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KEYWORDS:
congenital heart
disease;
adults;
transplantation;
outcomes;
mortality;
morbidity;
Fontan/Glenn
BACKGROUND: Studies assessing mortality and morbidity in adult transplant recipients with congenital
heart disease (CHD) are limited. We conducted a systematic review and meta-analysis comparing posttransplant outcomes in these 2 populations.
METHODS: After conducting an electronic database search, we selected studies evaluating mortality,
cause-specic mortality, and risk of reoperation and dialysis in adult CHD vs non-CHD patients. We
used random-effects models for the meta-analysis.
RESULTS: Thirty-day mortality was signicantly higher in CHD vs non-CHD patients (risk ratio [RR],
2.18; 95% condence interval [CI], 1.622.93; I2 41%). This was inuenced by increased mortality in
Fontan/Glenn patients compared with non-CHD patients (RR, 3.3; 95% CI, 1.895.77; I2 0%).
Mortality at 1 and 5 years was higher in the CHD population, although neither achieved statistical
signicance. Ten-year mortality was signicantly lower in CHD patients (RR, 0.75; 95% CI, 0.600.95,
I2 42%). Deaths caused by malignancy, infection, rejection, and cardiac allograft vasculopathy were
decreased in CHD patients, although only death from malignancy achieved signicance. Death
secondary to primary graft failure, stroke, and hemorrhage was signicantly higher in CHD patients.
Risk of reoperation and dialysis were not statistically different between the 2 groups.
CONCLUSIONS: Although adult CHD patients have higher early mortality, post-transplantation longterm survival is superior to non-CHD recipients. The challenge is to identify the CHD patients who will
benet from transplantation vs those who are higher risk.
J Heart Lung Transplant ]]]];]:]]]]]]
r 2016 International Society for Heart and Lung Transplantation. All rights reserved.
1053-2498/$ - see front matter r 2016 International Society for Heart and Lung Transplantation. All rights reserved.
http://dx.doi.org/10.1016/j.healun.2016.06.003
Methods
Study sources
A systematic search of the MEDLINE, Embase, and CINAHL
databases ending October 2013 was performed, with additional
studies identied from references of included sources and expert
recommendations (Supplement 1, available on the jhltonline.org
Web site). Observational studies comparing post-transplant
outcomes in adult (age Z 18 years) CHD and non-CHD patients
were selected. Two independent reviewers conducted the title/
abstract and full-text assessments. Unless different clinical out
comes were evaluated, duplicate populations were excluded. For
multiple publications from an institution or registry, the study with
the greatest number of CHD patients was included for that
particular outcome. The weighted score for the full-text screen
was 0.91, indicating excellent reviewer agreement.
Data abstraction
Data abstraction was performed in duplicate (Table 1).10 The
Kaplan-Meier mortality outcomes at 30 days and at 1, 5, and 10
years post-transplantation were collected. Data tables were used
when Kaplan-Meier analysis was not performed or if the survival
curve included pediatric patients. All values were rounded to the
nearest integer. Cause-specic mortality and morbidity outcomes
during the overall study follow-up were collected. The causespecic mortality outcomes were infection, acute or chronic
rejection, malignancy, cardiac allograft vasculopathy (CAV),
primary graft failure, stroke, and hemorrhage. The morbidity
outcomes were reoperation (profuse bleeding signied by postoperative chest tube drainage requiring surgical intervention11 or
post-operative cardiac complications12) and dialysis.
Data synthesis
Results were summarized using overall risk ratio (RR) and 95%
condence interval (CI). The I2 statistic was used to analyze
heterogeneity based on the Cochrane guide: 0% to 40% may not be
important, 30% to 60% may represent moderate heterogeneity, 50% to
90% may represent substantial heterogeneity, and 75% to 100% may
represent considerable heterogeneity.13 Random-effects models were
used to conduct the meta-analysis, derived through Mantel-Haenszel
analysis. Three studies evaluated mortality using multivariable analysis
but at different times, including overlapping populations, thus preventing
the performance of a meta-analysis. These results were qualitatively
summarized. A sub-group analysis was performed dividing CHD singleventricle patients with a prior Fontan or Glenn procedure from those
who did not undergo either operation, and compared mortality with nonCHD patients using the test for sub-group interaction. A p-value of
o 0.05 was considered statistically signicant. We analyzed the data
and generated plots using Review Manager 5.3 (Cochrane).
