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The Registry of the International Society for Heart and Lung Transplantation: Thirteenth official pediatric heart transplantation report—2010
http://www.jhltonline.org
The Registry of the International Society for Heart and Lung Transplantation: Thirteenth official pediatric heart transplantation report—2010 Richard Kirk, MA, FRCP, FRCPCH, Leah B. Edwards, PhD, Anna Y. Kucheryavaya, MS, Paul Aurora, PhD, MRCP, Jason D. Christie, MD, MS, Fabienne Dobbels, PhD, Axel O. Rahmel, MD, Josef Stehlik, MD, MPH, Marshall I. Hertz, MD From The ISHLT Transplant Registry, Dallas, Texas. The first pediatric heart transplantation reported to the International Society for Heart and Lung Transplantation (ISHLT) Registry was in 1982; since then, more than 8,500 pediatric heart transplants (recipient age ⬍18 years) have been reported. Many of these recipients have survived into adult life and some have had their own children. This 13th report continues to document the evolving management of pediatric transplant recipients and their outcomes.
analyses were performed using Cox proportional hazard regression analysis. Results of the multivariable analyses are reported as relative risks (RR) with 95% confidence intervals or a corresponding p-value, or both. Factors with a RR significantly ⬎1 indicate that the factor is associated with an increased likelihood of the event (eg, mortality, development of coronary allograft vasculopathy, etc) occurring. Conversely, a RR ⬍1 indicates that the event is less likely to occur when that factor is present.
Registry data source ISHLT Registry data are provided either by individual centers or by a data-sharing arrangement with a national or regional organ procurement organization or organ exchange organization. Approximately 450 pediatric (recipient age ⬍18 years) heart transplants are reported to the Registry each year. The Registry Committee continues to actively seek participation from all centers performing pediatric heart transplants. The tables and figures in this report and additional slides are all available from the ISHLT Web site (http://www.ishlt.org/registries/). Contributing centers are recognized in the Introduction to the Annual Reports.
Statistical methods Survival rates were calculated using the Kaplan-Meier method and compared using the log rank test. Multivariable Reprint requests: Marshall I. Hertz, MD, University of Minnesota, Pulmonary/Critical Care Medicine, 301 E River Rd, 350G VCRC, Minneapolis, MN 55455. Telephone: 612-624-5481. Fax: 612-625-2174. E-mail address: [email protected]
Centers and activity Heart transplants only account for approximately 16% of pediatric solid organ transplants.1 In the Registry, 80% pediatric thoracic transplants are heart transplants. In 2008 (the last complete year analyzed), 491 transplants were reported—most ever reported to the Registry. There continues to be a small trend towards an increasing number of transplants reported, although it is not clear whether this is due to an increase in the number of transplants performed worldwide or just an increased level of reporting by centers participating in the Registry. During the 1990s the annual average was 384 transplants compared with 428 through the 2000s. In total, 8,575 pediatric heart transplants have been reported to the Registry (Figure 1). Since January 2000, North America has contributed 77%, Europe reported 21%, and the rest of the world contributed 3% of reported pediatric transplants. A total of 883 centers reported transplant activity in 2008, of these 57% were in North America, 35% were in Europe, and 8% were elsewhere. During the last 8 years, 46% of transplants were undertaken in centers performing
1053-2498/$ -see front matter © 2010 International Society for Heart and Lung Transplantation. All rights reserved. doi:10.1016/j.healun.2010.08.009
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Number of Transplants
500 450
11-17 Years
400
1-10 Years
350
<1 Year
300 250 200 150 100 50
07 08 20
06
20
05
20
04
20
03
20
02
20
01
20
00
20
99
20
98
19
97
19
96
19
95
19
94
19
93
19
92
19
91
19
90
19
89
19
88
19
87
19
86
19
85
19
84
19
83
19
19
19
82
0
NOTE: This figure includes only the heart transplants that are reported to the ISHLT Transplant Registry. As such, this should not be construed as evidence that the number of hearts transplanted worldwide has increased and/or decreased in recent years.
Figure 1
Age distribution of heart recipients by year of transplant.
10 or more transplants per annum; however, 30% were undertaken in centers transplanting fewer than 5 per annum. Small center volumes were associated with somewhat poorer average outcomes. There was no effect on overall 1-year survival, but there was a detrimental effect on 1-year survival in children aged younger than 1 year. Those infants who received an allograft at centers undertaking fewer than 5 transplants per year had a RR of 1.13, compared with a RR of 1.0 for those undertaking 10 and a RR of 0.78 for those undertaking 20 transplants a year. Higher center transplant volume was associated with better 10-year survival (Figure 2) and low center volume with increased risk of early (within 5 years) cardiac allograft vasculopathy (CAV, Figure 3).
Recipient and donor characteristics
Patient survival The median survival (the time at which 50% of recipients remain alive) varied with the age of the recipient at transplant: median survival was 18.3 years for those who received a transplant during infancy and was 11.3 years for adolescents. The highest risk of dying was during the first year after transplant (Figure 6). If those who died within 1 year of transplant were excluded, the median conditional survival was 21.4 years for those who underwent transplantation in the first year of life, 19.3 years for those aged
Relative Risk of CAV within 5 Years
Relative Risk of 10 Year Mortality
The commonest indication for transplant during infancy was congenital heart disease (63%), followed by cardiomyopathy (31%). The reverse was true in older patients, and cardiomyopathy predominated (64%) over congenital heart disease (24%). There was a trend across the age groups, although more pronounced in infants (Figure 4), for con-
genital heart disease to become less common over time as a proportion of all transplants. Retransplantation was more common in the older age group and more frequent in the more recent era (Figure 5). Geographic differences exist between North America and Europe. In North America, for example, more transplants were undertaken during infancy and congenital heart disease was a far more common indication in infants. For details on this topic, please refer to the ISHLT Registry online slides (http://www.ishlt.org/ registries/).
2
1.5
1
0.5 p = 0.084
2
1.5
1
0.5 p = 0.0026 0 0
0 0
2
4
6
8
10
12
14
16
18
20
Center Volume (cases per year)
Figure 2 Center volume as a risk factor for 10-year mortality for transplants performed January 1995–June 1997. The dotted line represents the 95% confidence interval.
5
10
15
20
25
30
35
40
Center Volume (cases per year)
Figure 3 Center volume as a risk factor for the development of cardiac allograft vasculopathy (CAV) within 5 years, for transplants performed July 1997–June 2004. The dotted line represents the 95% confidence interval.
