LIVER TRANSPLANTATION 20:1356–1364, 2014
ORIGINAL ARTICLE
Reframing the Impact of Combined Heart-Liver Allocation on Liver Transplant Wait-List Candidates David S. Goldberg,1,2,3 Peter P. Reese,1,2,3,4 Sandra Amaral,2,5 and Peter L. Abt6 Department of Medicine, Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA; 2 Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA; 3Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, PA; 4 Renal, Electrolyte, and Hypertension Division, University of Pennsylvania, Philadelphia, PA; 5Division of Nephrology, Children’s Hospital of Philadelphia, Philadelphia, PA; and 6Division of Transplantation, Department of Surgery, University of Pennsylvania, Philadelphia, PA
1
Simultaneous heart-liver (H-L) transplantation, although rare, has become more common in the United States. When the primary organ is a heart or liver, patients receiving an offer for the primary organ automatically receive the second, nonprimary organ from that donor. This policy raises issues of equity, such as whether liver transplantation alone candidates bypassed by H-L recipients are disadvantaged. No prior published analyses have addressed this issue, and few methods have been developed as means of measuring the impact of such allocation policies. We analyzed Organ Procurement and Transplantation Network match run data from 2007 to 2013 to determine whether this combined organ allocation policy disadvantages bypassed liver transplant wait-list candidates in a clinically meaningful way. Among 65 H-L recipients since May 2007, 42 had substantially higher priority for the heart versus the liver, and these 42 bypassed 268 liver-alone candidates ranked 1 to 10 on these match runs. Bypassed patients had a lower risk of wait-list removal for death or clinical deterioration in comparison with controls selected by the match Model for End-Stage Liver Disease (MELD) score [hazard ratio (HR) 5 0.56, 95% confidence interval (CI) 5 0.40-0.79] and a risk similar to that of controls selected by the laboratory MELD score (HR 5 0.91, 95% CI 5 0.63-1.33) or on match runs of similar graft quality (HR 5 0.97, 95% CI 5 0.73-1.37). The waiting time from bypass to subsequent transplantation was significantly longer among bypassed candidates versus controls on match runs of similar graft quality [median: 87 days (interquartile range 5 27-192 days) versus 24 days (interquartile range 5 5-79 days), P < 0.001]. Although transplantation was delayed, liver transplant wait-list candidates bypassed by H-L recipients did not have excess mortality in comparison with 3 sets of matched controls. These analytic methods serve as a starting point for considering other potential approaches to C 2014 AASLD. evaluating the impact of multiorgan transplant allocation policies Liver Transpl 20:1356-1364, 2014. V Received March 31, 2014; accepted July 6, 2014.
Abbreviations: CI, confidence interval; DRI, donor risk index; H-L, heart-liver; HR, hazard ratio; IQR, interquartile range; LTA, liver transplantation alone; MELD, Model for End-Stage Liver Disease; MOT, multiorgan transplantation; OPTN, Organ Procurement and Transplantation Network; SHR, subhazard ratio; UNOS, United Network for Organ Sharing. This study was supported by grants from the National Institutes of Health (K08 DK098272 to David S. Goldberg and K23 DK083529 to Sandra Amaral), by the Greenwall Foundation (to Peter P. Reese), and in part by the Health Resources and Services Administration (contract 234-2005-37011C). The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. Potential conflict of interest: Nothing to report. Address reprint requests to David S. Goldberg, M.D., M.S.C.E., Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Blockley Hall, 423 Guardian Drive, Room 703, Philadelphia, PA 19104. Telephone: 215-746-8598; FAX: 215-349-5915; E-mail: [email protected] DOI 10.1002/lt.23957 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2014 American Association for the Study of Liver Diseases. V
LIVER TRANSPLANTATION, Vol. 20, No. 11, 2014
In the United States, certain types of simultaneous multiorgan transplantation (MOT), including combined liver-kidney and heart-liver (H-L) transplantation, have been increasingly practiced.1-7 This demand is attributable to several factors, including an aging population with congenital heart disease and congestive hepatopathy6 as well as an increased prevalence of chronic kidney disease in liver and heart transplant candidates.3-6 The need for the second organ may be for end-stage disease in the nonprimary organ necessitating a transplant independent of the primary organ (eg, a patient with decompensated cirrhosis on hemodialysis), or there may be end-stage disease in the nonprimary organ without overt clinical symptoms, but the organ is needed in order to optimize function of the primary organ (eg, end-stage heart failure with congestive hepatopathy and cirrhosis but preserved liver synthetic