Combined Orthotopic Heart and Liver Transplantation: The Need for Exception Status Listing 1

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1 SHORT REPORTS Combined Orthotopic Heart and Liver Transplantation: The Need for Exception Status Listing 1 Paige M. Porrett, 1 Shashank S. Desai, 2 Kathleen J. Timmins, 3 Carol R.Twomey, 4 Seema S. Sonnad, 5 and Kim M.Olthoff 6 Through May 2004, 33 combined orthotopic heart-liver transplants (OHT/OLT) have been performed nationwide. No published data exist to date regarding outcomes of patients awaiting such transplants, although progression of two organ disease processes may contribute to premature death for waiting patients. Retrospective data were collected on patients listed for combined OHT/OLT from both an individual tertiary care transplant center and the national UNOS registry to delineate listing criteria and evaluate patient outcomes in both the pre- and post-meld eras. All patients who survived to transplantation or died on the waiting list were included in the analysis. Results show that 29.6% of patients registered nationally and 42% of patients listed institutionally survived to transplantation. Survival to transplantation was associated with less severe liver disease, though patients with MELD scores ranging from 19 to 26 had significantly higher wait list mortality than expected when compared to single-organ liver transplants. Following combined orthotopic heart-liver transplantation, 80% and 70% of patients survive 1 and 3 years, respectively. In conclusion, combined OHT/OLT is a successful therapy, but current organ allocation policies may not ensure expeditious transplantation in critically ill patients with dual vital organ failure. Providing exception status listing to these patients would ensure more expeditious transplantation and potentially contribute to improved survival. (Liver Transpl 2004;10: ) Introduction Combined, simultaneous orthotopic heart and liver transplantation (OHT/OLT) remains a lifesaving procedure for patients suffering from coincident end-stage hepatic and cardiac disease. Following Starzl s initial description in 1985, early recipients of heart-liver transplants included individuals with dual vital organ failure caused by metabolic disorders or alcohol abuse. 1,2,3,4 In light of reports of 1-year survival rates of 80% in the late 1990s for combined OHT/OLT, 4 indications for this procedure have expanded to include patients such as those with end-stage ischemic heart disease who would otherwise be ineligible for liver transplantation. Despite growing indications for this procedure, however, the United Network for Organ Sharing (UNOS) has registered only 110 patients for combined OHT/OLT in the United States from 1987 through May 2004, and only 33 of these transplants have been performed. 5 Recipients of combined OHT/OLT therefore represent a mere 1% of multiple organ transplants performed nationwide, 6 and only 11 patients nationally are presently listed. 5 Although limited institutional experience, lack of organ availability, and a small pool of eligible patients may all limit the number of combined OHT/OLTs performed annually, no published data regarding patient selection and wait list survival in this population exist. These factors may also significantly influence the number of patients who are both listed for this procedure and subsequently transplanted. In an attempt to address this important issue, we detail the physiologic criteria and outcomes of patients listed for combined orthotopic heart and liver transplantation at a single tertiary transplant center. We further supplement this information with a brief discussion of outcomes for patients listed nationally for combined OHT/OLT in the UNOS registry. Abbreviations: MELD, Model for End-Stage Liver Disease; TT, time to