2010 Pediatric Heart Transplant Registry Report
1121 33%
Myopathy
17%
Congenital
0%
1% Other
2%
3%
80% ReTX
63% 1/1996-6/2009
100 75 50
Myopathy
Congenital
25 0
19 86 19 87 19 88 19 89 19 90 19 91 19 92 19 93 19 94 19 95 19 96 19 97 19 98 19 99 20 00 20 01 20 02 20 03 20 04 20 05 20 06 20 07 20 08 20 09
% of Cases
1988-1995
Figure 4
Infant heart recipient diagnosis according to year of transplant. Re-TX, retransplant.
Myopathy
25%
27% Congenital 68%
Other
65%
3%
3%
8%
ReTX
2%
1/1996-6/2009
100
Myopathy
Congenital
75 50 25 0 19 86 19 87 19 88 19 89 19 90 19 91 19 92 19 93 19 94 19 95 19 96 19 97 19 98 19 99 20 00 20 01 20 02 20 03 20 04 20 05 20 06 20 07 20 08 20 09
% of Cases
1988-1995
Figure 5
Diagnosis of heart recipients aged 11 to 17 years according to year of transplant. Re-TX, retransplant.
100 90
<1 Year (N = 2,049)
1-10 Years (N = 2,929)
11-17 Years (N = 3,027)
Overall (N = 8,005)
80
Survival (%)
Kirk et al.
70 60 0-<1 vs. 1-10: p < 0.0001; 0-<1 vs. 11-17: p=0.3284; 1-10 vs. 11-17: p=0.0003.
50 40 30 20
Half-life <1: 18.3 Years; 1-10: 15.5 Years; 11-17: 11.3 Years
10 0 0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20
Years
Figure 6
Survival analysis for transplants performed January 1982–June 2008.
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The Journal of Heart and Lung Transplantation, Vol 29, No 10, October 2010 100 Half-life: <1: 21.4; 1-10: 19.3 Years; 11-17: 15.2 Years
Survival (%)
90 80 70 0-<1 vs. 1-10: p = 0.0138; 0-<1 vs. 11-17: p < 0.0001; 1-10 vs. 11-17: p < 0.0001.
60 50 40
<1 Year (N = 1,422) 11-17 Years (N =2,399)
1-10 Years (N = 2,272) Overall (N = 6,093)
30 0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20
Years
Figure 7
Survival analysis for transplants performed January 1982–June 2008 and surviving to 1 year after transplant.
100
Survival (%)
80
1982-1989 (N=846)
1990-1994 (N=1,803)
1995-1999 (N=1,846)
2000-6/2008 (N=3,510)
Half-life 1982-1989: 9.5 years; 1990-1994: 11.7 years; 19951999: 14.3; 2000-6/2008: n.c.
60
40
20 All p-values significant at p = 0.01
0 0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20
Years
Figure 8
Percentage of Deaths
40
Survival analysis by era for transplants performed January 1982–June 2008.
CAV
Acute Rejection
Primary Failure
Graft Failure
Infection (non-CMV)
30
20
10
0 0-30 Days (N 31 Days – 1 = 226) Year (N = 266)
>1 Year – 3 Years (N = 173)
>3 Years – 5 >5 Years – 10 >10 Years (N Years (N = Years (N = = 190) 173) 306 )
Figure 9 Relative incidence of leading causes of death for deaths occurring January 1998 –June 2009. CAV, coronary artery vasculopathy; CMV, cytomegalovirus.
Kirk et al. Table 1
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Risk Factors for Mortality Within 1 Year for Transplants Performed January 1996 through June 2008 (N ⫽ 3,838)
Variable Congenital diagnosis Age ⫽ 0, on ECMO Age ⬎ 0 Retransplant Year of transplant 1996–1997 vs 2002–2003 1998–1999 vs. 2002–2003 On dialysis On ventilator Panel reactive antibody ⬎10% Donor cause of death Cerebrovascular/stroke vs head trauma Anoxia vs head trauma Donor/recipient variable Male/female vs male/male Diagnosis other than congenital, no ECMO, age ⫽ 0 Infection requiring IV drug therapy ⱕ2 wks pre-Tx Transfusions before transplant Recipient age Recipient height Donor age Ischemia time Creatinine
No.
RR
95% CI
p-value
81 921 230
2.86 2.02 1.96
1.99–4.09 1.60–2.56 1.33–2.89
⬍0.0001 ⬍0.0001 0.0007
523 509 83 717 349
1.68 1.49 1.66 1.54 1.36
1.22–2.32 1.08–2.07 1.08–2.55 1.23–1.94 1.04–1.79
0.0013 0.0166 0.0217 0.0002 0.0263
387 898
1.35 0.81
1.01–1.81 0.65–1.01
0.0401 0.065
971 290 584 1,159 ... ... ... ... ...
1.24 0.47 1.24 1.23 ... ... ... ... ...
1.01–1.51 0.31–0.72 0.98–1.56 1.00–1.52 ... ... ... ... ...
0.0404 0.0005 0.0735 0.0525 0.0024 ⬍0.0001 0.0270 0.0075 0.0040
CI, Confidence interval; ECMO, extracorporeal membrane oxygenation; RR, relative risk; Tx, transplant. Note: Reference diagnosis ⫽ cardiomyopathy.
between 1 and 10 years, and 15.2 years for older children (Figure 7). Survival was also shown to be improving in relation to era of transplantation (Figure 8), with the median survival increased from 9.5 years for the period 1982 to 1989, to 11.7 years for the period 1990 to 1994, to 14.3 years for the period 1995 to 1999 (the median survival was not calculable for more recent eras, as the 50% survival rate had not been reached). The improvements in 1-year survival were more marked for infants (63% vs 70%) and children (68% vs. 85%), than in adolescents (76% vs 90%). Likewise 10-year outcomes showed an absolute 15% (51% vs 66%) improvement for infants and 13% (49% vs 62%) for children, but only 2% (49% vs 51%) for adolescents.
Causes of death Figure 9 shows the causes of death over time after transplant. Nearly half of all deaths in the first 30 days after transplant were due to graft failure— either primary or secondary to rejection or technical factors. Acute rejection remained an ever-present threat, peaking at 20% during the first year and then declining. CAV and graft failure were tracked separately in the Registry; however, reporting centers may not distinguish so precisely, and the same clinical condition may therefore be placed in either category. Infection and CAV/graft failure mirrored each other, with the risk
of infection leading to death declining rapidly after the first year with a corresponding increase in the number of deaths from CAV/graft failure, which had an incidence of approximately 60% after 3 years post-transplant and was the leading cause of death.