function). To accommodate wait-list candidates in need of MOT, Organ Procurement and Transplantation Network (OPTN)/ United Network for Organ Sharing (UNOS) policy dictates that when the primary organ is a heart, lung, or liver, patients who receive an offer for 1 of these 3 primary organs automatically receive the second, nonprimary organ from that donor, regardless of their waitlist priority for that second organ, only when the organ will be allocated to a patient in the local organ distribution unit (it is voluntary if the recipient is outside the local organ distribution unit).8 Because annual liver transplant wait-list mortality rates exceed 20% in several UNOS regions,9 the current MOT allocation policy raises issues of equity and utility.10 Prioritizing an MOT candidate for the nonprimary organ may unfairly cause harm to a candidate who also has strong ethical claims to the same organ but must remain on the wait list. Additionally, questions of utility arise, such as whether allocating 2 organs to an MOT recipient yields more (or fewer) quality-adjusted lifeyears in comparison with allocating each organ to a single candidate. For example, when a patient with maximum priority for a heart transplant receives the heart and liver from the same donor, the policy may be perceived as unfair to liver transplantation alone (LTA) candidates bypassed during the match run for that liver. The problem of fairness to patients who are bypassed by MOT depends on how much harm these patients experience. Previous MOT studies have focused on wait-list mortality for potential MOT recipients6 or the benefit of incremental transplants versus simultaneous transplants, but none have focused on the outcomes of those individuals who are bypassed when organs are diverted to MOT recipients.10,11 Because of the lack of prior work addressing the impact of MOT allocation policies on wait-list candidates bypassed by such organ diversions, there are no established methods for measuring the impact of such policies. For liver transplantation, modeling approaches have been used to estimate the impact of broader regional and national organ sharing, but no empirical methods exist to evaluate this specific question of MOT organ allocation. Furthermore, there have
GOLDBERG ET AL. 1357
been few studies using recently available OPTN match run data,12 which may become a more frequent focus of research involving organ allocation and distribution. This study analyzes match run data from OPTN to determine whether the current H-L allocation policy leads to greater mortality or prolonged waiting times for transplantation among LTA candidates who are bypassed by H-L recipients.
PATIENTS AND METHODS Study Population and Approach The cohort of interest included any candidate on the liver transplant wait list who was ranked on a liver match run in which the liver was allocated to a combined H-L recipient instead of an LTA candidate. We focused specifically on H-L transplants because (1) that is the most commonly performed combined thoracic-liver transplant,6 (2) the number of combined H-L candidates is projected to rise with the aging congenital heart disease population,1,6 and (3) in many H-L transplants, the recipient has cirrhosis without overt complications of end-stage liver disease.1 All analyses were based on OPTN/UNOS data from May 10, 2007 through May 10, 2013. The initial date was the first date for which match run data were made available for research. OPTN/UNOS data included encrypted donor and wait-list candidate variables, match run position, and match Model for EndStage Liver Disease (MELD) scores for every transplant recipient in addition to all wait-list candidates ranked higher (ie, higher wait-list priority but turned down or bypassed for an organ) in every match run. Only match runs of combined H-L recipients 18 years of age were included because of the differences in organ allocation policies for adult wait-list candidates versus pediatric wait-list candidates. The analyses used 2 distinct matching techniques to identify comparator groups to assess the impact of bypassing single-organ candidates (Table 1). The first approach compared LTA wait-list candidates bypassed on H-L match runs with 2 separate cohorts of control wait-list candidates with similar characteristics matched for blood type, UNOS region, and MELD score (matched candidate cohort 1 was matched by the match MELD score, whereas matched candidate cohort 2 was matched by the laboratory MELD score; taken together, these analyses are called the matched candidate approach). The secondary approach used match runs in which the liver allografts were identical in quality, as measured by the donor risk index (DRI13; which we call the matched allograft approach), to the grafts of H-L recipients. These analyses were limited H-L match runs in which the heart sequestered the liver, and LTA candidates with higher wait-list priority were thereby bypassed.