transplant; OHT/OLT, combined orthotopic heart and liver transplant; CTP, Child-Turcotte-Pugh; OPTN, Organ Procurement and Transplantation Network; UNOS, United Network for Organ Sharing; EF, ejection fraction; PVR, pulmonary vascular resistance No funding for this work was provided by any source. From the 1 University of Pennsylvania Department of Surgery, 2 University of Pennsylvania Department of Medicine, Division of Cardiovascular Medicine, 3 University of Pennsylvania Department of Surgery, Liver Transplant Program, 4 University of Pennsylvania Department of Surgery, Division of Cardiothoracic Surgery, 5 University of Pennsylvania Department of Surgery, Office of Outcomes Research, and 6 Liver Transplant Program, University of Pennsylvania Department of Surgery, Philadelphia, PA. Address reprint requests to Kim M. Olthoff, MD, University of Pennsylvania Department of Surgery, Liver Transplant Program, 2 nd Floor Dulles Pavilion, 3400 Spruce Street, Philadelphia, PA Telephone: ; FAX: ; kim.olthoff@uphs.upenn.edu Copyright 2004 by the American Association for the Study of Liver Diseases Published online in Wiley InterScience ( DOI /lt Liver Transplantation, Vol 10, No 12 (December), 2004: pp

2 1540 Porrett et al. Table 1. Characteristics of Patients Listed for Combined Heart-Liver Transplantation at a Single Tertiary Transplant Center Patient Gender Age at listing (years) Etiology of CHF and Liver Cirrhosis 1 M 40 CHF: EtOH CM LC: HCV/EtOH 2 M 56 CHF: EtOH CM LC: EtOH 3 M 47 CHF: Dilated CM LC: HCV/HBV 4 M 57 CHF: Ischemic CM LC: HCV 5 M 58 CHF: Ischemic CM LC: Cryptogenic 6 F 39 CHF: Dilated CM LC: Cryptogenic 7 F 34/37* CHF: Congenital LC: HCV Diabetes Coronary Artery Disease Prior Cardiac Surgery Ascites or Encephalopathy Coronary A: revascularization Coronary revascularization A: Fontan procedure A: Abbreviations: LC, liver cirrhosis; A, ascites; E, encephalopathy; CM, cardiomyopathy; HBV, hepatitis B virus; HCV, hepatitis C virus; CHF, congestive heart failure; EtOH, alcohol; CM, cardiomyopathy; LC, liver cirrhosis. *First listed for liver transplantation; later listed for heart transplantation as well. Materials and Methods After institutional review board approval, a retrospective chart review of all patients listed for combined OHT/OLT from January 1997 to February 2004 at the University of Pennsylvania was performed. Relevant data gathered included information regarding predictor variables such as patient age, comorbidities, etiology and severity of organ failure, UNOS status (based on Child-Turcotte-Pugh [CTP] score), and time spent on the waiting list (Tables 1, 2, and 3). Outcome variables included overall patient survival and transplantation status. Left ventricular ejection fraction (EF) was established by serial echocardiograms. Coronary artery disease, cardiac index, pulmonary artery pressures, central venous pressures, and pulmonary vascular resistance (PVR) were determined by cardiac catheterization. Model for End-Stage Liver Disease (MELD) score was calculated from individual patient s INR, bilirubin, and creatinine at various time points by using the UNOS online MELD calculator. 7 Data from the UNOS registry were gathered retrospectively and included MELD score, cardiac listing status, date of listing for each organ, time to transplantation for each registration, reason for removal from the transplant waiting list, and survival or transplanta- Table 2. Physiologic Parameters at Listing for Individual Patients at a Single Center Patient UNOS Status (Heart/Liver) MELD Score Ejection Fraction (%) Cardiac Index (L/min/m 2 ) Pulmonary Artery Pressure (mmhg) Central Venous Pressure (mmhg) Pulmonary Vascular Resistance (Wood Units) 1 2/2A / /2B / / / / / B/2A / /2* / /2* n/a 3.1 *Listing substatus unknown or patient listed prior to liver status 2 subdivision. Fontan physiology.