Table 2 Risk Factors not Significant for Mortality Within 10 Years for Transplants Performed January 1995 through June 1998 (N ⫽ 910) Recipient factors Panel reactive antibody Diabetes Repeat transplant Transfusions Hospitalized Prostaglandin E1 Ventricular assist device Bilirubin Donor factors Cause of death Weight Height Age Clinical infection Transplant factors Ischemia time Cytomegalovirus mismatch
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The Journal of Heart and Lung Transplantation, Vol 29, No 10, October 2010 Risk Factors for Mortality Within 10 Years for Transplants Performed January 1995 through June 1998 (N ⫽ 910)
Variable Donor/recipient variables Male/female vs male/male Female/male vs male/male Female/female vs male/male HLA A locus MM (increasing MM vs 0 MM), No. 0 DR MM 1 DR MM 2 DR MM Diagnosis ⫽ cardiomyopathy, age ⫽ 0 yearsa Infection requiring IV drug therapy ⱕ2 weeks pre-Txb Donor age Recipient body surface area Creatinine Pediatric transplant volumeb
No.
RR
95% CI
p-value
372 386 154
1.41 1.40 0.62 1.25 ... ... ... 0.44 1.33 ... ... ... ...
1.05–1.90 1.05–1.86 0.40–0.97 1.04–1.51 ... ... ... 0.23–0.85 0.96–1.83 ... ... ... ...
0.0239 0.0201 0.0378 0.0198 ... ... ... 0.0141 0.0870 ⬍0.0001 0.0045 0.0110 0.0840
57 306 547 58 103 ... ... ... ...
CI, confidence interval; DR, D receptor; HLA, human leukocyte antigen; MM, mismatch; RR, relative risk; Tx, transplant. Reference diagnosis ⫽ cardiomyopathy. a Impact should be considered in context of donor age and recipient body surface area. b Borderline significance.
Risk factors for 1-year recipient mortality Risk factors predictive of 1-year mortality are listed in Table 1. In general, these risk factors were predictable, with those requiring the most pre-transplant support (eg, ventilation) having the greatest risk of dying. Similarly, factors reflecting recipient illness, such as pre-transplant creatinine, influenced the 1-year survival. Some factors were less intuitive; for example, grafts from donors who died of a cerebrovascular accident carried a RR of 1.24 compared with those who died after head trauma, whereas death from anoxia conferred a RR of 0.81 compared with head trauma. The differences related to donor cause of death may be explained by the severity of the adrenergic storm causing graft damage before implantation in those with a cerebrovascular accident, which may be less marked in trauma victims and even less in those with anoxia. Other differences in donor characteristics2 may also be involved. Although donor sex per se had no effect on survival, donor/recipient sex mismatches (eg, female donor into male recipient) appeared to have worse outcomes; the mechanism for this relationship remains unclear.3 Transplant factors that
had no influence included previous sternotomy, cytomegalovirus mismatch, and human leukocyte antigen (HLA) mismatch (the complete list can be found on the ISHLT Registry online slides at http://www.ishlt.org/registries/). Infants comprised 24% of pediatric cardiac transplant recipients. Risk factors for 1-year mortality in this group were similar to the overall group, but those on extracorporeal membrane oxygenation had a very high RR of 3.25 for those with an underlying diagnosis of congenital heart disease and an RR of 2.6 for those with cardiomyopathy. Those with an abnormally high creatinine also fared badly, with a serum creatinine of 0.9 mg/dl (80 mmol/liter) having a RR of 1.5. A shorter ischemic time (2 hours) reduced the risk of dying (RR, 0.68) compared with an ischemic time of 4 hours (RR, 1.0).
Risk factors for 5-year recipient mortality Recipient mortality remained similar to that reported last year.4 The updated data can be found on the ISHLT Registry online slides (http://www.ishlt.org/registries/).
100%
80%
60%
40%
20%
No Hospitalization
Hospitalized, Not Rejection/Not Infection
Hospitalized, Rejection
Hospitalized, Infection Only
Hospitalized, Rejection + Infection
0% 1 Year (N = 3,783)
Figure 10
5 Years (N =2,366)
10 Years (N = 958)
Rehospitalization of surviving recipients, for follow-ups April 1994 –June 2009.
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2010 Pediatric Heart Transplant Registry Report
1125
100
Survival (%)
90 Free from Rejection: CyA vs. TAC p = 0.0338 Rejection: CyA vs. TAC p = 0.1014 CyA: Rejection vs. no rejection p = 0.1693 TAC: Rejection vs. no rejection p = 0.3492
80
70 CyA: Free from Rejection during 1st Year (N = 41) CyA: Treated Rejection within 1st Year (N =32) TAC: Free from Rejection during 1st Year (N = 126) TAC: Treated Rejection within 1st Year (N = 67)
60
50 0
1
2
3
4
Years Treated rejection = Recipient was reported to (1) have at least one acute rejection episode that was treated with an anti-rejection agent; or (2) have been hospitalized for rejection. No rejection = Recipient had (i) no acute rejection episodes and (ii) was reported either as not hospitalized for rejection or did not receive anti-rejection agents.
Figure 11 Survival analysis for recipients aged 11 to 17 years based on treated rejection within 1 year of transplant, stratified by calcineurin use at discharge, and conditional on survival to 1 year (based on transplant with 1 year follow-ups submitted July 2004 –June 2008). CyA, cyclosporine A; Tac, tacrolimus.
Risk factors for 10-year recipient mortality
Rejection
Many of the factors associated with 1-year mortality did not influence 10-year mortality (Tables 2 and 3). A pre-transplant creatinine of 0.2 mg/dl (18 mmol/liter) or less conferred a RR of 0.2 compared with a creatinine of 1.34 mg/dl (141 mmol/liter) or more (RR, 1.6). However, as always, caution must be applied to interpreting this data. Older recipients (known to be associated with worse outcomes) will have higher pre-transplant creatinine levels than younger recipients due to increased muscle mass. A better indicator would be glomerular filtration rate, but even this varies with age. Factors not associated with outcomes include degree of sensitization as judged by panel reactive antibody, retransplantation, mechanical support with a ventricular assist device, donor cause of death, or ischemia time.
Rejection during the first year after transplant appeared not to affect short- to medium-term survival for the cohort as a whole. Rejection occurring in those on tacrolimus-based regimens in the teenaged years fared worse than those who did not reject (Figure 11), although this was not statistically significant. The percentage of patients who experienced acute rejection between discharge and the 1-year follow-up was not significantly different between those who had received induction therapy and those who had not.
Cardiac allograft vasculopathy Overall, 66% of patients were still free of cardiac allograft vasculopathy (CAV) 10 years after transplant (Figure 12). Age at the time of transplant influenced the development of CAV—freedom from CAV was 73% for infants and 73% for children aged 1 to 10 years compared with 53% for those aged older than 11 years who received a transplant. The
Transplant morbidity 100
% Freedom from CAV
Functional status was available for 561 patients who survived at least 10 years after transplant. Although the Registry measures of functional status are imperfect, they indicate that 93% had no limitations on physical activity and only 1% required total assistance. There was no significant difference between age groups, and the functional status of patients remained constant over time. Rehospitalization (Figure 10) in the first year after transplant was significant, with half the patients requiring readmission (36% for infection, 24% for rejection, 15% for both infection and rejection, 25% for other reasons). By their tenth year, hospitalization was much less frequent, with just under 25% hospitalized (35% for infection, 15% for rejection, 5% for both infection and rejection, 45% for other reasons).