Categorization of Combined H-L Match Runs Data for all match runs for which there was combined H-L allocation were evaluated. Match runs were
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TABLE 1. Selection of Experimental and Comparator Groups for Analyses of Wait-List Outcomes of Liver Transplant Wait-List Candidates Bypassed by Simultaneous H-L Recipients Analytic Approach Matched candidate cohort 1
Matched candidate cohort 2
Matched allograft approach
Experimental Group
Comparator Group
Rationale
268 liver candidates ranked in the top 10 positions of a match run bypassed by an H-L recipient during the years 2007 to 2013 268 liver candidates ranked in the top 10 positions of a match run bypassed by an H-L recipient during the years 2007 to 2013 268 liver candidates ranked in the top 10 positions of a match run bypassed by an H-L recipient during the years 2007 to 2013
2144 liver wait-list candidates matched 8:1 based on UNOS region, blood type, and match MELD score to bypassed liver wait-list candidates
Compare bypassed candidates with wait-list candidates with similar access to transplantation based on match MELD score Compare bypassed candidates with wait-list candidates with similar risk of wait-list mortality based on laboratory MELD score
2340 liver wait-list candidates matched 9:1 based on UNOS region, blood type, and laboratory MELD score to bypassed liver wait-list candidates 20,962 liver wait-list candidates who were (1) ranked in the top 10 of a match run of a liver-alone recipient who received a graft of similar quality to an H-L recipient and (2) ranked higher than the organ recipient on that match run
categorized as heart sequestering liver, liver sequestering heart, or equal priority. The assignment of categories was determined through comparisons of the transplant recipients’ ranks on the corresponding liver and heart match runs. Ranks within 2 places (eg, first on heart and third on liver) were considered equal, and differences of 3 or greater were assigned to the organ with the higher priority (eg, first on heart and ninth on liver was considered heart sequestering liver). Because there were only 8 match runs in which the liver sequestered the heart (eg, the candidate was ranked first on the liver match run but fiftieth on the heart match run, and thus the heart was diverted from other heart-alone candidates), the primary analyses were restricted to match runs in which the heart sequestered the liver. The liver graft quality, measured by the DRI, was calculated for each liver graft allocated in a combined H-L transplant and was converted into a categorical variable based on predicted graft survival for the purposes of matching (1.0, >1.0 & 1.4, >1.4 & 1.6, and >1.6).13
Selection of Control Liver Wait-List Candidates for the Matched Candidate Analysis This analysis compared liver wait-list candidates who were bypassed by an H-L recipient with 2 different sets of control liver wait-list candidates matched by the UNOS region, the blood type, and either (1) the laboratory MELD score or (2) the match MELD score. The utilization of these 2 methods tested whether the results were sensitive to the control group. Match MELD score controls served as a comparator group with similar access to transplantation based on wait-
Compare bypassed candidates to wait-list candidates on match runs of similar graft quality to “simulate” the outcomes had the liver in an H-L allocation been offered to a liver-alone candidate with the highest priority
list priority, whereas laboratory MELD score controls functioned as a comparator group with similar expected wait-list mortality (better predicted with the laboratory MELD score).14,15 To account for discrepancies between laboratory and match MELD scores, we included a variable indicating whether a wait-list candidate had exception points at the time of bypass or selection as a control. The process of identifying matched candidates did not rely on match run data but instead relied on candidate wait-list characteristics, including the most recently updated MELD score.
Selection of Control Liver-Alone Match Runs for the Matched Allograft Analysis Control liver-alone match runs were compared with H-L match runs in which the heart sequestered the liver. Specifically, control match runs were those in which the liver graft was of the same blood type and DRI category (graft quality), whereas in H-L match runs, the heart sequestered the liver. Only liver waitlist candidates in the top 10 rank positions of a control or H-L match run for a given liver were evaluated because >90% of comparable livers were distributed to LTA wait-list candidates ranked 1 to 10.
Outcomes The primary outcome was wait-list removal for death or clinical deterioration, which was defined as dying on the wait-list or within 90 days of removal from the wait list, when the reason for wait-list removal was “too sick to transplant” or “other.” Death within a
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short time of wait-list removal was reflective of the severity of illness and was viewed as equivalent to dying on the wait list15,16 and could be identified on the basis of the Social Security Death Master File death date.15,16
Index Date The index date for bypassed wait-list candidates was the date of the H-L match run from which they were bypassed. The index date for controls in the matched candidate analysis was the date on which the wait-list candidate met matching criteria because this was the date from which the control would be expected to have similar access to transplantation (match MELD score) or wait-list mortality (laboratory MELD score) in comparison with the bypassed wait-list candidate. The index date for controls in the matched allograft analysis was the first date on which the wait-list candidate was ranked 1 to 10 on an LTA match run of graft quality comparable to the liver in an H-L match run. Because many controls in the matched allograft approach were identified in more than 1 match run, we assigned these wait-list candidates to the first match run during the study period.12
Analytical Methods: Matched Candidate Approach Wait-listed liver transplant candidates bypassed on an H-L match run were compared with control candidates matched by the MELD score, blood type, and UNOS region with stratified Cox models that accounted for matched data. Models were stratified by the match group (ie, a cohort of bypassed candidates and controls with a given combination of MELD scores, regions, and blood types), and they incorporated a robust variance sandwich estimator to account for correlations resulting from matching.17 The MELD score was used for matching, so it could not be a covariate; however, the models included a covariate indicating whether the patient had exception points.
