Download Current Outcomes in US Children With Cardiomyopathy Listed for

Current Outcomes in US Children With Cardiomyopathy
Listed for Heart Transplantation
Tajinder P. Singh, MD, MSc; Christopher S. Almond, MD, MPH; Gary Piercey, BS;
Kimberlee Gauvreau, ScD
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Background—Previous studies have reported worse outcomes in children with nondilated cardiomyopathy (CMP) listed for
heart transplant compared with children with dilated CMP. We sought to compare wait-list and posttransplant outcomes
in these groups in the current era.
Methods and Results—We analyzed all children <18 years of age with a diagnosis of CMP listed for heart transplant in the
United States between July 2004 and December 2010. Multivariable risk factors for death on the wait-list (or becoming too
sick to transplant) and posttransplant graft loss (median follow-up 2 years) were assessed using Cox models. Of the 1436
children analyzed, 1197 (83%) had dilated CMP and 239 (17%) had nondilated CMP (167 restrictive CMP, 72 hypertrophic
CMP). In adjusted analysis, children with nondilated CMP were at higher risk of wait-list mortality only if they were on a
ventilator support at listing (hazard ratio, 2.3; CI, 1.2–4.5). The risk was similar among children not on a ventilator support
(hazard ratio, 0.6; CI, 0.3–1.1). Posttransplant 30-day and 1-year survival was 98% and 94%, respectively, in children with
dilated CMP versus 95% and 89%, respectively, in children with nondilated CMP (P=0.17, log-rank test). In adjusted analysis,
the risk of posttransplant graft loss was higher in nondilated CMP (hazard ratio, 1.8; CI, 1.2–2.7) versus dilated CMP.
Conclusions—The increased risk of wait-list mortality in children with nondilated CMP is limited to those on ventilator
support at listing. Although the risk of graft loss is modestly higher in children with nondilated forms of CMP, their shortterm transplant outcomes are good. (Circ Heart Fail. 2012;5:594-601.)
Key Words: heart transplantation ◼ outcomes ◼ pediatrics ◼ cardiomyopathy ◼ heart failure
W
ait-list and posttransplant outcomes have continued to
improve in children listed for a heart transplant (HT) in
the United States.1,2 Although most of the improvement may
be attributed to broad advances in pre-, intra- and posttransplant care, better patient selection and targeted management
of high-risk groups have also helped.3–5
CMP and those with nondilated CMP (hypertrophic or restrictive CMP) adjusted for baseline risk factors, and (2) to compare
posttransplant survival between the 2 groups in the current era.
Clinical Perspective on p 601
We identified all children <18 years of age in the Organ Procurement
and Transplantation Network database who were listed for HT in the
United States between July 1, 2004 and December 31, 2010, with
a d­iagnosis of CMP. The Organ Procurement and Transplantation
Network database includes demographic and clinical information
on all HT candidates in the United States submitted by their transplant centers. The Health Resources and Services Administration,
US Department of Health and Human Services, provides oversight to
the activities of the Organ Procurement and Transplantation Network
­contractor, United Network of Organ Sharing (UNOS). We excluded
children listed for heart retransplantation or multiorgan transplantation.
Methods
Study Population
Among children listed for HT, those with cardiomyopathy
(CMP) are known to have better outcomes compared with children with congenital heart disease.6,7 Furthermore, children with
a nondilated CMP phenotype (hypertrophic or restrictive CMP),
particularly infants, have been reported to be at higher risk of
wait-list and posttransplant mortality compared with children
with dilated CMP.6,8–10 Whether these differences in outcomes
between children with nondilated CMP and those with dilated
CMP are because of differences in heart failure severity or
because of risks uniquely related to CMP phenotype is unclear.11
We hypothesized that the risks of wait-list and posttransplant
mortality in children with dilated and nondilated CMP listed for
HT are similar in the current era after adjusting for baseline risk
factors. The specific objectives of this study were as follows:
(1) to compare wait-list mortality between children with dilated
Study Design and Definitions
We compared baseline characteristics and outcomes in children with
dilated CMP and those with nondilated CMP (hypertrophic or restrictive CMP) listed for HT during the study period. Children with CMP
known to be secondary to a structural heart disease were not included.
The primary end point for wait-list outcomes was a composite of death
on the wait-list or becoming too sick to transplant (removal from the
list because of clinical deterioration). Children who received an HT
Received April 12, 2012; accepted August 10, 2012.
From the Department of Cardiology, Boston Children’s Hospital, Boston, MA (T.P.S., C.A., G.P., K.G.); Department of Pediatrics, Harvard Medical
School, Boston, MA (T.P.S., C.A.); and Department of Biostatistics, Harvard School of Public Health, Boston, MA (K.G.).