90
80
70
60
50 0
1
2
3
4
5
6
7
8
9
10
Years
Figure 12 Freedom from coronary artery vasculopathy for follow-ups April 1994 –June 2009. CAV, coronary artery vasculopathy.
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Table 4 Risk Factors for the Development of Cardiac Allograft Vasculopathy Within 5 Years for Transplants Performed July 1997 through June 2004 (N ⫽ 1,470) Variable
No.
RR
95% CI
p-value
96 24 171 595 233 ... ...
2.13 2.03 1.45 1.36 0.61 ... ...
1.29–3.53 0.87–4.72 0.96–2.21 0.96–1.91 0.35–1.04 ... ...
0.0033 0.0999 0.0807 0.0797 0.0716 ⬍0.0001 0.0026
a
Diagnosis variables Retransplant Other than cardiomyopathy, congenital, or retransplantb Panel reactive antibody ⬎ 10%a Congenitala No steroids for discharge maintenance immunosuppressionb Donor height Total transplant volume CI, confidence interval; RR, relative risk. a Reference diagnosis ⫽ cardiomyopathy. b Borderline significance.
early development of CAV (within 5 years of transplant) was associated with retransplantation (RR, 2.13, 95% CI, 1.29 –3.53, p ⫽ 0.003), HLA sensitization, and congenital diagnosis. A steroid-free regimen reduced the likelihood that early CAV would develop (Table 4). Rejection within the first year did not increase the likelihood that CAV would develop within 3 years. Once CAV occurred, the expected 4-year graft survival was 45% to 50%.
Renal dysfunction Kaplan-Meier analysis of severe renal dysfunction, defined as a serum creatinine ⬎2.5 mg/dl (221 mol/liter), showed a linear increase after transplantation, occurring in 10% of recipients at 10 years after transplant. Five percent of patients required renal replacement therapy in the form of dialysis or renal transplant by 10 years after transplant. The type of calcineurin inhibitor selected had no demonstrable influence on late renal function.
Immunosuppression Induction Induction therapy is designed to reduce the incidence of early rejection and allow a delay, if necessary, of the introduction of maintenance immunosuppression. There continued to be a trend towards the use of induction therapy, and in 2009, more than 70% of patients received induction therapy: 66% received polyclonal anti-lymphocyte antibody, and 33% received an interleukin-2 receptor antagonist (Figure 17). There was no significant difference in survival between the induction groups or between induction vs no induction. This was despite a slight increase in rejection episodes (37% compared with 32%) in the group treated with interleukin-2 receptor antagonist group compared with those treated with polyclonal anti-lymphocyte antibody and those who received no induction therapy at all. Last year’s analysis4 demonstrated that induction therapy did not increase the risk of CMV disease or post-transplant lymphoproliferative disease.
Malignancy A malignancy developed in 2% patients in the first year after transplant, with at least 1 cancer developing in 12% by 12 years (Figure 13). Almost all malignancies were lymphomas. The use of induction therapy did not increase the risk of lymphoma.
Maintenance Most immunosuppressive regimens included a combination of a calcineurin inhibitor and cell-cycle inhibitor, and a
Retransplantation Retransplants now account for 5% of transplant operations (Figure 14). The interval between the initial transplant and the retransplant operation was quite variable (Figure 15), and survival was decreased when the inter-transplant interval was less than 3 years (Figure 16). Retransplantation had increased risks for mortality both at 1 year (RR, 1.96; Table 1) and 5 years (RR, 1.48) but not at 10 years (Table 2).
% Freedom from Malignancy
100
95
90
85 All malignancy
Lymph
Skin
Other
80 0
1
2
3
4
5
6
7
8
9
10
11
12
Years
Figure 13 Freedom from malignancy for follow-ups April 1994 –June 2009.
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2010 Pediatric Heart Transplant Registry Report
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40
Number of transplants
35 30 25 20 15 10 5
20 08
20 07
20 06
20 05
20 04
20 03
20 02
20 01
20 00
19 99
19 98
19 97
19 96
19 95
19 94
0
Year of re-transplant Only patients who were less than 18 years old at the time of re-transplant are included.
Figure 14
Retransplants according to retransplant year.
significant number of patients also received corticosteroids. At the 1-year follow-up, slightly more than 33% of patients received cyclosporine and 66% received tacrolimus. Cellcycle inhibitors were used by 86% of patients, including 22% azathioprine, 66% mycophenolate mofetil (MMF), and
50
% of Re-Transplants
0-10 Years
11-17 Years
40
30
20
10
0 <1 month
1-<12 months
12-<36 months
36-<60 months
60+ months Not reported
Time Between Previous and Current Transplant Only patients who were less than 18 years old at the time of re-transplant are included. Analysis is based on the age at the time of re-transplant
Figure 15 Retransplants according to intertransplant interval for retransplants performed January 1994 –June 2009. <1 Year (N=48)
1-<3 Years (N=34)
5+ Years (N=145)
Primary TX (N=5,417)
3-<5 Years (N=48)
70
2001 2002 2003 2004 2005 2006 2007 2008 2009
60
100
% of Patients
Comparison of survival for re-transplant groups: p = 0.0019
90
Surrvival (%)
2% on both azathioprine and MMF. Sixty-six percent received prednisone and 9% received a mammalian target of rapamycin (mTOR) inhibitor. A cohort of 789 patients was tracked from 1 to 5 years after transplant to see how their immunosuppression regimens changed (Figure 18). Overall, the proportion of patients on cyclosporine-based regimens decreased from 46% to 30%, whereas the proportion on tacrolimus-based regimens rose from 50% to 63%. Most of those changing from cyclosporine regimens changed to tacrolimus regimens, with the remainder going onto other combinations of therapy. The proportion receiving cyclosporine and a cell-cycle inhibitor halved during the 5 years, whereas those receiving a combination of tacrolimus and a cell-cycle inhibitor did not change significantly. Only a very few patients were reported to receive no immunosuppression (3 in Year 1 and 8 in Year 5). The use of tacrolimus compared with cyclosporine appeared to reduce the incidence of rejection between hospital discharge and 1 year after transplantation (Figure 19), but conferred no overall survival advantage. In conclusion, this Registry report continues to document the outcomes of pediatric heart transplant recipients. It is a
80 70
50 40 30 20
60
10
50
0 Any Induction
40 0
1
2
3
4
5
Time (years) since most recent transplant Only patients who were less than 18 years old at the time of re-transplant are included.