Analytical Methods: Match Allograft Approach Bypassed liver candidates from a match run in which the heart sequestered the liver were compared with liver candidates in control match runs. Competing risk Cox regression models evaluating the outcome of wait-list removal for death or clinical deterioration were fit. Transplantation was modeled as a competing risk because, in evaluating pretransplant survival, transplantation influences the probability that a waitlist candidate will be removed from the wait list for death or clinical deterioration.18-20 The primary covariate of interest was the match run type (H-L versus LTA). Whether the liver wait-list candidate had exception points (yes/no) was modeled as an interaction term to determine whether the risk of mortality for bypassed candidates was magnified whether the wait-
GOLDBERG ET AL. 1359
list priority was based on the laboratory MELD score or the exception MELD score. The interaction term was considered significant at P < 0.10. Covariates were reported as subhazard ratios (SHRs), the convention for competing risk models.18-20 Region was not a covariate because not all regions were included in the H-L match runs on account of the geographic distribution of H-L recipients. The time from bypass (or presence on a control match run) to transplantation was calculated and compared between bypassed candidates and matched allograft controls to determine whether the time from appearing on a match run to subsequent transplantation was longer for bypassed wait-list candidates. Both the matched candidate and matched allograft approaches considered other potential covariates of age, sex, race/ethnicity, and primary diagnosis. The matched allograft approach also considered the match MELD score at the time of ranking on a match run. Although the MELD exception status (yes/no) was evaluated in both models, it was a covariate in the matched candidate models because the MELD score was used for matching but an interaction term in the matched allograft models. All final models used a stepwise variable-selection process to retain variables with P 0.2. This study was approved by the institutional review board of the University of Pennsylvania. All analyses were performed with Stata 13.0 (Stata, College Station, TX).
RESULTS From May 10, 2007 through May 10, 2013, 59,268 LTA wait-list candidates were added to the wait list, and there were 32,447 LTA transplants performed during this time. By contrast, there were 197 H-L wait-list candidates added during this time, with 65 H-L recipients aged 18 years or older. In 2007 and 2008, there were 5 and 7 H-L recipients, respectively, whereas there was an average of 12 from 2009 to 2012. The majority of these 65 recipients were concentrated in 2 UNOS regions, regions 2 (n 5 28 or 43.1%) and 7 (n 5 19 or 29.2%), regions with aboveaverage wait times and match MELD scores at transplantation for LTA recipients.9 The 2 most common causes of liver disease in H-L recipients were cardiac cirrhosis (n 5 31 or 47.7%) and amyloidosis (n 5 21 or 32.3%), with heart failure most commonly caused by amyloidosis (n 5 20 or 30.8%), congenital heart disease (n 5 12 or 18.5%), or idiopathic dilated cardiomyopathy (n 5 11 or 16.9%; Table 2). Among the 65 H-L recipients, the heart sequestered the liver in 64.6% (n 5 42) of the match runs, the liver sequestered the heart in 20% (n 5 13) of the match runs, and there was equal priority in 15.4% (n 5 10) of the cases (Table 2). The median donor age was 28 years [interquartile range (IQR) 5 21-42 years], and the median donor left ventricular ejection fraction was 65% (IQR 5 60%-65%). The median liver DRI in these 65 transplants was 1.16 (IQR 5 1.05-1.34), which was significantly lower (P < 0.001) than the median DRI of
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TABLE 2. Categorization of 65 Match Runs of H-L Transplant Recipients Heart Sequestered
Liver Sequestered
Equal Priority
Liver (n 5 42)
Heart (n 5 13)†
(n 5 10)
P Value
2 (1, 4) 138 (49, 450) 2134 (245, 2444) 4 (9.5) 15 (11, 20) 15 (11, 20)
35 (11, 52) 1 (1, 3) 33 (8, 49) 12 (92.3) 10 (8, 17) 29 (25, 33)
3 (1, 5) 3 (2, 6) 0 (21,1) 6 (60.0) 13 (9, 16) 26 (22, 29)
ORIGINAL ARTICLE
Reframing the Impact of Combined Heart-Liver Allocation on Liver Transplant Wait-List Candidates David S. Goldberg,1,2,3 Peter P. Reese,1,2,3,4 Sandra Amaral,2,5 and Peter L. Abt6 Department of Medicine, Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA; 2 Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA; 3Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, PA; 4 Renal, Electrolyte, and Hypertension Division, University of Pennsylvania, Philadelphia, PA; 5Division of Nephrology, Children’s Hospital of Philadelphia, Philadelphia, PA; and 6Division of Transplantation, Department of Surgery, University of Pennsylvania, Philadelphia, PA