Correspondence to Tajinder P. Singh, MD, MSc, Department of Cardiology, Boston Children’s Hospital, 300 Longwood Ave, Boston, MA 02115. E-mail
[email protected]
© 2012 American Heart Association, Inc.
Circ Heart Fail is available at http://circheartfailure.ahajournals.orgDOI: 10.1161/CIRCHEARTFAILURE.112.969980
594
Singh et al Current Outcomes in Pediatric Cardiomyopathy 595
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or were removed from the list because of recovery or other reasons
were censored. The primary end point for posttransplant outcomes was
death or graft loss (retransplantation). For analysis of wait-list outcomes, children were followed from the time of listing until death, HT,
removal from the list, or the day of last observation on March 31, 2011.
For analysis of posttransplant outcomes, children who received an HT
were followed until death, retransplant, or the day of last observation.
Baseline variables were defined at the time of listing for analysis of
wait-list outcomes and at transplant for analysis of posttransplant outcomes. Race/ethnicity was recorded as reported by the transplant center and analyzed as white (non-Hispanic white), black (non-Hispanic
Black), Hispanic, or other. Renal function was analyzed as estimated
glomerular filtration rate (mL/min per 1.73 m2) and calculated from
serum creatinine using the modified Schwartz formula.12 Normal renal
function in children ≥1 year of age was defined as glomerular filtration
rate >60, moderate dysfunction as 30 to 60, and severe dysfunction as
<30/dialysis support.13 Because of the lower glomerular filtration rate
in normal infants <1 year of age, normal renal function, moderate dysfunction, and severe dysfunction were defined as glomerular filtration
rate >40, 20 to 40, and <20/dialysis support, respectively.13
None of the children analyzed had missing data for the variables
age, sex, race/ethnicity, blood type, mechanical support at listing
or transplant, medical insurance (Medicaid), UNOS listing status,
­dialysis and the dates of listing, transplant, death, or removal from the
wait-list. Missing values of creatinine (3.3% of children at listing and
3% at transplant) and total serum bilirubin (6.3% of children) were
imputed using multivariable linear regression analyses.
Statistical Analysis
Summary data are presented as median (25th, 75th percentile) or number (percent). Baseline characteristics between children with ­dilated,
hypertrophic, and restrictive CMP were compared using the χ2 test for
categorical and the Kruskal-Wallis test for continuous variables. Waitlist outcomes in children with dilated and nondilated CMP were characterized using competing outcomes analysis.14,15 A multivariable Cox
proportional hazards model for the composite wait-list end point was
­developed using a forward selection procedure, retaining variables significant at the 0.10 level based on a ­likelihood ratio test; all Table 1 variables
were considered. Posttransplant survival (freedom from death or retransplantation) was characterized using Kaplan-Meier survival analysis and
compared using the log-rank test. A Cox regression model was used to
compare posttransplant outcomes b­ etween HT recipients with dilated
and nondilated CMP adjusted for baseline risk factors. Assumptions
for Cox models were evaluated for both wait-list and posttransplant end
points. For both models, interaction of CMP phenotype with other risk
factors was evaluated to identify CMP subgroups at increased risk.
Data were analyzed using SAS statistical software version 9.3
(SAS Institute Inc, Cary, NC). All statistical tests were 2-sided, and a
P value <0.05 was used to define statistical significance. The authors
had full access to the data and take responsibility for its integrity. All
authors have read and agree to the manuscript as written.
Results
Study Population
During the study period, 3207 children <18 years of age were
listed in the United States for an HT. Of these, 211 children
were listed for retransplantation and 17 children for multiorgan transplantation. Of the 2979 children listed for a primary
HT, 1436 (48%) children had CMP as their listing diagnosis and formed the study cohort. Of these, 1197 (83%) had
dilated CMP and 239 (17%) had nondilated CMP (167 restrictive CMP, 72 hypertrophic CMP). Baseline characteristics of
children with dilated CMP and nondilated CMP at the time of
HT listing are summarized in Table 1.
Children with dilated CMP were more likely to be listed with
higher urgency as UNOS status 1A16 candidates (72% of dilated
CMP versus 38% of nondilated CMP). They were more likely
to be supported with intravenous inotropes (51% of dilated
CMP versus 26% of nondilated CMP), a ventilator (27% versus 13%), ventricular assist device (11% versus 1%), and any
mechanical support (29% versus 7%) compared with children
with nondilated CMP at listing (P<0.001 for all). The median
pulmonary artery pressure and pulmonary capillary wedge
pressure were similar among children with dilated and those
with nondilated CMP. Among infants <1 year old at listing with
CMP (n=350), those with dilated CMP (n=314) and nondilated
CMP (n=36) were equally likely to be listed as status 1A (80%
versus 78%) and supported on a ventilator at the time of listing
(48% versus 44%). Although 20% of infants with dilated CMP
were on mechanical support (15% on extracorporeal membrane
oxygenation, 1% on biventricular assist device, 4% on left ventricular assist device) at listing compared with 11% of infants
with nondilated CMP (all on extracorporeal membrane oxygenation), this difference was not statistically significant (P=0.24).