3 Heart-Liver Transplantation Exception Status 1541 Table 3. Outcomes of Patients Listed for Combined Heart-Liver Transplantation at a Single Institution Pulmonary Vascular Resistance (Wood Units) Patient Time from Listing to Death or Transplant UNOS Status at Death or Transplant (Heart/Liver) Cause of Death MELD Score at Death or Transplant EF (%) Cardiac Index (L/min/m 2 ) 1 Death: 66 days 2/2A Sepsis Death: 63 days 2/2A Sepsis Sepsis Death: 1140 days 4 Death: 1028 days 5 Transplant: 49 days 6 Transplant: 42 days 7 Transplant: 1335/373 days 7*/ Heart changed from listing status* 2/ Hepatorenal syndrome A/2A Heart upgraded from listing status 1/1 Liver upgraded from listing status 1/2 Heart upgraded from listing status Brain death following surgical technical complication n/a 25 n/a n/a 23 n/a Abbreviation: EF, ejection fraction. *Patient upgraded to 1A for 1 week prior to death; however, the patient developed MRSA bacteremia and was subsequently downgraded to UNOS cardiac status 7. He died 1 week after this downgrade in listing status from sepsis. UNOS CTP liver allocation system no longer in existence; these patients died after implementation of MELD in February Patient died 2 days after transplantation secondary to operative technical difficulty and bleeding. Patient listed at separate times for liver and heart (respectively). See Table 1. Listed for 8 days as liver UNOS status 1 before combined OHT/OLT. Liver listing substatus unknown or patient listed prior to liver status 2 subdivision. tion outcome for each patient ever registered for heart-liver transplantation (Table 4). Organs were allocated according to Organ Procurement and Transplantation Network (OPTN) protocol at the time period applicable to each patient, with top priority given to patients with the highest UNOS status. No priority exceptions were granted to patients listed for dual organs. Statistical analyses included the Fisher s exact test for nominal, dichotomous variables and the Mann-Whitney test statistic for non-parametric distributions. 8 Results Eight patients (6 men, 2 women) were listed for combined OHT/OLT from January 1997 through January 2004 at our institution. Seven of these eight patients reached the study end point of either transplantation or death on the wait list. At follow-up in February 2004, one male patient listed in 2003 remains alive to date awaiting combined OHT/OLT. He was excluded from subsequent statistical analysis. The mean age of analyzed patients in our institutional cohort was 47 years (range, 34 58, SD, 9.9). The etiology of end-stage organ failure varied throughout the cohort. Etiology of liver cirrhosis included alcohol, hepatitis C and B, and cryptogenic causes. Etiology of heart failure included idiopathic, ischemic, and/or alcohol-induced cardiomyopathy, as well as congenital heart disease. At listing, patients had a mean MELD score of 14.2 (range, 6 27), a mean EF of 31% (range, 10% 50%), a mean cardiac index (CI) of 3.0 L/min/m 2 (range, ), and a mean PVR of 1.4 Wood units (range,.4 3.1). Only 3 of the 7 listed patients included in our institutional analysis survived to transplantation (42%). One transplanted patient died from perioperative technical cardiac complications (patient #5, Table 3), and two transplanted patients remain alive to date (patients #6 and #7 [Table 3], transplanted in 1997 and 2001 respectively). All patients not receiving organs died while awaiting transplantation, 75% from sepsis. Time from listing to death for these patients varied widely from 63 days to 1140 days (Table 3). Overall survival was associated with transplantation (P.1), younger

4 1542 Porrett et al. Table 4. Patients Removed from the National UNOS Waiting List Reason Listed for Dual OHT/OLT (11/87 4/04) Listed for Solitary Heart (1/95 3/04) Listed for Solitary Liver (1/95 3/04) All reasons 99 patients 32,729 patients 75,310 patients Cadaveric Tx 33 Combined (35%) (63%) 42,065 (55%) 9* Solitary heart (9%) 4 Solitary liver (4%) 5 Sequential dual organ transplant (5%) Living donor n/a (3%) Medically unsuitable see below* 34 (0.1%) 81 (0.1%) Transferred to 2 (2%) 700 (2%) 2911 (4%) another center Died 24 awaiting combined OHT/OLT (25%) 6441 (20%) (19%) 1 awaiting liver only (1%) Other 11 (12%) 1402 (4%) 4802 (6.4%) Condition improved 4 (4%) 2363 (7%) 3457 (5%) Too Sick to Tx 6 (6%) 927 (3%) 3778 (5%) Tx at another center n/a 154 (0.5%) 1636 (2%) *8/9 pts received heart Tx only without clear reason for removal from liver wait list. 1/9 pts received heart Tx and delisted for liver because medically unsuitable to get liver. 