1
Simultaneous heart-liver (H-L) transplantation, although rare, has become more common in the United States. When the primary organ is a heart or liver, patients receiving an offer for the primary organ automatically receive the second, nonprimary organ from that donor. This policy raises issues of equity, such as whether liver transplantation alone candidates bypassed by H-L recipients are disadvantaged. No prior published analyses have addressed this issue, and few methods have been developed as means of measuring the impact of such allocation policies. We analyzed Organ Procurement and Transplantation Network match run data from 2007 to 2013 to determine whether this combined organ allocation policy disadvantages bypassed liver transplant wait-list candidates in a clinically meaningful way. Among 65 H-L recipients since May 2007, 42 had substantially higher priority for the heart versus the liver, and these 42 bypassed 268 liver-alone candidates ranked 1 to 10 on these match runs. Bypassed patients had a lower risk of wait-list removal for death or clinical deterioration in comparison with controls selected by the match Model for End-Stage Liver Disease (MELD) score [hazard ratio (HR) 5 0.56, 95% confidence interval (CI) 5 0.40-0.79] and a risk similar to that of controls selected by the laboratory MELD score (HR 5 0.91, 95% CI 5 0.63-1.33) or on match runs of similar graft quality (HR 5 0.97, 95% CI 5 0.73-1.37). The waiting time from bypass to subsequent transplantation was significantly longer among bypassed candidates versus controls on match runs of similar graft quality [median: 87 days (interquartile range 5 27-192 days) versus 24 days (interquartile range 5 5-79 days), P < 0.001]. Although transplantation was delayed, liver transplant wait-list candidates bypassed by H-L recipients did not have excess mortality in comparison with 3 sets of matched controls. These analytic methods serve as a starting point for considering other potential approaches to C 2014 AASLD. evaluating the impact of multiorgan transplant allocation policies Liver Transpl 20:1356-1364, 2014. V Received March 31, 2014; accepted July 6, 2014.
Abbreviations: CI, confidence interval; DRI, donor risk index; H-L, heart-liver; HR, hazard ratio; IQR, interquartile range; LTA, liver transplantation alone; MELD, Model for End-Stage Liver Disease; MOT, multiorgan transplantation; OPTN, Organ Procurement and Transplantation Network; SHR, subhazard ratio; UNOS, United Network for Organ Sharing. This study was supported by grants from the National Institutes of Health (K08 DK098272 to David S. Goldberg and K23 DK083529 to Sandra Amaral), by the Greenwall Foundation (to Peter P. Reese), and in part by the Health Resources and Services Administration (contract 234-2005-37011C). The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. Potential conflict of interest: Nothing to report. Address reprint requests to David S. Goldberg, M.D., M.S.C.E., Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Blockley Hall, 423 Guardian Drive, Room 703, Philadelphia, PA 19104. Telephone: 215-746-8598; FAX: 215-349-5915; E-mail: [email protected] DOI 10.1002/lt.23957 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2014 American Association for the Study of Liver Diseases. V
LIVER TRANSPLANTATION, Vol. 20, No. 11, 2014
In the United States, certain types of simultaneous multiorgan transplantation (MOT), including combined liver-kidney and heart-liver (H-L) transplantation, have been increasingly practiced.1-7 This demand is attributable to several factors, including an aging population with congenital heart disease and congestive hepatopathy6 as well as an increased prevalence of chronic kidney disease in liver and heart transplant candidates.3-6 The need for the second organ may be for end-stage disease in the nonprimary organ necessitating a transplant independent of the primary organ (eg, a patient with decompensated cirrhosis on hemodialysis), or there may be end-stage disease in the nonprimary organ without overt clinical symptoms, but the organ is needed in order to optimize function of the primary organ (eg, end-stage heart failure with congestive hepatopathy and cirrhosis but preserved liver synthetic function). To accommodate wait-list candidates in need of MOT, Organ Procurement and Transplantation Network (OPTN)/ United Network for Organ Sharing (UNOS) policy dictates that when the primary organ is a heart, lung, or liver, patients who receive an offer for 1 of these 