http://www.jhltonline.org
Pediatric heart transplant waiting list mortality in the era of ventricular assist devices Farhan Zafar, MD, Chesney Castleberry, MD, Muhammad S. Khan, MD, Vivek Mehta, BS, Roosevelt Bryant III, MD, Angela Lorts, MD, Ivan Wilmot, MD, John L. Jefferies, MD, MPH, Clifford Chin, MD, and David L.S. Morales, MD From the Heart Institute, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.
KEYWORDS: Pediatric ventricular assist device; pediatric heart transplant; waiting list mortality; heart transplant waiting list
BACKGROUND: Earlier reviews have reported unacceptably high incidence of pediatric heart transplant (PHT) waiting list mortality. An increase in ventricular assist devices (VAD) suggests a potential positive effect. This study evaluated PHT waiting list mortality in the era of pediatric VADs. METHODS: United Network of Organ Sharing (UNOS) database from 1999 to 2012 showed 5,532 pediatric candidates (aged r 18 years) actively listed for PHT: 2,191 were listed in 1999 to 2004 (Era 1) and 3,341 were listed in 2005 to 2012 (Era 2). RESULTS: Waiting list mortality was lower in Era 2 (8%) vs Era 1 (16%; p o 0.001). VAD therapy was used more frequently in Era 2 (16%) than in Era 1 (6%; p o 0.001) and was associated with better waiting list survival (p o 0.001). There were more UNOS Status 1A patients in Era 2 (80%) vs Era 1 (68%; p o 0.001). Independent predictors of waiting list mortality included weight o 10 kg (odds ratio [OR], 2.7 95% confidence interval [CI], 1.1–6.9), congenital heart disease diagnosis (OR, 2.4; 95% CI, 1.9–3.0), blood type O (OR, 2.2; 95% CI, 1.8–2.8)], extracorporeal membrane oxygenation (OR, 1.5; 95% CI, 1.1– 2.2), mechanical ventilation (OR, 1.8; 95% CI, 1.4–2.3), and renal dysfunction (OR 1.6; 95% CI, 1.2–2.0). Independent predictors of survival on the waiting list included VAD therapy (OR 4.2; 95% CI, 2.4–7.6), cardiomyopathy diagnosis (OR 3.3; 95% CI, 2.4–4.6), blood type A (OR, 2.2; 95% CI, 1.8–2.8), UNOS list Status 1B (OR, 1.9; 95% CI, 1.2–3.0), listed in Era 2 (OR 1.8; 95% CI, 1.4–2.2), and white race (OR 1.3; 95% CI, 1.1–1.6). CONCLUSIONS: Despite an increase in the number of children listed as Status 1A, there was more than a 50% reduction in waiting list mortality in the new era. Irrespective of other factors, patients supported with a VAD were 4 times more likely to survive to transplant. J Heart Lung Transplant 2015;34:82–88 r 2015 International Society for Heart and Lung Transplantation. All rights reserved.
Of all patients wait-listed for organ transplantation in the United States, children listed for heart transplantation face one of the highest waiting list mortalities, regardless of age.1 Every year, approximately 500 additional pediatric candidates are added to the heart transplant waiting list2; Reprint requests: Farhan Zafar, MD, 3333 Burnet Ave, MLC 2013, Cincinnati, OH 45229. Telephone: 513-803-9272. E-mail address: [email protected]
however, approximately 17% children die each year awaiting a donor cardiac graft.3 In adult patients, the use of ventricular assist devices (VADs) has dramatically changed waiting list mortality, with survival on a LVAD of nearly 90% at 1 year.4 As a result of this continuing improvement in survival, the United Network of Organ Sharing (UNOS) allocation system was changed in 1999 to allow for only 30 days of Status 1A time for VAD-supported adult heart transplant candidates, unless
1053-2498/$ - see front matter r 2015 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2014.09.018
Zafar et al.
PHT Waiting List Mortality in VAD Era
device-related complications occurred, such as infection, thromboembolic, bleeding complications, or other devicerelated issues that would place them at a higher risk of death. With this shift and broader regional sharing of donor hearts, there has been a 17% reduction in waiting list mortality in adult heart transplant patients.5 A similar reduction in waiting list mortality has been noted in children during a 20-year period, from 26% to 13%, that has also been attributed to the changes in heart allocation policies by UNOS, allowing for the differentiation of sicker patients with an additional listing status (1B). VAD use has also increased in the pediatric population during this same period.6 Many single-institution and multiinstitutional VAD studies have shown an improvement in outcomes for patients supported with VADs.7,8 This suggests a potential positive effect on waiting list mortality; however, no effect of VAD use on waiting list mortality has been established in pediatric patients. This study undertook an analysis of current waiting list mortality for pediatric cardiac transplantation and of its association with the increase use of VADs during the past decade.