2/4 pts received liver Tx but still await hearts data unavailable as to why combined transplant not performed at time of liver Tx. 2/4 pts with unclear reason for removal from heart Tx list. Unclear reason as to why this pt was delisted for heart. These 4 patients now await single organ transplantation (i.e., one organ system improved sufficiently to allow listing for only a heart or a liver). age at listing ( 40 years, P.025), and increased pulmonary vascular resistance ( 1.0 Wood units, P.05). A PVR 1.0 Wood units was statistically associated with listing as UNOS cardiac status 1, but overall UNOS cardiac status was surprisingly not statistically associated with survival (P.14). Further analysis of patient subgroups by UNOS status revealed that UNOS cardiac status 2 patients with MELD scores 25 all died within 90 days of listing (P.05), while all UNOS cardiac status 2 patients with MELD scores 10 survived longer than 1000 days before death (P.05). Etiology of organ failure, wait list time, and comorbid disease did not impact overall patient survival. From November 1987 through May 2004, 110 patients have been concurrently listed for orthotopic heart and liver transplantation nationally. Thirty-three combined, simultaneous OHT/OLTs have been performed (30%), 30 patients have either died or become too sick to transplant while awaiting combined OHT/ OLT (27%), and 11 patients are currently listed (10%). Of the remaining 34 patients ever listed for heart-liver transplantation, 5 patients received sequential heartliver transplants, 13 patients received single organ transplants (heart or liver), and 4 patients currently await single organ transplantation after recovery of one vital organ system (Table 4). According to the OPTN database, 80% of patients who undergo combined OHT/OLT are alive at 6 and 12 months post-transplant, and 72% of transplanted patients survive beyond 24 and 36 months. 5 Excluding patients currently awaiting combined heart-liver transplantation, 63 patients in the national cohort reached the study end point of either combined heart-liver transplantation (52%) or death (48%). The proportion of patients who reached these end points did not differ significantly between the national cohort and our institutional cohort (P 1.0). In the UNOS registry, 41 of these 63 patients were listed as cardiac status 1A or 1B, and 18 patients were listed as cardiac status 2. Data on cardiac status at transplant listing was not available for 4 patients. The listing cardiac status of transplanted patients versus patients who died did not differ significantly but did approach statistical significance (P.153) in the national cohort. Fifty-three patients were listed for combined OHT/OLT in the pre-meld era and 10 patients were listed after the implementation of MELD. When outcomes of patients listed before and after MELD implementation were compared, no significant difference in the proportion of patients reaching transplantation or death existed

5 Heart-Liver Transplantation Exception Status 1543 between the groups (P.49). The average MELD score of transplanted patients was significantly lower than the MELD score of patients who died (15.2 versus 28.8, respectively [P.024]). Furthermore, patients listed for combined OHT/OLT with MELD scores of died more frequently than predicted by MELD score over a 90-day period (P.018). Discussion Both our institutional data and the data from the UNOS transplant registry indicate that combined heart-liver transplantation is a successful therapy and confers survival benefit to patients with end-stage coincident cardiac and liver failure. In our institutional series, overall patient survival clearly correlated with survival to transplantation, and patients with less severe liver disease were most likely to survive to transplantation. Surprisingly, both our institutional data and the national data from the UNOS registry detected no statistical difference in survival of patients with respect to their cardiac listing status. Given the small number of patients included in the analysis, however, both the institutional and the national studies are significantly underpowered with respect to cardiac listing status, having less than 50% power to detect statistical significance between death or transplantation at the.05 level. Additional data is therefore required to elucidate the impact of cardiac listing status with survival in this population. In our institutional series, patients who had the shortest survival on the waiting list (patients #1 and #2, see Table 3) had more severe liver disease by MELD calculation and less severe cardiac dysfunction. However, because these patients never achieved UNOS cardiac/liver status higher than 2/2A in the pre-meld era, they unfortunately succumbed to disease before adequate organs became available. According to available 2001 data from the OPTN database, the median time to transplant (TT) in the pre-meld era for patients awaiting liver transplantation was 76 and 407 days for UNOS status 2A and 2B patients, respectively. While mortality rates on the wait list ranged 11% 30% annually for these patients, 6 the majority of patients listed as UNOS status 2 under the prior CTP liver allocation system had sufficient hepatic reserve to survive to transplantation. In our patient population, however, any patient with liver disease severe enough to warrant 2B status died in less than 90 days unless transplanted, suggesting that the CTP allocation system underestimated the risk of death in this patient population. The more accurate estimation of liver failure and hepatic reserve provided by MELD score has resulted in improved wait list survival for patients awaiting solitary liver transplantation. 