Wait-List Outcomes
Overall, 152 (11%) children with CMP reached the composite
wait-list end point (109 died on the wait-list, 43 became too sick
to transplant). Figure 1 illustrates competing outcomes for children with dilated CMP (Figure 1A), those with nondilated CMP
(Figure 1B), and the cumulative percentage of children in the 2
groups who died on the wait-list or became too sick to transplant (Figure 1C). Overall, 11% of children with dilated CMP
and 8% of children with nondilated CMP died on the wait-list
or became too sick to transplant. The incidence rate of dying on
the wait-list or becoming too sick to transplant was 30.2/100
patient-years in children with dilated CMP (95% CI, 25.3–
35.8/100 patient-years) and 16.6/100 patient-years in children
with nondilated CMP (95% CI, 10.0–25.9/100 patient-years).
Children with nondilated CMP had a lower unadjusted risk
of dying on the wait-list or becoming too sick to transplant
(hazard ratio [HR], 0.6; 95% CI, 0.4–0.9; P=0.02) compared
with children with dilated CMP. Other univariable factors
associated with higher risk of reaching the composite waitlist end point were younger age, listing status 1A, ventilator
support, mechanical support, and renal dysfunction. Race/
ethnicity and pulmonary artery pressure were not associated
wait-list mortality. Among children listed as status 2 (n=303),
3 (2.7%) of 110 children with nondilated CMP and 12 (6.2%)
of 193 children with dilated CMP reached the composite waitlist end point (HR, 0.4; 95% CI, 0.1–1.4; P=0.14).
In multivariable analysis, independent risk factors for waitlist mortality (or becoming too sick to transplant) included
age <1 year, ventilator support, mechanical support, and renal
dysfunction (Table 2). In addition, a significant interaction
between the CMP phenotype and ventilator support was identified. Children with nondilated CMP were at higher risk of
wait-list mortality versus children with dilated CMP only if
they were supported on a ventilator at listing (HR, 2.3; CI, 1.2–
4.5). The risk was similar in those who were not on ventilator
support (HR, 0.6; CI, 0.3–1.1). Importantly, the interaction of
CMP phenotype with age at listing was not significant, and
there was no difference in wait-list mortality between infants
(or older age groups) with dilated and nondilated CMP. In subgroup analysis, the risk of death on the wait-list (or becoming too sick to transplant) in infants with nondilated CMP was
596 Circ Heart Fail September 2012
Table 1. Baseline Characteristics of Study Children at Listing
Variable
Age, y
Dilated CMP
(n=1197)
Restrictive CMP
(n=167)
6 (0, 14)
8 (2, 14)
Hypertrophic CMP
(n=72)
13 (0, 16)
Total
(N=1436)
6 (1, 14)
Age categories (y)
0.006
<0.001
<1
314 (26%)
16 (10%)
20 (28%)
350 (24%)
1–10
440 (37%)
88 (53%)
14 (19%)
542 (38%)
11–17
443 (37%)
63 (38%)
38 (53%)
544 (38%)
Female sex
567 (47%)
96 (57%)
29 (40%)
692 (48%)
1A
859 (72%)
59 (35%)
31 (43%)
949 (66%)
1B
145 (12%)
23 (14%)
16 (22%)
184 (13%)
2
193 (16%)
85 (51%)
25 (35%)
303 (21%)
358 (30%)
67 (40%)
25 (35%)
450 (31%)
Listing status
0.02
<0.001
Blood type
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A
P Value
0.13
AB
46 (4%)
5 (3%)
2 (3%)
53 (4%)
B
176 (15%)
15 (9%)
8 (11%)
199 (14%)
O
617 (52%)
80 (48%)
37 (51%)
734 (51%)
White
553 (46%)
102 (61%)
42 (58%)
697 (49%)
Black
337 (28%)
20 (12%)
11 (15%)
368 (26%)
Hispanic