Methods Study cohort, data source, and definitions This was a retrospective analysis of all pediatric candidates (aged r 18 years) who were actively listed for a heart transplant from 1999 to 2012 in the United States (U.S.) identified from the UNOS database. UNOS is a private, non-profit organization that administers the Organ Procurement and Transplant Network (OPTN) under a federal contract. OPTN is a unified transplant network established by the U.S. Congress under the National Organ Transplant Act of 1982, which requires submission of data on all solid-organ transplants in the U.S., which is then internally audited. Data were limited to the year 1999 and beyond to eliminate the effect of change in allocation policy in January 1999, at which time Status 1 patients were subdivided into Status 1A and Status 1B to prioritize organ allocation to the sickest. Patients were divided into 2 cohorts based on year of listing to represent periods before and after introduction of pediatric-specific VADs. Era 1 was 1999 to 2004 and Era 2 was 2005 to 2012. Patients were further divided into VAD and no-VAD cohorts. Waiting list outcomes, as defined by UNOS, were transplanted, recovered (transplant not needed), or dead or alive on the waiting list. The outcomes analysis excluded patients who were removed from the list because they were too sick for transplant. Time on the waiting list was defined as time from the initial listing for heart transplantation to the time of waiting list removal due to transplantation, death, or recovery, or the time of data harvest (December 31, 2012) for patients alive on the waiting list. All clinical and demographics variables were defined at the time of listing for heart transplantation. VAD use was defined as VAD present at the time of listing or present at the time of transplant. Glomerular filtration rate (GFR) was estimated with the Schwartz formula to determine renal dysfunction.9
Statistical analysis Summary statistics are presented as median (range) or number (percentage). For baseline characteristics, continuous data were
83 compared using the t-test and analysis of variance with the Tukey method for normally distributed data and the non-parametric tests (Mann-Whitney U test for 2 samples and Kruskal-Wallis analysis of variance for multiple samples) for data without normal distribution. The chi-square test was used to compare categoric data. Mortality rates were computed as the number of deaths per 100 patient-years of waiting time for the given cohort. Survival curves were estimated using the Kaplan-Meier method, and equality of survival curves
Table 1
Variablesa
Baseline Characteristics for Patients in Different Eras Era 1 1999–2004 (n ¼ 2,191)
Age at listing, years 5 Infants 808 Weight at listing, kg 18 Weight categories, kg o10 713 10–19 408 20–39 408 40–59 356 Z60 281 Female 966 White 1,265 UNOS listing status Status 1A 1,490 Status 1B 311 Status 2 390 Cardiac diagnosis Cardiomyopathy 968 CHD 949 Myocarditis 47 Others 227 Blood type A 836 B 256 AB 84 O 1,015 ECMO 217 Ventilator 522 Inotropes 1,147 VAD 126 LVAD 21 RVAD 0 Total artificial heart 31 BiVAD 8 Unknown 66 VAD pump type Continuous 36 Pulsatile 76 Unknown 14 Dialysis 41 Creatinine, mg/dl 0.6 GFR o50% 251 Waiting list time, days 36
Era 2 2005–2012 (n ¼ 3,341)
(0–18) 5 (0–18) (37) 1,258 (38) (1.3–187) 17 (1.8–137) (33) (19) (19) (16) (13) (44) (58)
1,112 656 568 534 469 1,517 1,854
(33) (20) (17) (16) (14) (45) (56)
(68) (14) (18)
2,672 (80) 360 (11) 309 (9)
(44) (43) (2) (11)
1,454 1,381 133 373
(44) (41) (4) (11)
(38) (12) (4) (46) (10) (24) (52) (6) (1) (0) (1.4) (0.4) (3)
1,170 448 140 1,583 328 654 1,474 520 331 15 6 168 0
(35) (13) (4) (48) (10) (20) (44) (16) (10) (0.4) (0.2) (5) (0)
p-value 0.455 0.290 0.391 0.372
0.175 0.1 o0.001
0.214
0.06
(2) (3) (1) (2) (0.4–0.9) (15) (13–94)
101 396 23 61 0.5 270 45
0.475 0.001 0.001 o0.001
(3) (12) (1) (2) 0.922 (0.4–0.7) 0.001 (8) o0.001 (15–110) o0.001
BiVAD, biventricular assist device; CHD, congenital heart disease; ECMO, extracorporeal membrane oxygenation; GFR, glomerular filtration rate; LVAD, left ventricular assist device; RVAD, right ventricular assist device; VAD, ventricular assist device. a Continuous variables are shown as median (range) and categoric data as number (%).
84
The Journal of Heart and Lung Transplantation, Vol 34, No 1, January 2015
Baseline characteristics Patients in Era 2 were more likely than patients in Era 1 to be listed as Status 1A (80% vs 68%; p o 0.001), supported by a VAD (16% vs 6%; p o 0.001), and had longer median waiting list time (45 days vs 36 days; p o 0.001). Patients in Era 1 were more likely to be listed in Status 2 (18% vs 9%; p o 0.001), on ventilator support (24% vs 20%; p ¼ 0.001), on inotropic support (52% vs 44%; p ¼ 0.001), and have a GFR o 50% (15% vs 8%; p o 0.001). All other characteristics including age, gender, weight, diagnosis, race, were similar in both eras (Table 1).
Waiting list mortality
Figure 1
Waiting list survival for Era 1 and Era 2.
were tested using a log-rank test. Multivariate analyses were performed using Cox proportional hazards model and a stepwise selection technique to identify independent predictors of waiting list mortality. Analyses were performed using IBM SPSS Statistics 21 software (IBM Corp, Armonk, NY).
Results Of 5,912 pediatric candidates (aged r 18 years) who were actively listed during the study period, 2,191 (40%; 1,789 transplanted) were in Era 1 and 3,341 (60%; 2,894 transplanted) were in Era 2. A total of 380 patients (6%) were too sick to be transplanted, more in Era 1 (112 of 2,303 [5%]) than in Era 2 (268 of 3,609 [7%]; p ¼ 0.001); however, fewer patients had a VAD (26 of 672 [4%]) compared with no VAD (354 of 4886 [7%]). In further analysis, only 5,532 pediatric patients were included.
Figure 2
Waiting list mortality was lower in Era 2 (8%) vs Era 1 (16%; p o 0.001), and patients on the waiting list in Era 1 were more likely to die over time (p o 0.001; Figure 1). Patients supported with a VAD were more likely to survive in both eras, and patients on VAD in Era 2 had the best survival (Figure 2). Univariate predictors of waiting list mortality (Table 2) were infant age, weight o 10 kg, non-white race, UNOS list Status A, congenital heart disease, blood type O, extracorporeal membrane oxygenation (ECMO), ventilator, inotropes, GFR r 50%, shorter waiting list time, and listed for transplant in Era 1. Competing outcomes analysis showed 3% mortality and 69% transplant at 3 months in VAD patients compared with 10% mortality and only 61% transplanted in patients without VAD support. Similarly, patients in Era 2 only had 7% mortality at 3 months compared with 14% mortality for patients in Era 1 (Figure 3). Patients in Era 2 had 28 deaths/100 waiting list–years compared with 55 deaths/100 waiting list–years in Era 1 patients, which represents a 50% reduction. Patients on VAD support had 14 deaths/100 waiting list–years compared with 42 deaths/ 100 waiting list–years for patients with no VAD support, which represents a 66% reduction (Figure 4).
Waiting list survival for different groups by era and ventricular assist device (VAD) use.