Figure 16 Survival rates for retransplants, stratified by intertransplant interval, for retransplants performed January 1994 –June 2008.
Polyclonal ALG/ATG
IL2R-antagonist
Test of increasing trend over time: Any induction p < 0.0001 Polyclonal p < 0.0001 IL2 p < 0.0001
Analysis is limited to patients who were alive at the time of the follow-up
Figure 17 Induction immunosuppression for transplants performed January 2001–June 2009. ALG, anti-lymphocyte globulin; ATG, anti-thymocyte globulin; IL-2R, interleukin-2 receptor.
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The Journal of Heart and Lung Transplantation, Vol 29, No 10, October 2010 100% None
% of Patients
80%
Other Tacrolimus
60% Tacrolimus + MMF Tacrolimus + AZA
40%
Cyclosporine Cyclosporine + MMF
20%
Cyclosporine + AZA
0% Year 1 (N = 789)
Year 5 (N = 789) Analysis is limited to patients who were alive at the time of the follow-up
% experiencing acute rejection within 1 year
Figure 18 Maintenance immunosuppression at time of follow-up, for January 2001–June 2009 follow-ups. AZA, azathioprine; MMF, mycophenolate mofetil.
70 60
CyA + No induction, Treatment CyA + Induction (no OKT3), Treatment TAC + No induction, Treatment TAC + Induction (no OKT3), Treatment
CyA + No induction, No Treatment CyA + Induction (no OKT3), No Treatment TAC + No induction, No Treatment TAC + Induction (no OKT3), No Treatment
50 40 30 20 10 0 Overall
<1
1-10
10-17
Overall: all comparisons were statistically significant at 0.05 except CyA + no induction vs. CyA + induction and TAC + no induction vs. TAC + induction <1 year: CyA + no induction vs. TAC + no induction ( p=0.0268); 1-10 years: all comparisons were statistically significant at 0.05 except CyA + no induction vs. CyA + induction and TAC + no induction vs. TAC + induction 11-17 years: CyA + no induction vs. TAC + no induction (p = 0.0005); CyA + induction vs. TAC + no induction (p < 0.0001); CyA + induction vs. TAC + induction ( p =0.0025) Analysis is limited to patients who were alive at the time of the follow-up
Treated rejection = Recipient was reported to (1) have at least one acute rejection episode that was treated with an anti-rejection agent; or (2) have been hospitalized for rejection. No rejection = Recipient had (i) no acute rejection episodes and (ii) was reported either as not hospitalized for rejection or did not receive anti-rejection agents.
Figure 19 Percentage of recipients experiencing acute rejection between transplant discharge and 1-year follow-up, stratified by maintenance immunosuppression and induction for July 2004 –June 2009 follow-ups.
registry report and not a double-blind randomized trial of treatment options and outcomes. The information is therefore imperfect; nonetheless, it is a wonderful resource recording management and outcomes in pediatric cardiac transplantation over time.
Disclosure statement All relevant disclosures for the Registry Director, Executive Committee members and authors are on file with ISHLT and can be made available for review by contacting the Executive Director of ISHLT.
References 1. Organ Procurement and Transplantation Network. http://optn.transplant. hrsa.gov/latestData/viewDataReports.asp. 2. Ganesh JS, Rogers CA, Banner NR, et al. Donor cause of death and medium-term survival after heart transplantation: a United Kingdom national study. J Thorac Cardiovasc Surg 2005;129:1153-9. 3. Weiss ES, Allen JG, Patel ND, et al. The impact of donor-recipient sex matching on survival after orthotopic heart transplantation analysis of 18 000 transplants in the modern era. Circ Heart Fail 2009; 2:401-8. 4. Kirk R, Edwards LB, Aurora P, et al. Registry of the International Society for Heart and Lung Transplantation: twelfth official pediatric heart transplantation report—2009. J Heart Lung Transplant 2009;28: 993-1006.
The Registry of the International Society for Heart and Lung Transplantation: Thirteenth official pediatric heart transplantation report—2010 Richard Kirk, MA, FRCP, FRCPCH, Leah B. Edwards, PhD, Anna Y. Kucheryavaya, MS, Paul Aurora, PhD, MRCP, Jason D. Christie, MD, MS, Fabienne Dobbels, PhD, Axel O. Rahmel, MD, Josef Stehlik, MD, MPH, Marshall I. Hertz, MD From The ISHLT Transplant Registry, Dallas, Texas. The first pediatric heart transplantation reported to the International Society for Heart and Lung Transplantation (ISHLT) Registry was in 1982; since then, more than 8,500 pediatric heart transplants (recipient age ⬍18 years) have been reported. Many of these recipients have survived into adult life and some have had their own children. This 13th report continues to document the evolving management of pediatric transplant recipients and their outcomes.
analyses were performed using Cox proportional hazard regression analysis. Results of the multivariable analyses are reported as relative risks (RR) with 95% confidence intervals or a corresponding p-value, or both. Factors with a RR significantly ⬎1 indicate that the factor is associated with an increased likelihood of the event (eg, mortality, development of coronary allograft vasculopathy, etc) occurring. Conversely, a RR ⬍1 indicates that the event is less likely to occur when that factor is present.
Registry data source ISHLT Registry data are provided either by individual centers or by a data-sharing arrangement with a national or regional organ procurement organization or organ exchange organization. Approximately 450 pediatric (recipient age ⬍18 years) heart transplants are reported to the Registry each year. The Registry Committee continues to actively seek participation from all centers performing pediatric heart transplants. The tables and figures in this report and additional slides are all available from the ISHLT Web site (http://www.ishlt.org/registries/). Contributing centers are recognized in the Introduction to the Annual Reports.
Statistical methods Survival rates were calculated using the Kaplan-Meier method and compared using the log rank test. Multivariable Reprint requests: Marshall I. Hertz, MD, University of Minnesota, Pulmonary/Critical Care Medicine, 301 E River Rd, 350G VCRC, Minneapolis, MN 55455. Telephone: 612-624-5481. Fax: 612-625-2174. E-mail address: [email protected]
Centers and activity Heart transplants only account for approximately 16% of pediatric solid organ transplants.1 In the Registry, 80% pediatric thoracic transplants are heart transplants. In 2008 (the last complete year analyzed), 491 transplants were reported—most ever reported to the Registry. There continues to be a small trend towards an increasing number of transplants reported, although it is not clear whether this is due to an increase in the number of transplants performed worldwide or just an increased level of reporting by centers participating in the Registry. During the 1990s the annual average was 384 transplants compared with 428 through the 2000s. In total, 8,575 pediatric heart transplants have been reported to the Registry (Figure 1). Since January 2000, North America has contributed 77%, Europe reported 21%, and the rest of the world contributed 3% of reported pediatric transplants. A total of 883 centers reported transplant activity in 2008, of these 57% were in North America, 35% were in Europe, and 8% were elsewhere. During the last 8 years, 46% of transplants were undertaken in centers performing
1053-2498/$ -see front matter © 2010 International Society for Heart and Lung Transplantation. All rights reserved. doi:10.1016/j.healun.2010.08.009
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Number of Transplants
500 450
11-17 Years
400
1-10 Years
350
<1 Year
300 250 200 150 100 50
07 08 20
06
20
05
20
04
20
03
20
02
20
01
20
00
20
99
20
98
19
97
19
96
19
95
19
94
19
93
19
92
19
91
19
90
19
89
19
88
19
87
19
86
19
85
19
84
19
83
19
19
19
82
0
NOTE: This figure includes only the heart transplants that are reported to the ISHLT Transplant Registry. As such, this should not be construed as evidence that the number of hearts transplanted worldwide has increased and/or decreased in recent years.