9,10 However, our analysis of patients awaiting combined OHT/OLT in the UNOS registry does not indicate that MELD improves wait list survival for this special population, given that the same proportion of patients died awaiting combined OHT/ OLT both before and after the adoption of the MELD allocation system. Moreover, both our institutional data and the UNOS registry suggest that patients with moderate degrees of liver and cardiac failure (MELD scores of 20 29, cardiac status 2) seem to be most disadvantaged by current allocation policies. Prior published studies 9,10 indicate that approximately 75% of patients listed for single organ liver transplantation with MELD scores of will survive 90 days. In our institutional series, no patient with dual organ failure and similar MELD score survived longer than 90 days, and comparable patients in the UNOS registry had significantly higher mortality than predicted by MELD (data not shown). According to the OPTN, patients with MELD scores of in had a median waiting time of 127 days (95% confidence interval, days), and patients listed as cardiac status 2 waited a median of 335 days (95% confidence interval, days). Our data suggest that dual organ failure patients do not survive such waiting times. Survival on the wait list in the dual organ failure population more closely approximates the waiting time for patients listed with cardiac status 1A/1B (median, 40 and 73 days, respectively) or patients with MELD scores 30 (median, 22 days). 6 Accurate determination of organ failure severity allows implementation of rational organ allocation policies that assure timely transplantation of critically ill patients. Current prognostic constructs such as MELD that model single organ failure may not accurately predict mortality in liver failure patients with concomitant severe cardiac dysfunction. Similarly, indices of cardiac function currently employed to status heart failure patients may also be impacted by the hemodynamic alterations known to occur in hepatic failure. Patients who ordinarily require inotropic support and therefore earn UNOS cardiac 1A or 1B status may have their status inappropriately downgraded despite profound cardiac dysfunction if the decrease in systemic vascular resistance that occurs in liver failure provides sufficient afterload reduction to maintain cardiac output without pharmacologic support. Thus, organ allocation strate-

6 1544 Porrett et al. gies that fail to account for the unique pathophysiology of dual organ failure may systematically underestimate disease severity and contribute to diminished survival in patients awaiting combined heart-liver transplantation. While additional data in the post-meld era from other transplant centers and the UNOS registry will be required to confirm our findings, we would support exception status listing for patients awaiting combined orthotopic heart and liver transplantation given the results of this study. Providing exception MELD liver points or cardiac UNOS status 1 to patients requiring both heart and liver would ensure more expeditious transplantation and likely contribute to improved survival. Given the small number of patients who ultimately qualify for this procedure, exception status would likely provide significant benefit to distinct individuals without prolonging wait times for the thousands of patients awaiting single organ transplantation. References 1. Shaw BW, Bahnson HT, Hardesty RL, Griffith BP, Starzl TE. Combined transplantation of the heart and liver. An Surg 1985; 202: Olivieri NF, Liu PP, Sher GD, Daly PA, Greig PD, McCusker PJ, et al. Brief report: combined liver and heart transplantation for end-stage iron-induced organ failure in an adult with homozygous beta-thalassemia. N Engl J Med 1994;330: Surakomol S, Olson LJ, Rastogi A, Steers JL, Sterioff S, Daly RC, McGregor CG. Combined orthotopic heart and liver transplantation for genetic hemochromatosis. J Heart Lung Transplant 1997;16: Befeler AS, Schiano TD, Lissoos TW, Conjeevaram HS, Anderson AS, Millis JM, et al. Successful combined liver-heart transplantation in adults: report of three patients and review of the literature. Transplantation 1999;68: UNOS Data Request System. Based on OPTN data as of May 15, SAS analyst: Katarina Anderson. 6. URREA; UNOS Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data [Internet]. Rockville, MD: HHS/HRSA/OSP/DOT; 2003 (modified February 18). Available at: annualreport.asp. Accessed November MELD/PELD calculator. Available at: resources/meldpeldcalculator.asp. 8. Daniel WW. Biostatistics: A foundation for analysis in the health sciences. 6th ed. New Baskerville: John Wiley & Sons, Inc., Edwards EB, Harper AM. The impact of MELD on OPTN liver allocation: preliminary results. Clin Transpl 2002: Wiesner R, Edwards E, Freeman R, Harper A, Kim R, Kamath P, et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology 2003;124:91 96.