Zafar et al. Table 2
PHT Waiting List Mortality in VAD Era Univariate Predictors of Mortality
Predictorsa Age at listing, years Infants Weight at listing, kg Weight categories, kg o10 10–19 20–39 40–59 Z60 Female White UNOS listing status Status 1A Status 1B Status 2 Cardiac diagnosis Cardiomyopathy CHD Myocarditis Others Blood type A B AB O ECMO Ventilator Inotropes VAD LVAD RVAD Total artificial heart BiVAD Unknown VAD pump type Continuous Pulsatile Unknown Dialysis Creatinine, mg/dl GFR r 50% Waiting list time, days Era 1: 1999–2004 2: 2005–2012
Survived (n ¼ 4,895)
Died (n ¼ 637)
p-value
6 (0–13) 1 (0–8) o0.001 1,726 (35.3) 340 (53) o0.001 19 (1.3–187) 9 (1.5–126) o0.001 o0.001 1,513 (31) 311 (50) 941 (19) 123 (20) 892 (19) 84 (13) 841 (17) 49 (8) 695 (14) 55 (9) 2,202 (45) 281 (44) 0.677 2,783 (57) 336 (53) 0.049 o0.001 3,640 (74) 522 (82) 623 (13) 48 (8) 632 (13) 67 (10) 0.001 2,275 (47) 147 (23) 1,950 (40) 380 (60) 166 (3) 14 (2) 504 (10) 96 (15) o0.001 1,841 (38) 165 (26) 625 (13) 79 (12) 203 (4) 21 (3) 2,226 (45) 372 (59) 424 (9) 121 (19) o0.001 927 (19) 249 (39) o0.001 2,281 (47) 340 (53) 0.001 623 (13) 23 (4) o0.001 348 (7) 4 (0.6) 13 (0.3) 2 (0.3) 37 (0.8) 0 (0) 170 (3.5) 55 (1) 131 459 33 75 0.5 399 46
6 (0.9) 11 (1.7)
(3) 6 (1) (9) 13 (2) (1) 4 (1) (1.5) 27 (4) o0.001 (0.4–0.8) 0.6 (0.4–0.9) 0.011 (9) 122 (24) o0.001 (16–112) 26 (9–67) o0.001 o0.001
1,830 (37) 3,065 (63)
361 (57) 276 (43)
BiVAD, biventricular assist device; CHD, congenital heart disease; ECMO, extracorporeal membrane oxygenation; GFR, glomerular filtration rate; LVAD, left ventricular assist device; RVAD, right ventricular assist device; UNOS, United Network of Organ Sharing; VAD, ventricular assist device. a Continuous variables are shown as median (range) and categoric data as number (%).
A sub-group analysis for infants and older children found VAD support was associated with decreased waiting list mortality in both groups (p o 0.001; Table 3) Independent predictors of waiting list mortality (Figure 5) included weight o 10 kg (odds ratio [OR], 2.7;
85 95% confidence interval [CI], 1.1–6.9; p ¼ 0.03), congenital heart disease diagnosis (OR, 2.4; 95% CI, 1.9–3.0); p o 0.001), blood type O (OR, 2.2; 95% CI, 1.8–2.8; p o 0.001), ECMO (OR, 1.5; 95% CI, 1.1–2.2; p ¼ 0.01), mechanical ventilation (OR, 1.8; 95% CI, 1.4–2.3; p o 0.001), and renal dysfunction (OR, 1.6; 95% CI, 1.2–2.0; p o 0.001). Independent predictors of survival on the waiting list included VAD therapy (OR, 4.2; 95% CI, 2.4– 7.6; p o 0.001), cardiomyopathy diagnosis (OR, 3.3; 95% CI, 2.4–4.6; p o 0.001), blood type A (OR, 2.2; 95% CI, 1.8–2.8; p o 0.001), UNOS list Status 1B (OR, 1.9; 95% CI, 1.2–3.0; p ¼ 0.005), listed in Era 2 (OR, 1.8; 95% CI, 1.4–2.2; p o 0.001), and white race (OR, 1.3; 95% CI, 1.1– 1.6; p ¼ 0.003).
Discussion There has been an obvious change in waiting list survival in pediatric patients in the VAD-associated era, with 1-year survival of 86% vs 74% in those patients listed from 1999 to 2004. There has also been a decrease in patients dying on the list (55 vs 28 per 100 waiting list–years), with a concomitant increase in VAD use between these two eras (16% from 6%). Also, the use of VADs was clearly demonstrated to decrease waiting list mortality from 42 to 14 per 100 waiting list–years. In the contemporary era, endorgan dysfunction decreased despite an overall increase in waiting times. However, patients known to have less favorable VAD options, patients weighing o 10 kg, and those with congenital heart disease were at higher risk of dying while waiting for a transplant, regardless of era. The use of pediatric-specific VADs has increased dramatically since 2005, with 20% of pediatric patients being bridged to transplant with a device.10 For example, the pediatric-specific Berlin Heart EXCOR (Berlin Heart GmbH, Berlin, Germany) paracorporeal device has successfully bridged to transplant 70% of the patients implanted with the device and has allowed for greater end-organ recovery in many cases.8,11 VADs offer a long-term support option for these critical patients, with 12-month survival on these devices of 75%, allowing patients to wait longer for suitable donors in a relatively stable condition. Singh et al6 also demonstrated similar results when they examined trends in waiting list mortality in children across racial and ethnic groups. They found that the risk of waiting list mortality decreased by 66% from 1989 to 2009 at the same time VAD use increased from 1% to 7%. Regardless of era, patients with VAD support had better waiting list survival than those patients not supported with a VAD. Another means by which device support leads to diminished waiting list mortality is improved end-organ function with decreased inotropic and ventilator support after VAD implantation. These all are risk factors for death after transplant, and if they are avoided or reversed by VAD support, then supported patients may realize better outcomes. The current study demonstrated an era effect of decreased ventilator support and inotropic support in the pediatric VAD era. Serum creatinine was also decreased, as
86
The Journal of Heart and Lung Transplantation, Vol 34, No 1, January 2015
Figure 3
Competing outcomes analysis for different groups by era and ventricular assist device (VAD) use.
was the frequency of significant renal disease in the pediatric VAD era. Because survival is better in the post-VAD era, patients waited longer for a transplant. The median wait rose from 36
Figure 4
days to 45 days, without changes in any other demographic variables, including size and age, to explain this difference. This has been seen in other studies where increased use of the Berlin Heart device has led to increased waiting list
Mortality per 100 waiting list–years for different groups by era and ventricular assist device (VAD) support.
Zafar et al.
