9/30/2016 Exceptions as the rule: Disclosures UNOS exceptions for • Grant funding for unrelated research from pediatric liver transplant Gilead. candidates • No disclosures related to research that will be discussed in this presentation. Emily Rothbaum Perito, MD MAS Department of Pediatrics, Transplant Hepatology Department of Epidemiology and Biostatistics Objectives Priority ranking for liver transplant • Explain current priority ranking system March 2000: HHS Final Rule enacted, (MELD/PELD) for pediatric liver transplant to set “priority rankings… through objective and measurable medical • Understand: criteria” – Limitations of the current system – Role of the “Non-Standard Exception” Since then….how can we do this so that the system • Discuss policy change proposals/possibilities works fairly for all transplant candidates? 1
9/30/2016 Mar 2000: HHS Final Rule Also: MELD published, as risk score for TIPS MELD PELD (>12 years) (<12 years) Feb 2002: MELD/PELD system implemented Bilirubin Bilirubin Jan 2005: Adolescents listed as MELD + Share 15 Mar 2005: Criteria for exceptions established INR INR Aug 2005: Status 1 � Status 1A and 1B Creatinine Albumin May 2007: Criteria for status 1B listing narrowed Age <1yo Nov 2010: Pediatric donors nationally to 0-11 1A before adult Growth failure local 1A WAITING LIST WAITING LIST DEATH, Feb 2012: ICU not required for 1A/1B status DEATH TRANSPLANT, OR June 2013: Share 35 TRANSFER TO ICU Jan 2016: Serum sodium added to MELD (not PELD) How does PELD work in practice? ADULT DONOR 0-10yo DONOR 11-17yo DONOR Status 1A Age 0-17 Pediatric Status 1A Age 0-17 Pediatric Status 1A Status 1B • 8 month old female Age 0-11 Pediatric Status 1A Age 0-17 Pediatric Status 1A MELD/PELD >35 Adult Status 1A MELD/PELD 29-34 • Cholestasis Adult Status 1A Liver-Intestine Age 0-17 Pediatric Status 1B Age 0-17 Pediatric Status 1B MELD/PELD 15-28 • Failure to thrive Age 0-11 Age 0-17 Pediatric Status 1B MELD/PELD 15-34 Age 0-11 Status 1A Age 12-17 with MELD >15 Status 1B Adults with MELD >15 LAB VALUE MELD/PELD >15 Age 12-17 with MELD >15 AST 237 MELD/PELD <15 Adults with MELD >15 ALT 119 MELD/PELD <15 Age 12-17 all other Adults all other MELD/PELD <15 Alk phos 883 Age 12-17 all other Adults all other GGT 998 National TB 12.9 LEGEND Age 12-17 Pediatric Status 1A Adult Status 1A LOCAL DB 5.9 Pediatric Status 1B REGIONAL Age 0-11 all other Alb 2.2 LOCAL+REGIONAL All remaining pediatrics All remaining adults INR 1.1 NATIONAL 2
9/30/2016 PELD? 20 Median MELD score for adult, “Non-Standard Exception Requests” deceased donor liver transplants, 2012 (NSERs) • Medical urgency and risk of mortality may not be expressed by PELD/MELD • Request for “exception points” submitted to Regional Review Board (RRB) – Points requested + narrative justification • RRB members vote on whether to approve/deny – Urgency and potential for benefit comparable to that of other candidates having proposed PELD/MELD • RRB decision may be appealed on a conference *UNOS Annual call with RRB and transplant team Report 2012 3
9/30/2016 2015 Review of 2006 review of UNOS exceptions Non-Standard Exceptions • 3,728 pediatric patients with chronic liver • 1123 pediatric liver transplants – 441 - PELD did not determine liver allocation disease on liver waiting list (2002-2013) • 128 multi-organ • 118 living donor No • 27 split liver exception • 168 status 1A ( dx of acute liver failure ) requested – 682 – PELD influenced liver allocation Exception • 362 (53%) - calculated PELD was requested NOT used to determined organ allocation BL Shneider et al Liver Transplantation 2006;12:40-45 13mo with biliary atresia, recurrent cholangitis • 8/24: listed for liver transplant, PELD 7 Of 1,269 pediatric patients with • 9/11: Exception requested for PELD 28 – 6 hospitalizations for cholangitis and exception requests, bacteremia/sepsis, despite prophylactic antibiotics • 9/16: Exception APPROVED for PELD 28 90% were approved. • 9/25: Completed IV Abx for cholangitis • 10/5: Exception APPROVED PELD 35 • Cholangitis recurred � IV Abx • 10/14: Exception request: PELD 40 • 10/20: APPROVED: PELD 40 • 10/30: Living-related liver transplant….doing well! 4