Figure 1
Age distribution of heart recipients by year of transplant.
10 or more transplants per annum; however, 30% were undertaken in centers transplanting fewer than 5 per annum. Small center volumes were associated with somewhat poorer average outcomes. There was no effect on overall 1-year survival, but there was a detrimental effect on 1-year survival in children aged younger than 1 year. Those infants who received an allograft at centers undertaking fewer than 5 transplants per year had a RR of 1.13, compared with a RR of 1.0 for those undertaking 10 and a RR of 0.78 for those undertaking 20 transplants a year. Higher center transplant volume was associated with better 10-year survival (Figure 2) and low center volume with increased risk of early (within 5 years) cardiac allograft vasculopathy (CAV, Figure 3).
Recipient and donor characteristics
Patient survival The median survival (the time at which 50% of recipients remain alive) varied with the age of the recipient at transplant: median survival was 18.3 years for those who received a transplant during infancy and was 11.3 years for adolescents. The highest risk of dying was during the first year after transplant (Figure 6). If those who died within 1 year of transplant were excluded, the median conditional survival was 21.4 years for those who underwent transplantation in the first year of life, 19.3 years for those aged
Relative Risk of CAV within 5 Years
Relative Risk of 10 Year Mortality
The commonest indication for transplant during infancy was congenital heart disease (63%), followed by cardiomyopathy (31%). The reverse was true in older patients, and cardiomyopathy predominated (64%) over congenital heart disease (24%). There was a trend across the age groups, although more pronounced in infants (Figure 4), for con-
genital heart disease to become less common over time as a proportion of all transplants. Retransplantation was more common in the older age group and more frequent in the more recent era (Figure 5). Geographic differences exist between North America and Europe. In North America, for example, more transplants were undertaken during infancy and congenital heart disease was a far more common indication in infants. For details on this topic, please refer to the ISHLT Registry online slides (http://www.ishlt.org/ registries/).
2
1.5
1
0.5 p = 0.084
2
1.5
1
0.5 p = 0.0026 0 0
0 0
2
4
6
8
10
12
14
16
18
20
Center Volume (cases per year)
Figure 2 Center volume as a risk factor for 10-year mortality for transplants performed January 1995–June 1997. The dotted line represents the 95% confidence interval.
5
10
15
20
25
30
35
40
Center Volume (cases per year)
Figure 3 Center volume as a risk factor for the development of cardiac allograft vasculopathy (CAV) within 5 years, for transplants performed July 1997–June 2004. The dotted line represents the 95% confidence interval.
2010 Pediatric Heart Transplant Registry Report
1121 33%
Myopathy
17%
Congenital
0%
1% Other
2%
3%
80% ReTX
63% 1/1996-6/2009
100 75 50
Myopathy
Congenital
25 0
19 86 19 87 19 88 19 89 19 90 19 91 19 92 19 93 19 94 19 95 19 96 19 97 19 98 19 99 20 00 20 01 20 02 20 03 20 04 20 05 20 06 20 07 20 08 20 09
% of Cases
1988-1995
Figure 4
Infant heart recipient diagnosis according to year of transplant. Re-TX, retransplant.
Myopathy
25%
27% Congenital 68%
Other
65%
3%
3%
8%
ReTX
2%
1/1996-6/2009
100
Myopathy
Congenital
75 50 25 0 19 86 19 87 19 88 19 89 19 90 19 91 19 92 19 93 19 94 19 95 19 96 19 97 19 98 19 99 20 00 20 01 20 02 20 03 20 04 20 05 20 06 20 07 20 08 20 09
% of Cases
1988-1995
Figure 5
Diagnosis of heart recipients aged 11 to 17 years according to year of transplant. Re-TX, retransplant.
100 90
<1 Year (N = 2,049)
1-10 Years (N = 2,929)
11-17 Years (N = 3,027)
Overall (N = 8,005)
80
Survival (%)
Kirk et al.
70 60 0-<1 vs. 1-10: p < 0.0001; 0-<1 vs. 11-17: p=0.3284; 1-10 vs. 11-17: p=0.0003.
50 40 30 20
Half-life <1: 18.3 Years; 1-10: 15.5 Years; 11-17: 11.3 Years
10 0 0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20
Years
Figure 6
Survival analysis for transplants performed January 1982–June 2008.
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The Journal of Heart and Lung Transplantation, Vol 29, No 10, October 2010 100 Half-life: <1: 21.4; 1-10: 19.3 Years; 11-17: 15.2 Years
Survival (%)
90 80 70 0-<1 vs. 1-10: p = 0.0138; 0-<1 vs. 11-17: p < 0.0001; 1-10 vs. 11-17: p < 0.0001.
60 50 40
<1 Year (N = 1,422) 11-17 Years (N =2,399)
1-10 Years (N = 2,272) Overall (N = 6,093)
30 0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20
Years
Figure 7
Survival analysis for transplants performed January 1982–June 2008 and surviving to 1 year after transplant.
100
Survival (%)
80
1982-1989 (N=846)
1990-1994 (N=1,803)
1995-1999 (N=1,846)
2000-6/2008 (N=3,510)
Half-life 1982-1989: 9.5 years; 1990-1994: 11.7 years; 19951999: 14.3; 2000-6/2008: n.c.
60
40
20 All p-values significant at p = 0.01
0 0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20
Years
Figure 8
Percentage of Deaths
40
Survival analysis by era for transplants performed January 1982–June 2008.
CAV
Acute Rejection
Primary Failure
Graft Failure
Infection (non-CMV)
30
20
10
0 0-30 Days (N 31 Days – 1 = 226) Year (N = 266)
>1 Year – 3 Years (N = 173)
>3 Years – 5 >5 Years – 10 >10 Years (N Years (N = Years (N = = 190) 173) 306 )
Figure 9 Relative incidence of leading causes of death for deaths occurring January 1998 –June 2009. CAV, coronary artery vasculopathy; CMV, cytomegalovirus.