201 (17%)
31 (19%)
17 (24%)
249 (17%)
Other
106 (9%)
14 (8%)
2 (3%)
122 (9%)
Inotropes
615 (51%)
47 (28%)
16 (22%)
678 (47%)
<0.001
Ventilator
329 (27%)
13 (8%)
18 (25%)
360 (25%)
<0.001
ECMO
120 (10%)
5 (3%)
4 (6%)
129 (9%)
BIVAD
53 (4%)
1 (1%)
1 (1%)
55 (4%)
LVAD
83 (7%)
1 (1%)
0 (0%)
84 (6%)
None
941 (79%)
160 (96%)
67 (93%)
1168 (81%)
Serum creatinine (n=1389)
0.6 (0.4, 0.8)
0.5 (0.3, 0.7)
0.6 (0.4, 0.8)
0.6 (0.4, 0.8)
<0.001
GFR (n=1389)
81 (60, 103)
100 (83, 126)
81 (69, 100)
83 (63, 105)
<0.001
Dialysis
19 (2%)
2 (1%)
0 (0%)
21 (1%)
Normal
690 (58%)
116 (70%)
49 (68%)
855 (59%)
Moderate
Race/ethnicity
<0.001
Mechanical support
<0.001
Renal function*
0.02
446 (37%)
47 (28%)
22 (31%)
515 (37%)
Severe
61 (5%)
4 (2%)
1 (1%)
66 (5%)
Mean PAP (mm Hg) (n=790)
28 (21, 36)
28 (22, 35)
25 (20, 30)
28 (21, 36)
Mean PAP (mm Hg)
0.09
<0.001
≥30
287 (46%)
54 (46%)
12 (29%)
353 (45%)
<30
343 (54%)
64 (54%)
30 (71%)
437 (30%)
20 (16, 23)
17 (13, 21)
PCWP (mm Hg) (n=749)
0.90
20 (13, 26)
19 (13, 25)
PCWP (mm Hg)
0.43
<0.001
≥20
298 (50%)
58 (51%)
17 (41%)
373 (50%)
<20
297 (50%)
55 (49%)
24 (59%)
376 (50%)
Medicaid insurance
532 (44%)
54 (32%)
35 (49%)
621 (43%)
0.007
CMP indicates cardiomyopathy; ECMO, extracorporeal membrane oxygenation; BIVAD, biventricular assist device; LVAD, left ventricular assist device;
GFR, glomerular filtration rate; PCWP, pulmonary capillary wedge pressure; PAP, pulmonary artery pressure.
Data are presented as number (percent) or median (25th percentile, 75th percentile).
GFR is expressed as mL/min per 1.73 m2.
*Includes imputed values.
Singh et al Current Outcomes in Pediatric Cardiomyopathy 597
A
Table 2. Multivariable Predictors of Death on the Wait-List or
Becoming Too Sick to Transplant
1
Proportion of Patients
.8
On Wait-list
Transplanted
69.4%
60.3%
.6
27.7%
3.2%
0
30
0
<0.001
Ventilator
2.0 (1.3–3.0)
0.001
Nondilated CMP, no ventilator
0.6 (0.3–1.1)
0.10
Nondilated CMP, ventilator
2.3 (1.2–4.5)
0.02
10.0%
4.7%
ECMO/BIVAD*
1.6 (1.0–2.5)
0.04
LVAD
1.1 (0.5–2.2)
Removed
0.78
90
120
Days on Wait-list
150
Moderate
2.0 (1.4–3.0)
<0.001
Severe
3.1 (1.7–5.4)
<0.001
Renal dysfunction (ref: normal)
180
HR indicates hazard ratio; CMP, cardiomyopathy; ECMO, extracorporeal membrane
oxygenation; BIVAD, biventricular assist device; LVAD, left ventricular assist device.
*Because patients on ECMO are also supported on a ventilator, the risk in
ECMO patients is higher compared with risk in BIVAD patients not on a ventilator
On Wait-list
Transplanted
.6
63.6%
51.5%
41.8%
.4
25.9%
.2
0
0
30
60
5.0%
Death/deterioration
2.1%
Removed
90
120
Days on Wait-list
150
7.1%
2.1%
180
0.12
Dilated CMP
0.10
0.08
Non-Dilated CMP
0.06
0.04
CMP and 184 children with nondilated CMP received an HT.
The median waiting time was 32 days (interquartile range, 11–76
days) in children with dilated CMP and 54 days (interquartile
range, 18–118 days) in children with nondilated CMP (P<0.001).
Among 303 study children listed as status 2 candidates, 226
(75%) received an HT. Of these, 71% of those with dilated CMP
and 54% of those with nondilated CMP received HT after listing
upgrade to a higher urgency status (1A or 1B). Of the children
who received an HT, 23% of those with dilated CMP and 5% of
those with nondilated CMP were supported on a ventricular assist
device at the time of HT (see Table 3 for baseline variables at HT).