PHT Waiting List Mortality in VAD Era
Table 3
Waiting List Mortality in Different Age Groups
Group
VAD
Survived (n ¼ 4,895) No. (%)
Infants
No Yes No Yes
1,262 85 3,010 538
Children
(81) (98) (90) (96)
Died (n ¼ 637) No. (%) 292 2 322 21
(19) (2) (10) (4)
p-value o0.001 o0.001
VAD, ventricular assist device.
duration.12 Also of concern was the decreased median time on the waiting list in those patients who died (26 days vs 46 days). These patients may represent the more ill patients in the current era who could not be bridged with a durable device or higher-risk patients were device support was attempted realizing the increased waiting list time in the current era. Patients who were not supported on a VAD were also more likely to be delisted because they were too sick for transplant (7% vs 4%, regardless of era). The current allocation system gives priority to VAD patients with no limited Status 1A time in the pediatric population, although survival on VAD has clearly risen. With increased use of VADs, this has led to a greater proportion of pediatric patients listed as Status 1, meeting criteria based on VAD use. This is also seen with a rise in Status 1A listing rising to 80% in the most recent era. The high proportion of patients listed as 1A leads to organ allocation based on time on the waiting list rather than medical urgency because essentially all patients who attain this status will receive organ offers based on waiting list time. Patients who are at higher risk of VAD complications, namely congenital heart disease patients and smaller infants, are at a disadvantage because they are often not mechanically supported and may not benefit from priority listing.
Figure 5
87 Mechanical support priority was appropriate in the era before pediatric specific VADs, when ECMO support was the primary device available to many pediatric patients because of its association with a time-dependent high rate of complications and death. The use of ECMO as a primary means of mechanical support as a bridge to cardiac transplantation in the current era is minimal, only approximately 4% of all patients listed for transplant. Unlike ECMO, duration of support is not a risk factor for worse outcomes in patients bridged to transplant with pediatric VADs.12 Therefore, in time the pediatric cardiac transplant community may have to consider that patients with VAD support have a limited period of priority listing. At the time of this report, various changes had been proposed to the current allocation system in the U.S. that were under revision. The proposed changes would allow for increased status to 1A for patients with significant congenital heart disease who were admitted to the hospital and required high-dose or multiple inotropes. Patients on inotropic support alone were not given priority status; however, anyone on mechanical circulatory support would still receive status 1A with no time restriction.13 This study has some limitations. The UNOS data set is limited by the data available and its retrospective data collection. This analysis does not account for improvement and/or deterioration in a patient’s clinical status while on the waiting list. In conclusion, during the past 15 years, the strongest predictor of waiting list survival has been VAD use, with its affect increasing over time. In the past 7 years, when pediatric VAD support has increased significantly, there has been a substantial reduction in end-organ dysfunction of patients on the waiting list and, most noteworthy, a 50% reduction in waiting list death. As pediatric VAD clinical experience and technology improve, a further reduction in waiting list mortality may be realized.
Multivariate analysis of risk factors for waiting list mortality.
88
The Journal of Heart and Lung Transplantation, Vol 34, No 1, January 2015
Disclosure statement This study used data provided by UNOS. The authors’ institution funded the study. Dr. Morales is a member of an advisory committee for Berlin Heart, Inc and he is a Proctor for Syncardia, Inc training. Dr. Morales has also travelled for academic activities on behalf of the following companies: Berlin Heart, Inc, Syncardia, Inc, Thoratec, Inc, and HeartWare, Inc. Dr. Morales' institution has received travel reimbursement from these companies for these activities. Dr. Morales has not received any personal remuneration from these companies. None of the other authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.
References 1. McDiarmid SV, Cherikh WS, Sweet SC. Preventable death: children on the transplant waiting list. Am J Transplant 2008;8:2491-5. 2. Health Resources and Services Administration. Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients. Annual data report 2012: heart. Available at: http://srtr.transplant.hrsa. gov/annual_reports/2012/flash/05_heart_13/v2index.html. Accessed March 20, 2014. 3. Almond CS, Thiagarajan RR, Piercey GE, et al. Waiting list mortality among children listed for heart transplantation in the United States. Circulation 2009;119:717-27. 4. John R, Kamdar F, Liao K, Colvin-Adams M, Boyle A, Joyce L. Improved survival and decreasing incidence of adverse events with the HeartMate II left ventricular assist device as bridge-to-transplant therapy. Ann Thorac Surg 2008;86:1227-35.
5. Singh TP, Almond CS, Taylor DO, Graham DA. Decline in heart transplant wait list mortality in the United States following broader regional sharing of donor heart. Circ Heart Fail 2012;5: 249-58. 6. Singh TP, Almond CS, Piercey G, Gauvreau K. Trends in wait-list mortality in children listed for heart transplantation in the United States: era effect across racial/ethnic groups. Am J Transplant 2011;11:2692-9. 7. Jeewa A, Manlhiot C, McCrindle BW, Van Arsdell G, Humpl T, Dipchand AI. Outcomes with ventricular assist device versus extracorporeal membrane oxygenation as a bridge to pediatric heart transplantation. Artif Organs 2010;34:1087-91. 8. Almond CS, Morales DL, Blackstone EH, et al. The Berlin Heart EXCORs pediatric ventricular assist device for bridge to heart transplantation in US children. Circulation 2013;127:1702-11. 9. Schwartz GJ, Haycock GB, Edelmann CM Jr, Spitzer A. A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics 1976;58:259-63. 10. Kirk R, Dipchand AI, Edwards LB, et al. The registry of the International Society of Heart and Lung Transplantation: fifteenth pediatric heart transplantation report—2012. J Heart Lung Transplant 2012;31:1065-72. 11. Morales DL, Almond CS, Jaquiss RD, et al. Bridging children of all sizes to cardiac transplantation: the initial multicenter North American experience with the Berlin Heart EXCOR ventricular assist device. J Heart Lung Transplant 2011;30:1-8. 12. Cassidy J, Dominquez T, Haynes S, et al. A longer waiting game: bridging children to heart transplant with the Berlin Heart EXCOR device—the United Kingdom experience. J Heart Lung Transplant 2013;32:1101-6. 13. U.S. Health Resources and Services Administration. Organ Procurement and Transplantation Network. Proposal to change pediatric heart allocation policy. Available at: http://optn.transplant.hrsa.gov/Public Comment/pubcommentPropSub_321.pdf. Accessed April 11, 2014.