Results
Study selection and characteristics
The search yielded 4,053 studies, with 13 studies fullling the
inclusion critieria,1112,1525 (Figure 1) all of which were
retrospective, unmatched cohort studies. Included were 9
single-center and 4 registry studies consisting of 899 CHD
and 43,452 non-CHD patients. The most frequent congenital
diagnoses were transposition of the great arteries (TGA; 22%,
including dextro-TGA and congenitally corrected TGA) and
tricuspid atresia (8%; Table 2), with comorbidities listed in
Supplement 2 (available on the jhltonline.org Web site).
Mortality
Thirty-day mortality was analyzed in 9 studies of 855 CHD and
41,722 non-CHD patients. For CHD patients, 30-day mortality
was signicantly higher (RR, 2.18; 95% CI, 1.622.93; I2
41%) at 17.4% vs 7.4% in non-CHD patients (Figure 2A).
One-year mortality was assessed in 856 CHD and 42,515
non-CHD patients in 8 studies. The mortality difference was
not signicant, being 20.6% in the CHD population vs
15.4% in the non-CHD group (RR, 1.26; 95% CI, 0.95
1.66, I2 36%; Figure 2B).
Five-year mortality was evaluated in 9 studies with
861 CHD and 42,826 non-CHD patients. The difference in
5-year mortality between the 2 populations was 30.8% in the
CHD group and 29.5% in the non-CHD population, which is
not signicant (RR, 1.05; 95% CI, 0.831.33; I2 45%;
Figure 2C).
Doumouras et al.
Table 1
Non-CHD patients
Transplant
Age
Male
period
No. (years)a (%) No.
Age
Male
(years)a (%) Outcomes
Besik, 2016;
Single center
Czech Republic
19992014 25
38
68
634
NR
NR
Bhama, 2013;
Single center
United States
20012011 19
39
63
428
55
75
Chen, 2004;
Single center
United States
19842004 39
4 18
NR
1,419
NR
NR
Coskun, 2007;
Single center
Germany
19892005 12
38
58
1,216b NR
NR
Davies, 2011;
UNOS study
United States
60c
25,497 52c
77c
Greutmann, 2009;
Single center
Switzerland
19852006 9
33
NR
309
48
86
Hsu, 2007;
Single center
Taiwan
19932005 1
39
43
83
Mortality: 30 days
Cause-specic mortality: infection,
hemorrhage
Morbidity: reoperation, dialysis
Irving, 2010;
Single center
United Kingdom
19882009 37
34
49
620e
NR
NR
Mortality: 30 days
Karamlou, 2010;
UNOS study
United States
19902008 575 28
63
7,921
35
69
19842009 55
62
3,111
NR
86
Patel, 2009;
UNOS study
United States
63
34,645 417
78
Pigula, 2001;
Single center
United States
19841999 8
35
38
753
NR
NR
NR
NR
311
50f
84f
Mortality: 5 years
Study
26
CAV, cardiac allograft vasculopathy; CHD, congenital heart disease; NR, not reported; SD, sudden death; UNOS, United Network for Organ Sharing.
a
Age is reported as a mean. If the mean is not stated, then the age restriction is listed or NR as applicable.
b
The non-CHD population is from another publication at the same institution. This was published by Minami et al10 (2005), and reported actuarial
survival rates in adults receiving heart transplantation for dilated and ischemic cardiomyopathy between 1989 and 2004.
c
These values are for patients listed for transplantation.
d
A UNOS study of the same population: Davies 2011, Karamlou 2010, and Patel 2009. The Patel 2009 study was used for the mortality outcomes because
a larger population was studied.
e
The non-CHD population was not specically evaluated in the study. However, the authors stated the 30-day mortality for non-CHD patients at their
institution during the time period and also provided the total number of heart transplants performed.
f
Values include CHD and non-CHD patients.
Figure 1
Cause-specic mortality
Mortality secondary to malignancy was assessed in 3 studies
(639 CHD and 11,341 non-CHD patients), with 1.1% mortality
in CHD vs 4.7% in non-CHD. There was a signicant 2.63times reduced risk of cancer-related mortality in CHD patients
(RR, 0.38; 95% CI, 0.180.79; I2 0%; Figure 4A).