The median posttransplant follow-up period was 2 years
(11 months, 4 years), during which 141 children died or lost
their graft (123 deaths, 18 retransplants). Figure 3 illustrates
posttransplant Kaplan-Meier survival in children with dilated
CMP and nondilated CMP. There was a trend toward better
survival in children with dilated CMP compared with children
with nondilated CMP both at 30 days (98.1% versus 95.5%)
and at 1 year (94.3% versus 88.5%); however, the difference
did not reach statistical significance (P=0.17).
0.02
.8
0.00
0
30
60
90
120
Days on Wait-list
150
180
Figure 1. Competing outcomes in children with dilated cardiomyopathy (CMP) (A) and nondilated CMP (B) listed for a heart
transplant14 in the United States between July 2004 and December 2010 and the cumulative percentage of those who died or
became too sick to transplant in the 2 groups (C).
similar to infants with dilated CMP (HR, 1.3; 95% CI, 0.5–3.4;
P=0.55) in analysis adjusted for mechanical support, ventilator support, and renal function. Blood type, race/ethnicity, and
medical insurance were not associated with wait-list mortality.
Cumulative Probability of Transplant
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Proportion of Patients
60
15.9%
Death/deterioration
1
.8
Cumulative Wait-list Mortality
P Value
2. 1 (1.5–3.1)
Mechanical support (ref: none)
8.8%
C
HR (95% CI)
Age <1 y
Diagnosis (ref: dilated CMP)
.4
.2
B
Predictor
Dilated CMP
.7
.6
Non-Dilated CMP
.5
.4
.3
.2
.1
0
0
Posttransplant Outcomes
Figure 2 illustrates the cumulative transplant rate in children with
dilated and nondilated CMP. Overall, 910 children with dilated
30
60
90
120
Days on Wait-list
150
Figure 2. Cumulative percentage of children with dilated and
nondilated cardiomyopathy (CMP) who received a heart transplant during the study period.
180
598 Circ Heart Fail September 2012
In multivariable analysis (Table 4), the risk of death/graft
loss was higher in children with nondilated CMP compared
with children with dilated CMP (HR, 1.8; 95% CI, 1.2–2.7;
P=0.008). Other risk factors for death/graft loss included recipient age <1 year, black race, mechanical support (extracorporeal
membrane oxygenation or biventricular assist device), renal
dysfunction, and higher serum bilirubin. No interaction of CMP
phenotype with any other variable was statistically significant.
Discussion
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This study has 4 major findings. First, children with dilated
CMP are, on average, sicker at the time of listing and are listed
with higher urgency compared with children with nondilated
CMP. Second, several risk factors associated with wait-list
mortality, such as age <1 year, level of hemodynamic support,
and renal function, are also associated with posttransplant
mortality. As a result, CMP children with higher risk of waitlist mortality are also at higher risk of posttransplant mortality on receiving an HT. Third, in adjusted analysis, the risk
of death on the wait-list (or becoming too sick to transplant)
is similar in children with dilated and nondilated CMP who
are not supported on a ventilator at listing. However, among
children supported on a ventilator, this risk is 2.3-fold in those
with nondilated CMP. Finally, despite a higher risk of posttransplant graft loss in children with nondilated CMP, their
posttransplant 1-year survival of 89% approaches the current
1-year posttransplant survival in children.1,17 These findings
are important in informing clinical decisions during HT evaluation and for parental counseling in these children.
