0.957 + LN (creatinine) = 0.378 x LN (bilirubin) + 1.12 x Ln (INR + 0.643) * continuous scoring from 7 40 ** creat. caps at 4.0

Implemented in 2002 Status 1 remained unchanged All other patients listed by MELD score and blood type Regional Review Boards (RRB s) were established to review cases where MELD was felt not predictive of true mortality and possibly grant exception points

Very accurate at predicting 30, 90, 180, and 360 day mortality (validated by multiple analysis) Can be updated on a daily basis Has eliminated wait time as an important variable except in ties Decreases deaths on the wait list

Does not factor in severity of complications of portal hypertension (presumably RRB s can address this regionally) Creates significant variation in scores at time of transplant (e.g. 48% of region 6 recipients had scores in the 11-20 range, but only 20% in region 1)

Standardized formula for patients with Stage II hepato-cellular CA (HCC) used nationally All other indications for requested exception points non-standardized with resultant large variation in number of patients who receive points and number of exception points allocated

So What can be done to level the playing field?

RRB Regional Inequities: Standardize criteria Nationally (as has been done for HCC) for 12 most common indications for exception point requests (would leave a relatively small number of outlier cases requiring actual RRB review)

Major Problem = No consensus on goal: Direct organs to regions with high MELD scores at time of transplant? Direct organs to minority/poor patients? Are harvested organs a national, regional, or local resource? (all hotly debated)

MELD re-weighting, add other parameters ( MELDNA, MELD-D, & SHARE I5 ) Regional or even National sharing at a specific MELD threshold ( share is concept) Expanding the donor pool (ECD, opt-in vs. opt-out concept) Net benefit model (statistically calculate the difference between 5 year wait list mortality and expected post-transplant survival (SRTR is robust enough to support this) All of these proposals are being studied Each has theoretical benefits and pitfalls No consensus exists for any of these models At this juncture regional sharing (which could be initiated differently in each region) has the best chance of reaching a consensus

Regional based If an OPO within a region harvests a liver, but has no recipient to match with a MELD > 15, the organ is offered to the rest of the OPO s within that region Statistically, at a MELD of 15, the risks of transplant outweigh the potential benefit There is growing consensus to nationalize SHARE 15

Each region would set a MELD threshold for sharing outside the harvesting OPO that statistically maximizes benefit in that region Geographic considerations that might significantly increase cold ischemia and time would have to considered An accepted sharing threshold would be developed (difference of 2 MELD points required between local and non-local candidates)

Current system serves the majority of patients with ESLD WELC Standardization of RRB exception point criteria long over due Regional inequities will likely drive acceptance of some form of MELD revision and some for of expanded sharing Every effort to expand the donor pool should be explored