Kirk et al. Table 1
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1123
Risk Factors for Mortality Within 1 Year for Transplants Performed January 1996 through June 2008 (N ⫽ 3,838)
Variable Congenital diagnosis Age ⫽ 0, on ECMO Age ⬎ 0 Retransplant Year of transplant 1996–1997 vs 2002–2003 1998–1999 vs. 2002–2003 On dialysis On ventilator Panel reactive antibody ⬎10% Donor cause of death Cerebrovascular/stroke vs head trauma Anoxia vs head trauma Donor/recipient variable Male/female vs male/male Diagnosis other than congenital, no ECMO, age ⫽ 0 Infection requiring IV drug therapy ⱕ2 wks pre-Tx Transfusions before transplant Recipient age Recipient height Donor age Ischemia time Creatinine
No.
RR
95% CI
p-value
81 921 230
2.86 2.02 1.96
1.99–4.09 1.60–2.56 1.33–2.89
⬍0.0001 ⬍0.0001 0.0007
523 509 83 717 349
1.68 1.49 1.66 1.54 1.36
1.22–2.32 1.08–2.07 1.08–2.55 1.23–1.94 1.04–1.79
0.0013 0.0166 0.0217 0.0002 0.0263
387 898
1.35 0.81
1.01–1.81 0.65–1.01
0.0401 0.065
971 290 584 1,159 ... ... ... ... ...
1.24 0.47 1.24 1.23 ... ... ... ... ...
1.01–1.51 0.31–0.72 0.98–1.56 1.00–1.52 ... ... ... ... ...
0.0404 0.0005 0.0735 0.0525 0.0024 ⬍0.0001 0.0270 0.0075 0.0040
CI, Confidence interval; ECMO, extracorporeal membrane oxygenation; RR, relative risk; Tx, transplant. Note: Reference diagnosis ⫽ cardiomyopathy.
between 1 and 10 years, and 15.2 years for older children (Figure 7). Survival was also shown to be improving in relation to era of transplantation (Figure 8), with the median survival increased from 9.5 years for the period 1982 to 1989, to 11.7 years for the period 1990 to 1994, to 14.3 years for the period 1995 to 1999 (the median survival was not calculable for more recent eras, as the 50% survival rate had not been reached). The improvements in 1-year survival were more marked for infants (63% vs 70%) and children (68% vs. 85%), than in adolescents (76% vs 90%). Likewise 10-year outcomes showed an absolute 15% (51% vs 66%) improvement for infants and 13% (49% vs 62%) for children, but only 2% (49% vs 51%) for adolescents.
Causes of death Figure 9 shows the causes of death over time after transplant. Nearly half of all deaths in the first 30 days after transplant were due to graft failure— either primary or secondary to rejection or technical factors. Acute rejection remained an ever-present threat, peaking at 20% during the first year and then declining. CAV and graft failure were tracked separately in the Registry; however, reporting centers may not distinguish so precisely, and the same clinical condition may therefore be placed in either category. Infection and CAV/graft failure mirrored each other, with the risk
of infection leading to death declining rapidly after the first year with a corresponding increase in the number of deaths from CAV/graft failure, which had an incidence of approximately 60% after 3 years post-transplant and was the leading cause of death.
Table 2 Risk Factors not Significant for Mortality Within 10 Years for Transplants Performed January 1995 through June 1998 (N ⫽ 910) Recipient factors Panel reactive antibody Diabetes Repeat transplant Transfusions Hospitalized Prostaglandin E1 Ventricular assist device Bilirubin Donor factors Cause of death Weight Height Age Clinical infection Transplant factors Ischemia time Cytomegalovirus mismatch
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The Journal of Heart and Lung Transplantation, Vol 29, No 10, October 2010 Risk Factors for Mortality Within 10 Years for Transplants Performed January 1995 through June 1998 (N ⫽ 910)
Variable Donor/recipient variables Male/female vs male/male Female/male vs male/male Female/female vs male/male HLA A locus MM (increasing MM vs 0 MM), No. 0 DR MM 1 DR MM 2 DR MM Diagnosis ⫽ cardiomyopathy, age ⫽ 0 yearsa Infection requiring IV drug therapy ⱕ2 weeks pre-Txb Donor age Recipient body surface area Creatinine Pediatric transplant volumeb
No.
RR
95% CI
p-value
372 386 154
1.41 1.40 0.62 1.25 ... ... ... 0.44 1.33 ... ... ... ...
1.05–1.90 1.05–1.86 0.40–0.97 1.04–1.51 ... ... ... 0.23–0.85 0.96–1.83 ... ... ... ...
0.0239 0.0201 0.0378 0.0198 ... ... ... 0.0141 0.0870 ⬍0.0001 0.0045 0.0110 0.0840
57 306 547 58 103 ... ... ... ...
CI, confidence interval; DR, D receptor; HLA, human leukocyte antigen; MM, mismatch; RR, relative risk; Tx, transplant. Reference diagnosis ⫽ cardiomyopathy. a Impact should be considered in context of donor age and recipient body surface area. b Borderline significance.
Risk factors for 1-year recipient mortality Risk factors predictive of 1-year mortality are listed in Table 1. In general, these risk factors were predictable, with those requiring the most pre-transplant support (eg, ventilation) having the greatest risk of dying. Similarly, factors reflecting recipient illness, such as pre-transplant creatinine, influenced the 1-year survival. Some factors were less intuitive; for example, grafts from donors who died of a cerebrovascular accident carried a RR of 1.24 compared with those who died after head trauma, whereas death from anoxia conferred a RR of 0.81 compared with head trauma. The differences related to donor cause of death may be explained by the severity of the adrenergic storm causing graft damage before implantation in those with a cerebrovascular accident, which may be less marked in trauma victims and even less in those with anoxia. Other differences in donor characteristics2 may also be involved. Although donor sex per se had no effect on survival, donor/recipient sex mismatches (eg, female donor into male recipient) appeared to have worse outcomes; the mechanism for this relationship remains unclear.3 Transplant factors that
had no influence included previous sternotomy, cytomegalovirus mismatch, and human leukocyte antigen (HLA) mismatch (the complete list can be found on the ISHLT Registry online slides at http://www.ishlt.org/registries/). Infants comprised 24% of pediatric cardiac transplant recipients. Risk factors for 1-year mortality in this group were similar to the overall group, but those on extracorporeal membrane oxygenation had a very high RR of 3.25 for those with an underlying diagnosis of congenital heart disease and an RR of 2.6 for those with cardiomyopathy. Those with an abnormally high creatinine also fared badly, with a serum creatinine of 0.9 mg/dl (80 mmol/liter) having a RR of 1.5. A shorter ischemic time (2 hours) reduced the risk of dying (RR, 0.68) compared with an ischemic time of 4 hours (RR, 1.0).