An important previous report in a cohort similar to ours is
from the Pediatric Heart Transplant Study (PHTS). The authors
reported outcomes in 1320 children with CMP (83% with
dilated CMP and 17% with nondilated CMP) listed for HT during 1993–2006.6,8–10 The overall wait-list mortality was higher
at 17% reflecting the earlier era (versus 11% for the composite
wait-list end point in the current analysis), and posttransplant
1-year survival was 91%. Children with nondilated CMP (particularly those <1 year) and black children were reported to be
at higher risk of wait-list mortality. The present study cohort had
important differences in baseline characteristics and outcomes
from children in the PHTS analyses. First, the use of VAD in
the present cohort far exceeds that in the previous analyses as
the EXCOR Berlin Heart has gradually become the preferred
mechanical circulatory support in children who fail conventional
medical therapy.18 The outcomes and risk factors, therefore, pertain more closely to contemporary support options in the United
States. We found that the risk of death on the wait-list and in
the posttransplant period associated with mechanical support is
hierarchical, being highest in children with extracorporeal membrane oxygenation and less so in children on biventricular assist
device and left ventricular assist device. Second, the degree of
renal dysfunction is an important risk factor for wait-list and
posttransplant mortality. This finding was not reported in the
PHTS report but is consistent with our previous work in other
cohorts.7,19–21 Third, although black children remain at higher
risk of posttransplant mortality,1 we did not find any association
of race/ethnicity with wait-list mortality. This finding is consistent with a recent report that showed that racial gaps, previously present in children awaiting HT in the United States, are
absent in the current era.2 Finally, wait-list and posttransplant
outcomes in children with dilated and nondilated CMP seem to
have improved compared with the PHTS analyses.6,8–10
The interaction of CMP phenotype with ventilator support as
a determinant of wait-list mortality is an important new finding
and may be explained by examining current management options
in children supported on a ventilator at listing. Although assisted
ventilation can be lifesaving in children with severe heart failure,
ventilator dependence is an accepted indication for VAD implantation. This is so because VAD implantation reduces the risk of
multiorgan failure in these children and allows patient rehabilitation while awaiting HT.18 This option is readily available to
infants and children with dilated CMP with the availability of
Berlin EXCOR heart.18 In contrast, a nondilated left ventricle is a
technical challenge for VAD implantation because of space constraints in the left ventricle. The inflow cannula in these children
is often placed in the left atrium, a strategy which increases the
risks of VAD support18,22 and limits available options in children
with nondilated CMP who are ventilator dependent.
The higher risk of posttransplant mortality in children with
nondilated CMP is not well explained by our data. Because
children with nondilated forms of CMP often have a physiology that does not benefit from intravenous inotropes, they
may be sicker at the time of HT than their urgency at listing
and transplant indicate. It may also be that some children with
unique features, such as systemic malformations, syndromes,
or inborn errors of metabolism associated with nondilated
CMP, were listed and contributed to their increased risk; this
speculation is not supported by data, however.
The findings of this study have important implications. First,
a close examination of the risk models for wait-list and posttransplant mortality (Tables 2 and 4) suggests that the risk associated with nondilated CMP phenotype is small compared with
the aggregate risk associated with factors, such as age, patient
support, and end-organ function. Furthermore, overall wait-list
and posttransplant outcomes in children with nondilated CMP
approach those in children with dilated CMP. Therefore, a diagnosis of nondilated CMP in itself should not deter listing in a
child, and the decision should be individualized based on presenting features, comorbidities, and risk assessment. Second, in an
allocation system that prioritizes children on the wait-list based
on transplant urgency (as the intent of the current system is),16 the
differences in outcomes between the CMP groups do not appear
large enough to merit allocation prioritization by CMP phenotype
at any age. Third, the similarity in risk factors for wait-list and