3 primary organs automatically receive the second, nonprimary organ from that donor, regardless of their waitlist priority for that second organ, only when the organ will be allocated to a patient in the local organ distribution unit (it is voluntary if the recipient is outside the local organ distribution unit).8 Because annual liver transplant wait-list mortality rates exceed 20% in several UNOS regions,9 the current MOT allocation policy raises issues of equity and utility.10 Prioritizing an MOT candidate for the nonprimary organ may unfairly cause harm to a candidate who also has strong ethical claims to the same organ but must remain on the wait list. Additionally, questions of utility arise, such as whether allocating 2 organs to an MOT recipient yields more (or fewer) quality-adjusted lifeyears in comparison with allocating each organ to a single candidate. For example, when a patient with maximum priority for a heart transplant receives the heart and liver from the same donor, the policy may be perceived as unfair to liver transplantation alone (LTA) candidates bypassed during the match run for that liver. The problem of fairness to patients who are bypassed by MOT depends on how much harm these patients experience. Previous MOT studies have focused on wait-list mortality for potential MOT recipients6 or the benefit of incremental transplants versus simultaneous transplants, but none have focused on the outcomes of those individuals who are bypassed when organs are diverted to MOT recipients.10,11 Because of the lack of prior work addressing the impact of MOT allocation policies on wait-list candidates bypassed by such organ diversions, there are no established methods for measuring the impact of such policies. For liver transplantation, modeling approaches have been used to estimate the impact of broader regional and national organ sharing, but no empirical methods exist to evaluate this specific question of MOT organ allocation. Furthermore, there have
GOLDBERG ET AL. 1357
been few studies using recently available OPTN match run data,12 which may become a more frequent focus of research involving organ allocation and distribution. This study analyzes match run data from OPTN to determine whether the current H-L allocation policy leads to greater mortality or prolonged waiting times for transplantation among LTA candidates who are bypassed by H-L recipients.
PATIENTS AND METHODS Study Population and Approach The cohort of interest included any candidate on the liver transplant wait list who was ranked on a liver match run in which the liver was allocated to a combined H-L recipient instead of an LTA candidate. We focused specifically on H-L transplants because (1) that is the most commonly performed combined thoracic-liver transplant,6 (2) the number of combined H-L candidates is projected to rise with the aging congenital heart disease population,1,6 and (3) in many H-L transplants, the recipient has cirrhosis without overt complications of end-stage liver disease.1 All analyses were based on OPTN/UNOS data from May 10, 2007 through May 10, 2013. The initial date was the first date for which match run data were made available for research. OPTN/UNOS data included encrypted donor and wait-list candidate variables, match run position, and match Model for EndStage Liver Disease (MELD) scores for every transplant recipient in addition to all wait-list candidates ranked higher (ie, higher wait-list priority but turned down or bypassed for an organ) in every match run. Only match runs of combined H-L recipients 18 years of age were included because of the differences in organ allocation policies for adult wait-list candidates versus pediatric wait-list candidates. The analyses used 2 distinct matching techniques to identify comparator groups to assess the impact of bypassing single-organ candidates (Table 1). The first approach compared LTA wait-list candidates bypassed on H-L match runs with 2 separate cohorts of control wait-list candidates with similar characteristics matched for blood type, UNOS region, and MELD score (matched candidate cohort 1 was matched by the match MELD score, whereas matched candidate cohort 2 was matched by the laboratory MELD score; taken together, these analyses are called the matched candidate approach). The secondary approach used match runs in which the liver allografts were identical in quality, as measured by the donor risk index (DRI13; which we call the matched allograft approach), to the grafts of H-L recipients. These analyses were limited H-L match runs in which the heart sequestered the liver, and LTA candidates with higher wait-list priority were thereby bypassed.