9/30/2016 2015: Exceptions increase the chance of What about MELD for pediatric patients? getting a liver transplant • 13 year old female s/p 1st liver transplant in for pediatric patients 12/2003 for biliary atresia – 2012: Bridging fibrosis, portal hypertension – 6/2015 : AST/ALT >1000. New liver lesions (not thought HCC) and large RLQ mesenteric and retroperitoneal varices. • 7/2/15: Relisted for transplant, MELD 19 – TB 8.3. INR 1.5, alb 3.0 • 7/2015 Persistent hepatitis and worsening jaundice, total bilirubin 20s. • 7/29: Exception requested for increased MELD 13 yo awaiting re-transplant Are all NSERs approved equally? • APPEAL DENIED • 8/6 - 8/8: New onset insulin-dependent diabetes • 8/13 – 8/19: Encephalopathy, INR 1.7, Bili 21.3 NSER Approved NSER Denied No NSER p (n=1,060) (n=74) (n=1,447) • 8/18: Re-appealed for MELD 30 (calculated 26) • 8/28: APPEAL DENIED • 9/13-9/17: Fever, encephalopathy Median 2 years 9 years 2 years • 9/15: Re-appealed for MELD 31 (calculated 29) age at <0.01 (0-11) (0-15) (0-11) • 9/29: APPROVED for MELD 31 listing • 10/19-10/22: Re-admitted for low K+, long QTc Biliary • 10/20: Exception requested for MELD 40 47% 35% 41% <0.01 atresia • 11/1: APPROVED for MELD 40 • 12/16: Transplanted, deceased donor. 5
9/30/2016 400 no NSER * After accounting for NSERs, older NSER never-approved Total number of waitlist candidates children and those without biliary NSER approved 300 atresia less likely to get transplant 200 100 0 6 11 10 3 8 7 4 2 1 9 5 Region ADULT LOW MEDIUM HIGH Median * Hsu et al, AJT 2015. Model accounts for NSER status, MELD/PELD, race, insurance status MELD: NSER approval associated with lower waitlist mortality Non-standard exceptions impact NSER denial associated with increased waitlist mortality transplant…but do they actually .2 NSER Approved (p=0.01) impact survival? NSER Never-approved (p=0.09) No NSER (REF) .15 Cumulative Incidence .1 .05 0 0 1 2 3 4 5 6 Time since listing (months) 6
9/30/2016 Even for children that get What next? transplanted, NSER denial increases Can we improve the system? risk of post-transplant death * Braun, Perito, Dodge et al. AJT 2016. Adjusted for race, diagnosis (tumor vs. other), medical condition at transplant, MELD/PELD at waitlist removal. Age not significant in UV/MV analysis. Increase NSER transparency: % of all NSER Odds of denial Analysis of NSER narrative content Associated with approval Failure to thrive 47.8 0.56* Risk of Death 39.4 0.57* • NSER narratives on 1,138 pediatric liver transplant Biliary complications 21.0 0.48* waitlist candidates coded for “justifications” Associated with denial Standard category, outside criteria 34.1 1.51* • Categories: examples Varices, bleeding not specified 24.7 1.69* – Complications of liver disease: FTT, ascites, infection Impact on other organ system (renal, bone, lung) 19.3 1.79* Impaired quality of life 9.8 3.01* – Disease trajectory: risk of death, prolonged 9.5 Encephalopathy 2.09* hospitalization, time on waitlist Impact on other organ system: Renal 5.9 2.83* – Access limited by current status: no living donors, Not associated with approval or denial Complications of liver disease, any 85.9 1.07 inadequate offers at current MELD/PELD Fluid overload (ascites, hydrothorax, anasarca) 36.9 0.87 – Standard exception category, outside standard criteria: Infection, any (cholangitis, sepsis, peritonitis, other) 34.1 0.83 tumors, other metabolic diseases, post-transplant Cholangitis 25.0 0.79 Prolonged Hospitalization 24.2 complications 0.91 Varices, with bleeding 18.2 1.19 7
9/30/2016 National Liver Review Board Proposed 8 district map • OPTN/UNOS Liver and Intestinal Organ Transplantation Committee pursuing for both pediatric and adult review boards • Recent guidelines to clarify evidence for NSERs in ADULTS – Consider for exception points: Budd-Chiari, Hepatic Epithelioid Hemangioendothelioma , multiple adenomas, post-transplant late vascular complications, polycystic liver disease with severe symptoms, cirrhotic PSC with ICU admissions + resistant bacterial infection or untreatable strictures – No evidence for exception points: ascites, GI bleeding, pruritus, chronic rejection, post-transplant small-for-size Thank you! Conclusions emily.perito@ucsf.edu • The current MELD/PELD system has limitations, • Hillary Braun, MD • Sue Rhee, Phil Rosenthal which impacts pediatric patients differentially by • age, diagnosis, and region. John Roberts, Sandy Feng and UCSF Liver Transplant • Jennifer Dodge, UCSF Liver Center • • For now, NSERs impact patient outcomes—use Lisa Gallagher, Aurora Bermudez, Kathryn Smith and liver transplant fellows them to advocate for your patients! • Funding: NIH-NIDDK, UCSF Department of Pediatrics, UCSF Liver Center, American Gastroenterological Association Emmet B. Keeffe • Adjustments to the MELD/PELD and NSER system Award are needed to achieve liver transplant “priority rankings… through objective and measurable medical criteria” 8
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