posttransplant mortality suggests that the sickest children with
CMP on the wait-list are also at a higher risk of posttransplant
mortality. Models such as those presented may allow estimation
of these risks using values of variables at the time of listing. This
approach may allow estimation of transplant benefit at the time of
listing similar to the current practice in lung transplant candidates
in the United States.23 Considering transplant benefit in addition
to transplant urgency in allocation policy may help avoid futile
transplants and lower overall mortality in children listed for HT.
This study has several limitations. First, being a retrospective analysis of a national database, the submitted data may
lack the rigor and quality control expected of data from a prospective, controlled study. However, because these data are
used by UNOS for real-time organ allocation and for periodic
Singh et al Current Outcomes in Pediatric Cardiomyopathy 599
Table 3. Baseline Characteristics of Study Children at Transplant
Age (y)
Dilated CMP
(n=910)
Restrictive CMP
(n=128)
8 (1, 14)
9 (4, 14)
Hypertrophic CMP
(n=56)
14 (0, 16)
Total
(N=1094)
8 (1, 14)
Age categories (y)
202 (22%)
12 (9%)
15 (27%)
229 (21%)
1–10
345 (38%)
63 (49%)
9 (16%)
417 (38%)
11–17
363 (40%)
53 (41%)
32 (57%)
448 (41%)
Female sex
428 (47%)
76 (59%)
24 (43%)
528 (48%)
1A
660 (73%)
47 (37%)
22 (39%)
729 (67%)
1B
109 (12%)
18 (14%)
12 (21%)
139 (13%)
2
141 (15%)
63 (49%)
22 (39%)
226 (21%)
288 (32%)
53 (41%)
20 (36%)
361 (33%)
Listing status
0.02
<0.001
Blood type
0.30
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AB
42 (5%)
4 (3%)
1 (2%)
47 (4%)
B
139 (15%)
13 (10%)
7 (13%)
159 (15%)
O
441 (48%)
58 (45%)
28 (50%)
527 (48%)
White
415 (46%)
81 (63%)
35 (63%)
531 (49%)
Black
258 (28%)
14 (11%)
7 (13%)
279 (26%)
Hispanic
149 (16%)
20 (16%)
12 (21%)
181 (17%)
88 (10%)
13 (10%)
2 (4%)
103 (9%)
Race/ethnicity
Other
0.02
<0.001
<1
A
P Value
<0.001
Inotropes (n=1080)
459 (51%)
44 (35%)
21 (38%)
524 (49%)
<0.001
Ventilator (n=1080)
167 (19%)
10 (8%)
10 (18%)
187 (17%)
0.006
53 (6%)
3 (2%)
4 (7%)
60 (5%)
BIVAD
72 (8%)
3 (2%)
2 (4%)
77 (7%)
LVAD
136 (15%)
3 (2%)
2 (4%)
141 (13%)
None of above
649 (71%)
119 (93%)
48 (86%)
816 (75%)
Serum creatinine (n=1061)
0.5 (0.3, 0.8)
0.5 (0.4, 0.7)
0.6 (0.4, 0.8)
0.5 (0.4, 0.8)
0.24
GFR (n=1061)
87 (67, 114)
95 (82, 116)
89 (68, 105)
89 (69, 114)
0.009
Dialysis
20 (2%)
3 (2%)
2 (4%)
25 (2%)
0.58
Normal
559 (61%)
84 (65%)
38 (68%)
681 (62%)
Moderate
Mechanical support
ECMO
<0.001
Renal dysfunction*
0.82
299 (33%)
38 (30%)
15 (27%)
352 (32%)
Severe
52 (6%)
6 (5%)
3 (5%)
61 (6%)
Mean PAP (mm Hg) (n=606)
26 (19, 35)
28 (24, 35)
26 (20, 30)
26 (20, 35)
0.03
Mean PAP (mm Hg)
>30
188 (39%)
39 (46%)
10 (29%)
237 (39%)
<30
298 (61%)
46 (54%)
25 (71%)
369 (61%)
20 (15, 23)
16 (12, 21)
PCWP (mm Hg) (n=571)
18 (11, 25)
18 (12, 24)
PCWP (mm Hg)
0.01
0.17
0.16
≥20
202 (44%)
39 (50%)
12 (39%)
253 (44%)
<20
260 (56%)
39 (50%)
19 (61%)
318 (56%)
Bilirubin (mg/dL) (n=994)
0.7 (0.4, 1.2)
0.7 (0.4, 1.2)
0.7 (0.4, 1.3)
0.7 (0.4, 1.2)
<0.6
370 (41%)
48 (38%)
19 (34%)
437 (40%)
0.6–1.9
417 (46%)
67 (52%)
29 (52%)
513 (37%)
≥2.0
123 (13%)
13 (10%)
8 (14%)
144 (13%)
Bilirubin (mg/dL)*
0.51
0.54
(continued)
600 Circ Heart Fail September 2012
Table 3. Continued
Dilated CMP
(n=910)
Restrictive CMP
(n=128)
Hypertrophic CMP
(n=56)
Total
(N=1094)
PRA class 1 (n=949)
P Value
0.44
>10%
90 (11%)
8 (7%)
3 (6%)
101 (11%)
≤10%
702 (89%)
99 (93%)
47 (94%)
848 (89%)
PRA class 2 (n=892)
0.40
>10%
60 (8%)
3 (3%)
3 (6%)
66 (7%)
≤10%
683 (92%)
99 (97%)
44 (94%)
826 (93%)
>10%
119 (15%)
8 (7%)
4 (8%)
131 (14%)
≤10%
674 (85%)
100 (93%)
46 (92%)
820 (86%)
>3.5
328 (38%)
62 (50%)
22 (42%)
412 (39%)
≤3.5
539 (62%)
62 (50%)
31 (58%)
632 (61%)
Medicaid insurance
407 (45%)
41 (32%)
30 (54%)
478 (44%)
PRA class 1 or 2 (n=951)
0.13
Ischemic time (h) (n=1044)
0.10
auditing of transplant centers, certain safeguards to data quality are to be expected. Second, because of their small sample
size and low event frequency, we chose to analyze outcomes in
children with nondilated CMP as a single group. This approach
is similar to that used in a previous multicenter analysis6 and
allows comparison of outcomes in the 2 cohorts. Third, the
risks associated with predictors of wait-list mortality are applicable only in the context of the current heart allocation in the
United States16 and may be different in countries with different
allocation policies or donor availability. Finally, our analysis is
limited to children already listed for HT and does not provide
any insight into natural history of children with CMP, selection criteria for HT listing, or outcomes in children not listed.