Pediatric heart transplant waiting list mortality in the era of ventricular assist devices Farhan Zafar, MD, Chesney Castleberry, MD, Muhammad S. Khan, MD, Vivek Mehta, BS, Roosevelt Bryant III, MD, Angela Lorts, MD, Ivan Wilmot, MD, John L. Jefferies, MD, MPH, Clifford Chin, MD, and David L.S. Morales, MD From the Heart Institute, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.
KEYWORDS: Pediatric ventricular assist device; pediatric heart transplant; waiting list mortality; heart transplant waiting list
BACKGROUND: Earlier reviews have reported unacceptably high incidence of pediatric heart transplant (PHT) waiting list mortality. An increase in ventricular assist devices (VAD) suggests a potential positive effect. This study evaluated PHT waiting list mortality in the era of pediatric VADs. METHODS: United Network of Organ Sharing (UNOS) database from 1999 to 2012 showed 5,532 pediatric candidates (aged r 18 years) actively listed for PHT: 2,191 were listed in 1999 to 2004 (Era 1) and 3,341 were listed in 2005 to 2012 (Era 2). RESULTS: Waiting list mortality was lower in Era 2 (8%) vs Era 1 (16%; p o 0.001). VAD therapy was used more frequently in Era 2 (16%) than in Era 1 (6%; p o 0.001) and was associated with better waiting list survival (p o 0.001). There were more UNOS Status 1A patients in Era 2 (80%) vs Era 1 (68%; p o 0.001). Independent predictors of waiting list mortality included weight o 10 kg (odds ratio [OR], 2.7 95% confidence interval [CI], 1.1–6.9), congenital heart disease diagnosis (OR, 2.4; 95% CI, 1.9–3.0), blood type O (OR, 2.2; 95% CI, 1.8–2.8)], extracorporeal membrane oxygenation (OR, 1.5; 95% CI, 1.1– 2.2), mechanical ventilation (OR, 1.8; 95% CI, 1.4–2.3), and renal dysfunction (OR 1.6; 95% CI, 1.2–2.0). Independent predictors of survival on the waiting list included VAD therapy (OR 4.2; 95% CI, 2.4–7.6), cardiomyopathy diagnosis (OR 3.3; 95% CI, 2.4–4.6), blood type A (OR, 2.2; 95% CI, 1.8–2.8), UNOS list Status 1B (OR, 1.9; 95% CI, 1.2–3.0), listed in Era 2 (OR 1.8; 95% CI, 1.4–2.2), and white race (OR 1.3; 95% CI, 1.1–1.6). CONCLUSIONS: Despite an increase in the number of children listed as Status 1A, there was more than a 50% reduction in waiting list mortality in the new era. Irrespective of other factors, patients supported with a VAD were 4 times more likely to survive to transplant. J Heart Lung Transplant 2015;34:82–88 r 2015 International Society for Heart and Lung Transplantation. All rights reserved.
Of all patients wait-listed for organ transplantation in the United States, children listed for heart transplantation face one of the highest waiting list mortalities, regardless of age.1 Every year, approximately 500 additional pediatric candidates are added to the heart transplant waiting list2; Reprint requests: Farhan Zafar, MD, 3333 Burnet Ave, MLC 2013, Cincinnati, OH 45229. Telephone: 513-803-9272. E-mail address: [email protected]
however, approximately 17% children die each year awaiting a donor cardiac graft.3 In adult patients, the use of ventricular assist devices (VADs) has dramatically changed waiting list mortality, with survival on a LVAD of nearly 90% at 1 year.4 As a result of this continuing improvement in survival, the United Network of Organ Sharing (UNOS) allocation system was changed in 1999 to allow for only 30 days of Status 1A time for VAD-supported adult heart transplant candidates, unless
1053-2498/$ - see front matter r 2015 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2014.09.018
Zafar et al.
PHT Waiting List Mortality in VAD Era
device-related complications occurred, such as infection, thromboembolic, bleeding complications, or other devicerelated issues that would place them at a higher risk of death. With this shift and broader regional sharing of donor hearts, there has been a 17% reduction in waiting list mortality in adult heart transplant patients.5 A similar reduction in waiting list mortality has been noted in children during a 20-year period, from 26% to 13%, that has also been attributed to the changes in heart allocation policies by UNOS, allowing for the differentiation of sicker patients with an additional listing status (1B). VAD use has also increased in the pediatric population during this same period.6 Many single-institution and multiinstitutional VAD studies have shown an improvement in outcomes for patients supported with VADs.7,8 This suggests a potential positive effect on waiting list mortality; however, no effect of VAD use on waiting list mortality has been established in pediatric patients. This study undertook an analysis of current waiting list mortality for pediatric cardiac transplantation and of its association with the increase use of VADs during the past decade.