Categorization of Combined H-L Match Runs Data for all match runs for which there was combined H-L allocation were evaluated. Match runs were
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TABLE 1. Selection of Experimental and Comparator Groups for Analyses of Wait-List Outcomes of Liver Transplant Wait-List Candidates Bypassed by Simultaneous H-L Recipients Analytic Approach Matched candidate cohort 1
Matched candidate cohort 2
Matched allograft approach
Experimental Group
Comparator Group
Rationale
268 liver candidates ranked in the top 10 positions of a match run bypassed by an H-L recipient during the years 2007 to 2013 268 liver candidates ranked in the top 10 positions of a match run bypassed by an H-L recipient during the years 2007 to 2013 268 liver candidates ranked in the top 10 positions of a match run bypassed by an H-L recipient during the years 2007 to 2013
2144 liver wait-list candidates matched 8:1 based on UNOS region, blood type, and match MELD score to bypassed liver wait-list candidates
Compare bypassed candidates with wait-list candidates with similar access to transplantation based on match MELD score Compare bypassed candidates with wait-list candidates with similar risk of wait-list mortality based on laboratory MELD score
2340 liver wait-list candidates matched 9:1 based on UNOS region, blood type, and laboratory MELD score to bypassed liver wait-list candidates 20,962 liver wait-list candidates who were (1) ranked in the top 10 of a match run of a liver-alone recipient who received a graft of similar quality to an H-L recipient and (2) ranked higher than the organ recipient on that match run
categorized as heart sequestering liver, liver sequestering heart, or equal priority. The assignment of categories was determined through comparisons of the transplant recipients’ ranks on the corresponding liver and heart match runs. Ranks within 2 places (eg, first on heart and third on liver) were considered equal, and differences of 3 or greater were assigned to the organ with the higher priority (eg, first on heart and ninth on liver was considered heart sequestering liver). Because there were only 8 match runs in which the liver sequestered the heart (eg, the candidate was ranked first on the liver match run but fiftieth on the heart match run, and thus the heart was diverted from other heart-alone candidates), the primary analyses were restricted to match runs in which the heart sequestered the liver. The liver graft quality, measured by the DRI, was calculated for each liver graft allocated in a combined H-L transplant and was converted into a categorical variable based on predicted graft survival for the purposes of matching (1.0, >1.0 & 1.4, >1.4 & 1.6, and >1.6).13
Selection of Control Liver Wait-List Candidates for the Matched Candidate Analysis This analysis compared liver wait-list candidates who were bypassed by an H-L recipient with 2 different sets of control liver wait-list candidates matched by the UNOS region, the blood type, and either (1) the laboratory MELD score or (2) the match MELD score. The utilization of these 2 methods tested whether the results were sensitive to the control group. Match MELD score controls served as a comparator group with similar access to transplantation based on wait-
Compare bypassed candidates to wait-list candidates on match runs of similar graft quality to “simulate” the outcomes had the liver in an H-L allocation been offered to a liver-alone candidate with the highest priority
list priority, whereas laboratory MELD score controls functioned as a comparator group with similar expected wait-list mortality (better predicted with the laboratory MELD score).14,15 To account for discrepancies between laboratory and match MELD scores, we included a variable indicating whether a wait-list candidate had exception points at the time of bypass or selection as a control. The process of identifying matched candidates did not rely on match run data but instead relied on candidate wait-list characteristics, including the most recently updated MELD score.
Selection of Control Liver-Alone Match Runs for the Matched Allograft Analysis Control liver-alone match runs were compared with H-L match runs in which the heart sequestered the liver. Specifically, control match runs were those in which the liver graft was of the same blood type and DRI category (graft quality), whereas in H-L match runs, the heart sequestered the liver. Only liver waitlist candidates in the top 10 rank positions of a control or H-L match run for a given liver were evaluated because >90% of comparable livers were distributed to LTA wait-list candidates ranked 1 to 10.
Outcomes The primary outcome was wait-list removal for death or clinical deterioration, which was defined as dying on the wait-list or within 90 days of removal from the wait list, when the reason for wait-list removal was “too sick to transplant” or “other.” Death within a
LIVER TRANSPLANTATION, Vol. 20, No. 11, 2014
short time of wait-list removal was reflective of the severity of illness and was viewed as equivalent to dying on the wait list15,16 and could be identified on the basis of the Social Security Death Master File death date.15,16
Index Date The index date for bypassed wait-list candidates was the date of the H-L match run from which they were bypassed. The index date for controls in the matched candidate analysis was the date on which the wait-list candidate met matching criteria because this was the date from which the control would be expected to have similar access to transplantation (match MELD score) or wait-list mortality (laboratory MELD score) in comparison with the bypassed wait-list candidate. The index date for controls in the matched allograft analysis was the first date on which the wait-list candidate was ranked 1 to 10 on an LTA match run of graft quality comparable to the liver in an H-L match run. Because many controls in the matched allograft approach were identified in more than 1 match run, we assigned these wait-list candidates to the first match run during the study period.12
Analytical Methods: Matched Candidate Approach Wait-listed liver transplant candidates bypassed on an H-L match run were compared with control candidates matched by the MELD score, blood type, and UNOS region with stratified Cox models that accounted for matched data. Models were stratified by the match group (ie, a cohort of bypassed candidates and controls with a given combination of MELD scores, regions, and blood types), and they incorporated a robust variance sandwich estimator to account for correlations resulting from matching.17 The MELD score was used for matching, so it could not be a covariate; however, the models included a covariate indicating whether the patient had exception points.