In conclusion, children with dilated CMP listed for HT are, on
average, sicker at the time of listing than children with nondilated
CMP. The risk of wait-list mortality is higher in children with
nondilated CMP who are supported on a ventilator at listing but
Probability of Freedom from Death/Graft Loss
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0.007
CMP indicates cardiomyopathy; ECMO, extracorporeal membrane oxygenation; BIVAD, biventricular assist device; LVAD, left ventricular assist device;
GFR, glomerular filtration rate; PAP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; PRA, panel reactive antibodies.
Data are presented as number (percent) or median (25th percentile, 75th percentile).
GFR is expressed as mL/min per 1.73 m2.
*Included imputed values.
1.00
Dilated CMP
0.80
Non-Dilated CMP
0.60
0.40
Table 4. Multivariable Model of Posttransplant Mortality/Graft Loss
Predictor
HR (95% CI)
P Value
Age <1 y
1.7 (1.1–2.7)
0.009
Nondilated CMP (ref: dilated CMP)
1.8 (1.2–2.7)
0.008
Black race/ethnicity
2.0 (1.4–2.9)
<0.001
ECMO
3.1 (1.8–5.2)
<0.001
BIVAD
1.8 (1.0–3.2)
0.06
Moderate
1.4 (0.9–2.0)
0.11
Severe
1.7 (0.9–3.1)
0.08
0.6–1.9
1.2 (0.8–1.8)
0.29
>2.0
1.6 (1.0–2.6)
0.06
Mechanical support (ref: none/LVAD)
Renal dysfunction (ref: normal)
Serum bilirubin (ref: <0.6 mg/dL)
HR indicates hazard ratio; CMP, cardiomyopathy; LVAD, left ventricular assist
device; ECMO, extracorporeal membrane oxygenation; BIVAD, biventricular
assist device.
not in those who are not supported on a ventilator. Among those
who receive HT, the risk of death or graft loss is modestly higher
in children with nondilated CMP. However, their short-term
transplant outcomes are good, and their 1-year survival of 89%
approaches the current overall posttransplant survival in children.
Acknowledgments
0.20
0.00
910
184
0
762
149
3
6
637
127
9
12
553
112
15
18
466
91
21
24
Time Since Transplant (months)
Figure 3. Posttransplant freedom from death or retransplant in
children with dilated and nondilated cardiomyopathy (CMP). The
difference in survival was not significant (P=0.17, log-rank test).
Dr Gauvreau had full access to the data in the study and takes responsibility for the integrity of the data and the accuracy of analysis.
The work was supported, in part, by Health Resources and Services
Administration contract 234-2005-370011C. The data were supplied by the United Network of Organ Sharing as the contractor for
the Organ Procurement and Transplantation Network (OPTN). The
interpretation and reporting of these data are the responsibility of the
authors and not an official policy of or interpretation by the OPTN or
the US Government.
Singh et al Current Outcomes in Pediatric Cardiomyopathy 601
Sources of Funding
This study was supported by Heart Transplant Research and Education
Fund, Department of Cardiology, Boston Children’s Hospital, MA.
Disclosures
None.
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CLINICAL PERSPECTIVE
Previous studies have reported worse outcomes in children with nondilated cardiomyopathy (CMP) listed for a heart transplant compared with children with dilated CMP. Because wait-list and posttransplant outcomes in children listed for a heart transplant have
improved in recent years, the authors sought to compare these outcomes between children with dilated and nondilated forms of CMP
in the current era. They analyzed all children <18 years of age with CMP listed for heart transplant in the United States between July
2004 and December 2010. Of 1436 children analyzed, 83% had dilated and 17% had nondilated form of CMP (167 with restrictive
CMP, 72 with hypertrophic CMP). In adjusted analysis, children with nondilated CMP were at higher risk of dying on the wait-list
(or becoming too sick to transplant) only if they were on a ventilator support at the time of listing. The risk was similar between the
groups among children not on a ventilator support. In children who received a transplant, posttransplant 1-year survival was 94% in
children with dilated CMP and 89% in children with nondilated CMP. In adjusted analysis, the risk of posttransplant graft loss was
1.8× in children with nondilated versus those with dilated cardiomyopathy. The authors conclude that the increased risk of dying on
the wait-list among children with nondilated CMP is limited to those on a ventilator support at listing. The risk of posttransplant graft
loss remains modestly higher in children with nondilated CMP. However, their short-term transplant outcomes are good.
Current Outcomes in US Children With Cardiomyopathy Listed for Heart
Transplantation
Tajinder P. Singh, Christopher S. Almond, Gary Piercey and Kimberlee Gauvreau
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Circ Heart Fail. 2012;5:594-601; originally published online August 16, 2012;
doi: 10.1161/CIRCHEARTFAILURE.112.969980
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