Methods Study cohort, data source, and definitions This was a retrospective analysis of all pediatric candidates (aged r 18 years) who were actively listed for a heart transplant from 1999 to 2012 in the United States (U.S.) identified from the UNOS database. UNOS is a private, non-profit organization that administers the Organ Procurement and Transplant Network (OPTN) under a federal contract. OPTN is a unified transplant network established by the U.S. Congress under the National Organ Transplant Act of 1982, which requires submission of data on all solid-organ transplants in the U.S., which is then internally audited. Data were limited to the year 1999 and beyond to eliminate the effect of change in allocation policy in January 1999, at which time Status 1 patients were subdivided into Status 1A and Status 1B to prioritize organ allocation to the sickest. Patients were divided into 2 cohorts based on year of listing to represent periods before and after introduction of pediatric-specific VADs. Era 1 was 1999 to 2004 and Era 2 was 2005 to 2012. Patients were further divided into VAD and no-VAD cohorts. Waiting list outcomes, as defined by UNOS, were transplanted, recovered (transplant not needed), or dead or alive on the waiting list. The outcomes analysis excluded patients who were removed from the list because they were too sick for transplant. Time on the waiting list was defined as time from the initial listing for heart transplantation to the time of waiting list removal due to transplantation, death, or recovery, or the time of data harvest (December 31, 2012) for patients alive on the waiting list. All clinical and demographics variables were defined at the time of listing for heart transplantation. VAD use was defined as VAD present at the time of listing or present at the time of transplant. Glomerular filtration rate (GFR) was estimated with the Schwartz formula to determine renal dysfunction.9
Statistical analysis Summary statistics are presented as median (range) or number (percentage). For baseline characteristics, continuous data were
83 compared using the t-test and analysis of variance with the Tukey method for normally distributed data and the non-parametric tests (Mann-Whitney U test for 2 samples and Kruskal-Wallis analysis of variance for multiple samples) for data without normal distribution. The chi-square test was used to compare categoric data. Mortality rates were computed as the number of deaths per 100 patient-years of waiting time for the given cohort. Survival curves were estimated using the Kaplan-Meier method, and equality of survival curves
Table 1
Variablesa
Baseline Characteristics for Patients in Different Eras Era 1 1999–2004 (n ¼ 2,191)
Age at listing, years 5 Infants 808 Weight at listing, kg 18 Weight categories, kg o10 713 10–19 408 20–39 408 40–59 356 Z60 281 Female 966 White 1,265 UNOS listing status Status 1A 1,490 Status 1B 311 Status 2 390 Cardiac diagnosis Cardiomyopathy 968 CHD 949 Myocarditis 47 Others 227 Blood type A 836 B 256 AB 84 O 1,015 ECMO 217 Ventilator 522 Inotropes 1,147 VAD 126 LVAD 21 RVAD 0 Total artificial heart 31 BiVAD 8 Unknown 66 VAD pump type Continuous 36 Pulsatile 76 Unknown 14 Dialysis 41 Creatinine, mg/dl 0.6 GFR o50% 251 Waiting list time, days 36
Era 2 2005–2012 (n ¼ 3,341)
(0–18) 5 (0–18) (37) 1,258 (38) (1.3–187) 17 (1.8–137) (33) (19) (19) (16) (13) (44) (58)
1,112 656 568 534 469 1,517 1,854
(33) (20) (17) (16) (14) (45) (56)
(68) (14) (18)
2,672 (80) 360 (11) 309 (9)
(44) (43) (2) (11)
1,454 1,381 133 373
(44) (41) (4) (11)
(38) (12) (4) (46) (10) (24) (52) (6) (1) (0) (1.4) (0.4) (3)
1,170 448 140 1,583 328 654 1,474 520 331 15 6 168 0
(35) (13) (4) (48) (10) (20) (44) (16) (10) (0.4) (0.2) (5) (0)
p-value 0.455 0.290 0.391 0.372
0.175 0.1 o0.001
0.214
0.06
(2) (3) (1) (2) (0.4–0.9) (15) (13–94)
101 396 23 61 0.5 270 45
0.475 0.001 0.001 o0.001
(3) (12) (1) (2) 0.922 (0.4–0.7) 0.001 (8) o0.001 (15–110) o0.001
BiVAD, biventricular assist device; CHD, congenital heart disease; ECMO, extracorporeal membrane oxygenation; GFR, glomerular filtration rate; LVAD, left ventricular assist device; RVAD, right ventricular assist device; VAD, ventricular assist device. a Continuous variables are shown as median (range) and categoric data as number (%).
84
The Journal of Heart and Lung Transplantation, Vol 34, No 1, January 2015
Baseline characteristics Patients in Era 2 were more likely than patients in Era 1 to be listed as Status 1A (80% vs 68%; p o 0.001), supported by a VAD (16% vs 6%; p o 0.001), and had longer median waiting list time (45 days vs 36 days; p o 0.001). Patients in Era 1 were more likely to be listed in Status 2 (18% vs 9%; p o 0.001), on ventilator support (24% vs 20%; p ¼ 0.001), on inotropic support (52% vs 44%; p ¼ 0.001), and have a GFR o 50% (15% vs 8%; p o 0.001). All other characteristics including age, gender, weight, diagnosis, race, were similar in both eras (Table 1).
Waiting list mortality
Figure 1
Waiting list survival for Era 1 and Era 2.
were tested using a log-rank test. Multivariate analyses were performed using Cox proportional hazards model and a stepwise selection technique to identify independent predictors of waiting list mortality. Analyses were performed using IBM SPSS Statistics 21 software (IBM Corp, Armonk, NY).
Results Of 5,912 pediatric candidates (aged r 18 years) who were actively listed during the study period, 2,191 (40%; 1,789 transplanted) were in Era 1 and 3,341 (60%; 2,894 transplanted) were in Era 2. A total of 380 patients (6%) were too sick to be transplanted, more in Era 1 (112 of 2,303 [5%]) than in Era 2 (268 of 3,609 [7%]; p ¼ 0.001); however, fewer patients had a VAD (26 of 672 [4%]) compared with no VAD (354 of 4886 [7%]). In further analysis, only 5,532 pediatric patients were included.
Figure 2
Waiting list mortality was lower in Era 2 (8%) vs Era 1 (16%; p o 0.001), and patients on the waiting list in Era 1 were more likely to die over time (p o 0.001; Figure 1). Patients supported with a VAD were more likely to survive in both eras, and patients on VAD in Era 2 had the best survival (Figure 2). Univariate predictors of waiting list mortality (Table 2) were infant age, weight o 10 kg, non-white race, UNOS list Status A, congenital heart disease, blood type O, extracorporeal membrane oxygenation (ECMO), ventilator, inotropes, GFR r 50%, shorter waiting list time, and listed for transplant in Era 1. Competing outcomes analysis showed 3% mortality and 69% transplant at 3 months in VAD patients compared with 10% mortality and only 61% transplanted in patients without VAD support. Similarly, patients in Era 2 only had 7% mortality at 3 months compared with 14% mortality for patients in Era 1 (Figure 3). Patients in Era 2 had 28 deaths/100 waiting list–years compared with 55 deaths/100 waiting list–years in Era 1 patients, which represents a 50% reduction. Patients on VAD support had 14 deaths/100 waiting list–years compared with 42 deaths/ 100 waiting list–years for patients with no VAD support, which represents a 66% reduction (Figure 4).
Waiting list survival for different groups by era and ventricular assist device (VAD) use.