Analytical Methods: Match Allograft Approach Bypassed liver candidates from a match run in which the heart sequestered the liver were compared with liver candidates in control match runs. Competing risk Cox regression models evaluating the outcome of wait-list removal for death or clinical deterioration were fit. Transplantation was modeled as a competing risk because, in evaluating pretransplant survival, transplantation influences the probability that a waitlist candidate will be removed from the wait list for death or clinical deterioration.18-20 The primary covariate of interest was the match run type (H-L versus LTA). Whether the liver wait-list candidate had exception points (yes/no) was modeled as an interaction term to determine whether the risk of mortality for bypassed candidates was magnified whether the wait-
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list priority was based on the laboratory MELD score or the exception MELD score. The interaction term was considered significant at P < 0.10. Covariates were reported as subhazard ratios (SHRs), the convention for competing risk models.18-20 Region was not a covariate because not all regions were included in the H-L match runs on account of the geographic distribution of H-L recipients. The time from bypass (or presence on a control match run) to transplantation was calculated and compared between bypassed candidates and matched allograft controls to determine whether the time from appearing on a match run to subsequent transplantation was longer for bypassed wait-list candidates. Both the matched candidate and matched allograft approaches considered other potential covariates of age, sex, race/ethnicity, and primary diagnosis. The matched allograft approach also considered the match MELD score at the time of ranking on a match run. Although the MELD exception status (yes/no) was evaluated in both models, it was a covariate in the matched candidate models because the MELD score was used for matching but an interaction term in the matched allograft models. All final models used a stepwise variable-selection process to retain variables with P 0.2. This study was approved by the institutional review board of the University of Pennsylvania. All analyses were performed with Stata 13.0 (Stata, College Station, TX).
RESULTS From May 10, 2007 through May 10, 2013, 59,268 LTA wait-list candidates were added to the wait list, and there were 32,447 LTA transplants performed during this time. By contrast, there were 197 H-L wait-list candidates added during this time, with 65 H-L recipients aged 18 years or older. In 2007 and 2008, there were 5 and 7 H-L recipients, respectively, whereas there was an average of 12 from 2009 to 2012. The majority of these 65 recipients were concentrated in 2 UNOS regions, regions 2 (n 5 28 or 43.1%) and 7 (n 5 19 or 29.2%), regions with aboveaverage wait times and match MELD scores at transplantation for LTA recipients.9 The 2 most common causes of liver disease in H-L recipients were cardiac cirrhosis (n 5 31 or 47.7%) and amyloidosis (n 5 21 or 32.3%), with heart failure most commonly caused by amyloidosis (n 5 20 or 30.8%), congenital heart disease (n 5 12 or 18.5%), or idiopathic dilated cardiomyopathy (n 5 11 or 16.9%; Table 2). Among the 65 H-L recipients, the heart sequestered the liver in 64.6% (n 5 42) of the match runs, the liver sequestered the heart in 20% (n 5 13) of the match runs, and there was equal priority in 15.4% (n 5 10) of the cases (Table 2). The median donor age was 28 years [interquartile range (IQR) 5 21-42 years], and the median donor left ventricular ejection fraction was 65% (IQR 5 60%-65%). The median liver DRI in these 65 transplants was 1.16 (IQR 5 1.05-1.34), which was significantly lower (P < 0.001) than the median DRI of
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TABLE 2. Categorization of 65 Match Runs of H-L Transplant Recipients Heart Sequestered
Liver Sequestered
Equal Priority
Liver (n 5 42)
Heart (n 5 13)†
(n 5 10)
P Value
2 (1, 4) 138 (49, 450) 2134 (245, 2444) 4 (9.5) 15 (11, 20) 15 (11, 20)
35 (11, 52) 1 (1, 3) 33 (8, 49) 12 (92.3) 10 (8, 17) 29 (25, 33)
3 (1, 5) 3 (2, 6) 0 (21,1) 6 (60.0) 13 (9, 16) 26 (22, 29)