Mortality secondary to primary graft failure was
evaluated in 2 studies (296 CHD and 17,376 non-CHD
patients). It was signicantly higher in the CHD (10.5%) vs
the non-CHD (4.7%) group (RR, 2.20; 95% CI, 1.493.23;
I2 21%; Figure 4B).
Mortality secondary to stroke was assessed in 2 studies
(252 CHD and 14,780 non-CHD patients). There was a
statistically signicant higher mortality in CHD patients
(RR, 2.29; 95% CI, 1.214.33; I2 0%) at 3.6% compared
with 1.7% in non-CHD patients (Figure 4C).
Finally, mortality secondary to hemorrhage (Days 146
post-transplant) was analyzed in 2 studies of 576 CHD and
7,927 non-CHD patients. Results showed a signicantly
higher mortality due to hemorrhage in CHD (2.8%) than in
non-CHD (1.0%) patients (RR, 2.86, 95% CI, 1.674.89;
I2 0%; Figure 4D).
Death due to infection, rejection, and CAV were all
decreased in the CHD population; however, none of these
outcomes achieved statistical signicance (Figure 4EG)
Morbidity
Reoperation and risk of dialysis were assessed in 2 studies
of 559 CHD and 25,503 non-CHD patients. Although more
CHD patients required reoperation (21.1% vs 10.5%) and
dialysis (21.5% vs 8.4%), neither outcome was statistically
signicant (Figure 5).
Doumouras et al.
Table 2
Study
Congenital diagnosis
Non-CHD cardiomyopathy
Besik, 2016
Not reported
Bhama, 2013
Single ventricle: 7 (37%), failed Fontan: 5 (26%), TGA: 5 Ischemic: 216 (51%), idiopathic: 164 (38%),
(26%), ASD/VSD: 3 (16%), tetralogy of Fallot: 1 (5%), other: 48 (11%)
other: 3 (16%)
Chen, 2004b
Not reported
Single ventricle: 65 (61%), single ventricle not
otherwise specied: 22 (21%), tricuspid atresia: 13
(12%), HLHS/Shones complex: 12 (11%), DILV: 10
(9%), pulmonary atresia/intact septum: 8 (8%),
Fontan: 29 (27%), Glenn: 8 (8%) d-TGA: 10 (9%),
tetralogy of Fallot (/ pulmonary atresia): 9 (8%),
ccTGA: 6 (6%), Ebsteins anomaly: 3 (3%), other: 13
(12%)
Coskun, 2007
Davies, 2011c
Not reported
Greutmann, 2009
Not reported
Hsu, 2007
Irving, 2010
Not reported
Single ventricle: 15 (41%) DILV: 6 (16%), tricuspid
atresia: 5 (14%), Fontan: 3 (8%), Glenn: 1 (3%)
d-TGA: 8 (22%), ccTGA: 3 (8%), tetralogy of Fallot: 2
(5%), Ebsteins anomaly: 1 (3%), other: 8 (22%)
Karamlou, 2010
Not reported
Patel, 2009
Not reported
Not reported
Pigula, 2001
ALVT, aortic-left ventricular tunnel; ASD, atrial septal defect; ccTGA, congenitally corrected transposition of the great arteries; CHD, congenital heart
disease; d-TGA, dextro-transposition of the great arteries; DILV, double inlet left ventricle; DOLV, double outlet left ventricle; DORV, double outlet right
ventricle; HLHS, hypoplastic left heart syndrome; RV, right ventricle; VSD, ventricular septal defect.
a
Values are expressed as the total number with the percentage in parentheses.
b
The study reports the diagnoses for both the adult and pediatric population.
c
The study reports the cardiomyopathies for patients listed for transplant.
Figure 2
Mortality outcomes in congenital heart disease (CHD) transplant recipients vs non-CHD transplant recipients at (A) 30 days,
(B) 1 year, (C) 5 years, and (D) 10 years after transplantation. The solid squares indicate the mean difference and are proportional to the
weights used in the meta-analysis. The solid vertical line indicates no effect. The horizontal lines represent the 95% condence interval (CI).
The diamond indicates the weighted mean difference, and the lateral tips of the diamond indicate the associated CI. M-H, Mantel-Haenszel.