Zafar et al. Table 2
PHT Waiting List Mortality in VAD Era Univariate Predictors of Mortality
Predictorsa Age at listing, years Infants Weight at listing, kg Weight categories, kg o10 10–19 20–39 40–59 Z60 Female White UNOS listing status Status 1A Status 1B Status 2 Cardiac diagnosis Cardiomyopathy CHD Myocarditis Others Blood type A B AB O ECMO Ventilator Inotropes VAD LVAD RVAD Total artificial heart BiVAD Unknown VAD pump type Continuous Pulsatile Unknown Dialysis Creatinine, mg/dl GFR r 50% Waiting list time, days Era 1: 1999–2004 2: 2005–2012
Survived (n ¼ 4,895)
Died (n ¼ 637)
p-value
6 (0–13) 1 (0–8) o0.001 1,726 (35.3) 340 (53) o0.001 19 (1.3–187) 9 (1.5–126) o0.001 o0.001 1,513 (31) 311 (50) 941 (19) 123 (20) 892 (19) 84 (13) 841 (17) 49 (8) 695 (14) 55 (9) 2,202 (45) 281 (44) 0.677 2,783 (57) 336 (53) 0.049 o0.001 3,640 (74) 522 (82) 623 (13) 48 (8) 632 (13) 67 (10) 0.001 2,275 (47) 147 (23) 1,950 (40) 380 (60) 166 (3) 14 (2) 504 (10) 96 (15) o0.001 1,841 (38) 165 (26) 625 (13) 79 (12) 203 (4) 21 (3) 2,226 (45) 372 (59) 424 (9) 121 (19) o0.001 927 (19) 249 (39) o0.001 2,281 (47) 340 (53) 0.001 623 (13) 23 (4) o0.001 348 (7) 4 (0.6) 13 (0.3) 2 (0.3) 37 (0.8) 0 (0) 170 (3.5) 55 (1) 131 459 33 75 0.5 399 46
6 (0.9) 11 (1.7)
(3) 6 (1) (9) 13 (2) (1) 4 (1) (1.5) 27 (4) o0.001 (0.4–0.8) 0.6 (0.4–0.9) 0.011 (9) 122 (24) o0.001 (16–112) 26 (9–67) o0.001 o0.001
1,830 (37) 3,065 (63)
361 (57) 276 (43)
BiVAD, biventricular assist device; CHD, congenital heart disease; ECMO, extracorporeal membrane oxygenation; GFR, glomerular filtration rate; LVAD, left ventricular assist device; RVAD, right ventricular assist device; UNOS, United Network of Organ Sharing; VAD, ventricular assist device. a Continuous variables are shown as median (range) and categoric data as number (%).
A sub-group analysis for infants and older children found VAD support was associated with decreased waiting list mortality in both groups (p o 0.001; Table 3) Independent predictors of waiting list mortality (Figure 5) included weight o 10 kg (odds ratio [OR], 2.7;
85 95% confidence interval [CI], 1.1–6.9; p ¼ 0.03), congenital heart disease diagnosis (OR, 2.4; 95% CI, 1.9–3.0); p o 0.001), blood type O (OR, 2.2; 95% CI, 1.8–2.8; p o 0.001), ECMO (OR, 1.5; 95% CI, 1.1–2.2; p ¼ 0.01), mechanical ventilation (OR, 1.8; 95% CI, 1.4–2.3; p o 0.001), and renal dysfunction (OR, 1.6; 95% CI, 1.2–2.0; p o 0.001). Independent predictors of survival on the waiting list included VAD therapy (OR, 4.2; 95% CI, 2.4– 7.6; p o 0.001), cardiomyopathy diagnosis (OR, 3.3; 95% CI, 2.4–4.6; p o 0.001), blood type A (OR, 2.2; 95% CI, 1.8–2.8; p o 0.001), UNOS list Status 1B (OR, 1.9; 95% CI, 1.2–3.0; p ¼ 0.005), listed in Era 2 (OR, 1.8; 95% CI, 1.4–2.2; p o 0.001), and white race (OR, 1.3; 95% CI, 1.1– 1.6; p ¼ 0.003).
Discussion There has been an obvious change in waiting list survival in pediatric patients in the VAD-associated era, with 1-year survival of 86% vs 74% in those patients listed from 1999 to 2004. There has also been a decrease in patients dying on the list (55 vs 28 per 100 waiting list–years), with a concomitant increase in VAD use between these two eras (16% from 6%). Also, the use of VADs was clearly demonstrated to decrease waiting list mortality from 42 to 14 per 100 waiting list–years. In the contemporary era, endorgan dysfunction decreased despite an overall increase in waiting times. However, patients known to have less favorable VAD options, patients weighing o 10 kg, and those with congenital heart disease were at higher risk of dying while waiting for a transplant, regardless of era. The use of pediatric-specific VADs has increased dramatically since 2005, with 20% of pediatric patients being bridged to transplant with a device.10 For example, the pediatric-specific Berlin Heart EXCOR (Berlin Heart GmbH, Berlin, Germany) paracorporeal device has successfully bridged to transplant 70% of the patients implanted with the device and has allowed for greater end-organ recovery in many cases.8,11 VADs offer a long-term support option for these critical patients, with 12-month survival on these devices of 75%, allowing patients to wait longer for suitable donors in a relatively stable condition. Singh et al6 also demonstrated similar results when they examined trends in waiting list mortality in children across racial and ethnic groups. They found that the risk of waiting list mortality decreased by 66% from 1989 to 2009 at the same time VAD use increased from 1% to 7%. Regardless of era, patients with VAD support had better waiting list survival than those patients not supported with a VAD. Another means by which device support leads to diminished waiting list mortality is improved end-organ function with decreased inotropic and ventilator support after VAD implantation. These all are risk factors for death after transplant, and if they are avoided or reversed by VAD support, then supported patients may realize better outcomes. The current study demonstrated an era effect of decreased ventilator support and inotropic support in the pediatric VAD era. Serum creatinine was also decreased, as
86
The Journal of Heart and Lung Transplantation, Vol 34, No 1, January 2015
Figure 3
Competing outcomes analysis for different groups by era and ventricular assist device (VAD) use.
was the frequency of significant renal disease in the pediatric VAD era. Because survival is better in the post-VAD era, patients waited longer for a transplant. The median wait rose from 36
Figure 4
days to 45 days, without changes in any other demographic variables, including size and age, to explain this difference. This has been seen in other studies where increased use of the Berlin Heart device has led to increased waiting list
Mortality per 100 waiting list–years for different groups by era and ventricular assist device (VAD) support.
Zafar et al.
PHT Waiting List Mortality in VAD Era
Table 3
Waiting List Mortality in Different Age Groups
Group
VAD
Survived (n ¼ 4,895) No. (%)
Infants
No Yes No Yes
1,262 85 3,010 538
Children
(81) (98) (90) (96)
Died (n ¼ 637) No. (%) 292 2 322 21
(19) (2) (10) (4)
p-value o0.001 o0.001
VAD, ventricular assist device.
duration.12 Also of concern was the decreased median time on the waiting list in those patients who died (26 days vs 46 days). These patients may represent the more ill patients in the current era who could not be bridged with a durable device or higher-risk patients were device support was attempted realizing the increased waiting list time in the current era. Patients who were not supported on a VAD were also more likely to be delisted because they were too sick for transplant (7% vs 4%, regardless of era). The current allocation system gives priority to VAD patients with no limited Status 1A time in the pediatric population, although survival on VAD has clearly risen. With increased use of VADs, this has led to a greater proportion of pediatric patients listed as Status 1, meeting criteria based on VAD use. This is also seen with a rise in Status 1A listing rising to 80% in the most recent era. The high proportion of patients listed as 1A leads to organ allocation based on time on the waiting list rather than medical urgency because essentially all patients who attain this status will receive organ offers based on waiting list time. Patients who are at higher risk of VAD complications, namely congenital heart disease patients and smaller infants, are at a disadvantage because they are often not mechanically supported and may not benefit from priority listing.
Figure 5
87 Mechanical support priority was appropriate in the era before pediatric specific VADs, when ECMO support was the primary device available to many pediatric patients because of its association with a time-dependent high rate of complications and death. The use of ECMO as a primary means of mechanical support as a bridge to cardiac transplantation in the current era is minimal, only approximately 4% of all patients listed for transplant. Unlike ECMO, duration of support is not a risk factor for worse outcomes in patients bridged to transplant with pediatric VADs.12 Therefore, in time the pediatric cardiac transplant community may have to consider that patients with VAD support have a limited period of priority listing. At the time of this report, various changes had been proposed to the current allocation system in the U.S. that were under revision. The proposed changes would allow for increased status to 1A for patients with significant congenital heart disease who were admitted to the hospital and required high-dose or multiple inotropes. Patients on inotropic support alone were not given priority status; however, anyone on mechanical circulatory support would still receive status 1A with no time restriction.13 This study has some limitations. The UNOS data set is limited by the data available and its retrospective data collection. This analysis does not account for improvement and/or deterioration in a patient’s clinical status while on the waiting list. In conclusion, during the past 15 years, the strongest predictor of waiting list survival has been VAD use, with its affect increasing over time. In the past 7 years, when pediatric VAD support has increased significantly, there has been a substantial reduction in end-organ dysfunction of patients on the waiting list and, most noteworthy, a 50% reduction in waiting list death. As pediatric VAD clinical experience and technology improve, a further reduction in waiting list mortality may be realized.
Multivariate analysis of risk factors for waiting list mortality.
88
The Journal of Heart and Lung Transplantation, Vol 34, No 1, January 2015
Disclosure statement This study used data provided by UNOS. The authors’ institution funded the study. Dr. Morales is a member of an advisory committee for Berlin Heart, Inc and he is a Proctor for Syncardia, Inc training. Dr. Morales has also travelled for academic activities on behalf of the following companies: Berlin Heart, Inc, Syncardia, Inc, Thoratec, Inc, and HeartWare, Inc. Dr. Morales' institution has received travel reimbursement from these companies for these activities. Dr. Morales has not received any personal remuneration from these companies. None of the other authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.
References 1. McDiarmid SV, Cherikh WS, Sweet SC. Preventable death: children on the transplant waiting list. Am J Transplant 2008;8:2491-5. 2. Health Resources and Services Administration. Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients. Annual data report 2012: heart. Available at: http://srtr.transplant.hrsa. gov/annual_reports/2012/flash/05_heart_13/v2index.html. Accessed March 20, 2014. 3. Almond CS, Thiagarajan RR, Piercey GE, et al. Waiting list mortality among children listed for heart transplantation in the United States. Circulation 2009;119:717-27. 4. John R, Kamdar F, Liao K, Colvin-Adams M, Boyle A, Joyce L. Improved survival and decreasing incidence of adverse events with the HeartMate II left ventricular assist device as bridge-to-transplant therapy. Ann Thorac Surg 2008;86:1227-35.
5. Singh TP, Almond CS, Taylor DO, Graham DA. Decline in heart transplant wait list mortality in the United States following broader regional sharing of donor heart. Circ Heart Fail 2012;5: 249-58. 6. Singh TP, Almond CS, Piercey G, Gauvreau K. Trends in wait-list mortality in children listed for heart transplantation in the United States: era effect across racial/ethnic groups. Am J Transplant 2011;11:2692-9. 7. Jeewa A, Manlhiot C, McCrindle BW, Van Arsdell G, Humpl T, Dipchand AI. Outcomes with ventricular assist device versus extracorporeal membrane oxygenation as a bridge to pediatric heart transplantation. Artif Organs 2010;34:1087-91. 8. Almond CS, Morales DL, Blackstone EH, et al. The Berlin Heart EXCORs pediatric ventricular assist device for bridge to heart transplantation in US children. Circulation 2013;127:1702-11. 9. Schwartz GJ, Haycock GB, Edelmann CM Jr, Spitzer A. A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics 1976;58:259-63. 10. Kirk R, Dipchand AI, Edwards LB, et al. The registry of the International Society of Heart and Lung Transplantation: fifteenth pediatric heart transplantation report—2012. J Heart Lung Transplant 2012;31:1065-72. 11. Morales DL, Almond CS, Jaquiss RD, et al. Bridging children of all sizes to cardiac transplantation: the initial multicenter North American experience with the Berlin Heart EXCOR ventricular assist device. J Heart Lung Transplant 2011;30:1-8. 12. Cassidy J, Dominquez T, Haynes S, et al. A longer waiting game: bridging children to heart transplant with the Berlin Heart EXCOR device—the United Kingdom experience. J Heart Lung Transplant 2013;32:1101-6. 13. U.S. Health Resources and Services Administration. Organ Procurement and Transplantation Network. Proposal to change pediatric heart allocation policy. Available at: http://optn.transplant.hrsa.gov/Public Comment/pubcommentPropSub_321.pdf. Accessed April 11, 2014.