Doumouras et al.
Figure 3
Subgroup analysis of mortality outcomes in single-ventricle transplant recipients with and without Fontan/Glenn at (A) 30 days,
(B) 1 year, (C) 5 years, and (D) 10 years. Paniagua Martin et al22 included mortality outcomes for the following single ventricle patients:
(1) single-ventricle with different degrees of pulmonary stenosis (non-Fontan/non-Glenn), and (2) single-ventricle with tricuspid atresia with
Fontan/Glenn, The study also included congenital heart disease (CHD) patients with different degrees of right ventricle overload, including
double-outlet right ventricle (DORV). How many patients in this group had a diagnosis of DORV is unclear. These patients are not included
in this analysis. The solid squares indicate the mean difference and are proportional to the weights used in the meta-analysis. The solid
vertical line indicates no effect. The horizontal lines represent the 95% condence interval (CI). The diamond indicates the weighted mean
difference, and the lateral tips of the diamond indicate the associated CI. M-H, Mantel-Haenszel.
Figure 4
Cause-specic mortality secondary to (A) malignancy, (B) primary graft failure, (C) stroke, (D) hemorrhage, (E) infection,
(F) rejection (acute and chronic), and (G) cardiac allograft vasculopathy in transplant recipients with and without congenital heart disease
(CHD). The solid squares indicate the mean difference and are proportional to the weights used in the meta-analysis. The solid vertical line
indicates no effect. The horizontal lines represent the 95% condence interval (CI). The diamond indicates the weighted mean difference, and
the lateral tips of the diamond indicate the associated CI. M-H: Mantel-Haenszel.
Doumouras et al.
Figure 5
Morbidity outcomes in transplant recipients with and without congenital heart disease (CHD). (A) Reoperation requirement
after transplantation and (B) dialysis requirement. The solid squares indicate the mean difference and are proportional to the weights used in
the meta-analysis. The solid vertical line indicates no effect. The horizontal lines represent the 95% condence interval (CI). The diamond
indicates the weighted mean difference, and the lateral tips of the diamond indicate the associated CI. M-H: Mantel-Haenszel.
criteria14 and assessed via funnel plots. This was done for
the mortality outcomes (Supplement 5, available on the
jhltonline.org Web site) because the others consisted of a
small number of studies. Lastly, based on an RR value of
4 2 or o 0.5, 6 outcomes were upgraded for large effect.
The quality of evidence for each outcome was deemed low
or very low (Supplement 6, available on the jhltonline.org
Web site).
Discussion
This meta-analysis found that despite increased early
mortality after heart transplant, adult CHD patients have
improved long-term survival compared with non-CHD
recipients. The early increased mortality risk was observed
in Fontan/Glenn-CHD patients, with non-Fontan/non-Glenn
single-ventricle patients having outcomes similar to those of
non-CHD transplant recipients. In studies that performed
multivariable analysis taking into account time post-transplantation, CHD was an independent risk factor for early
death although associated with improved long-term survival. However, these studies did not adjust by type of CHD or
procedural history. In the ISHLT 2015 registry, 1-year
survival post-transplant was signicantly lower in CHD
patients (77%) vs patients with a pre-transplant diagnosis of
cardiomyopathy (83%) or coronary artery disease (CAD)
(81%).26 The median survival was 14.6 years for CHD
patients, 11.6 years for cardiomyopathy patients, and
9.4 years for CAD patients. Long-term median survival
conditional on survival to 1 year post-transplant was higher
in CHD patients (20.2 years) than in other cardiomyopathy
(14.1 years) and CAD (11.7 years) patients.26
In this meta-analysis, the Fontan/Glenn population
represented a high-risk population, with increased early
post-transplant mortality. In a combined adult and pediatric
registry study, prior Fontan operation was a risk factor
for early death.27 Although small in number, patients who
die early after transplant are often those with a prior
Fontan.17,22,28 Owing to the manner in which the studies
10
Disclosure statement
None of the authors has a nancial relationship with a commercial
entity that has an interest in the subject of the presented manuscript
or other conicts of interest to disclose.
The authors thank Ani Orchanian-Cheff, Information Specialist,
who completed the database literature search.
Supplementary material
Supplementary data are available in the online version of
this article at www.jhltonline.org.
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