Risk factors for 5-year recipient mortality Recipient mortality remained similar to that reported last year.4 The updated data can be found on the ISHLT Registry online slides (http://www.ishlt.org/registries/).
100%
80%
60%
40%
20%
No Hospitalization
Hospitalized, Not Rejection/Not Infection
Hospitalized, Rejection
Hospitalized, Infection Only
Hospitalized, Rejection + Infection
0% 1 Year (N = 3,783)
Figure 10
5 Years (N =2,366)
10 Years (N = 958)
Rehospitalization of surviving recipients, for follow-ups April 1994 –June 2009.
Kirk et al.
2010 Pediatric Heart Transplant Registry Report
1125
100
Survival (%)
90 Free from Rejection: CyA vs. TAC p = 0.0338 Rejection: CyA vs. TAC p = 0.1014 CyA: Rejection vs. no rejection p = 0.1693 TAC: Rejection vs. no rejection p = 0.3492
80
70 CyA: Free from Rejection during 1st Year (N = 41) CyA: Treated Rejection within 1st Year (N =32) TAC: Free from Rejection during 1st Year (N = 126) TAC: Treated Rejection within 1st Year (N = 67)
60
50 0
1
2
3
4
Years Treated rejection = Recipient was reported to (1) have at least one acute rejection episode that was treated with an anti-rejection agent; or (2) have been hospitalized for rejection. No rejection = Recipient had (i) no acute rejection episodes and (ii) was reported either as not hospitalized for rejection or did not receive anti-rejection agents.
Figure 11 Survival analysis for recipients aged 11 to 17 years based on treated rejection within 1 year of transplant, stratified by calcineurin use at discharge, and conditional on survival to 1 year (based on transplant with 1 year follow-ups submitted July 2004 –June 2008). CyA, cyclosporine A; Tac, tacrolimus.
Risk factors for 10-year recipient mortality
Rejection
Many of the factors associated with 1-year mortality did not influence 10-year mortality (Tables 2 and 3). A pre-transplant creatinine of 0.2 mg/dl (18 mmol/liter) or less conferred a RR of 0.2 compared with a creatinine of 1.34 mg/dl (141 mmol/liter) or more (RR, 1.6). However, as always, caution must be applied to interpreting this data. Older recipients (known to be associated with worse outcomes) will have higher pre-transplant creatinine levels than younger recipients due to increased muscle mass. A better indicator would be glomerular filtration rate, but even this varies with age. Factors not associated with outcomes include degree of sensitization as judged by panel reactive antibody, retransplantation, mechanical support with a ventricular assist device, donor cause of death, or ischemia time.
Rejection during the first year after transplant appeared not to affect short- to medium-term survival for the cohort as a whole. Rejection occurring in those on tacrolimus-based regimens in the teenaged years fared worse than those who did not reject (Figure 11), although this was not statistically significant. The percentage of patients who experienced acute rejection between discharge and the 1-year follow-up was not significantly different between those who had received induction therapy and those who had not.
Cardiac allograft vasculopathy Overall, 66% of patients were still free of cardiac allograft vasculopathy (CAV) 10 years after transplant (Figure 12). Age at the time of transplant influenced the development of CAV—freedom from CAV was 73% for infants and 73% for children aged 1 to 10 years compared with 53% for those aged older than 11 years who received a transplant. The
Transplant morbidity 100
% Freedom from CAV
Functional status was available for 561 patients who survived at least 10 years after transplant. Although the Registry measures of functional status are imperfect, they indicate that 93% had no limitations on physical activity and only 1% required total assistance. There was no significant difference between age groups, and the functional status of patients remained constant over time. Rehospitalization (Figure 10) in the first year after transplant was significant, with half the patients requiring readmission (36% for infection, 24% for rejection, 15% for both infection and rejection, 25% for other reasons). By their tenth year, hospitalization was much less frequent, with just under 25% hospitalized (35% for infection, 15% for rejection, 5% for both infection and rejection, 45% for other reasons).
90
80
70
60
50 0
1
2
3
4
5
6
7
8
9
10
Years
Figure 12 Freedom from coronary artery vasculopathy for follow-ups April 1994 –June 2009. CAV, coronary artery vasculopathy.
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The Journal of Heart and Lung Transplantation, Vol 29, No 10, October 2010
Table 4 Risk Factors for the Development of Cardiac Allograft Vasculopathy Within 5 Years for Transplants Performed July 1997 through June 2004 (N ⫽ 1,470) Variable
No.
RR
95% CI
p-value
96 24 171 595 233 ... ...
2.13 2.03 1.45 1.36 0.61 ... ...
1.29–3.53 0.87–4.72 0.96–2.21 0.96–1.91 0.35–1.04 ... ...
0.0033 0.0999 0.0807 0.0797 0.0716 ⬍0.0001 0.0026
a
Diagnosis variables Retransplant Other than cardiomyopathy, congenital, or retransplantb Panel reactive antibody ⬎ 10%a Congenitala No steroids for discharge maintenance immunosuppressionb Donor height Total transplant volume CI, confidence interval; RR, relative risk. a Reference diagnosis ⫽ cardiomyopathy. b Borderline significance.
early development of CAV (within 5 years of transplant) was associated with retransplantation (RR, 2.13, 95% CI, 1.29 –3.53, p ⫽ 0.003), HLA sensitization, and congenital diagnosis. A steroid-free regimen reduced the likelihood that early CAV would develop (Table 4). Rejection within the first year did not increase the likelihood that CAV would develop within 3 years. Once CAV occurred, the expected 4-year graft survival was 45% to 50%.
Renal dysfunction Kaplan-Meier analysis of severe renal dysfunction, defined as a serum creatinine ⬎2.5 mg/dl (221 mol/liter), showed a linear increase after transplantation, occurring in 10% of recipients at 10 years after transplant. Five percent of patients required renal replacement therapy in the form of dialysis or renal transplant by 10 years after transplant. The type of calcineurin inhibitor selected had no demonstrable influence on late renal function.
Immunosuppression Induction Induction therapy is designed to reduce the incidence of early rejection and allow a delay, if necessary, of the introduction of maintenance immunosuppression. There continued to be a trend towards the use of induction therapy, and in 2009, more than 70% of patients received induction therapy: 66% received polyclonal anti-lymphocyte antibody, and 33% received an interleukin-2 receptor antagonist (Figure 17). There was no significant difference in survival between the induction groups or between induction vs no induction. This was despite a slight increase in rejection episodes (37% compared with 32%) in the group treated with interleukin-2 receptor antagonist group compared with those treated with polyclonal anti-lymphocyte antibody and those who received no induction therapy at all. Last year’s analysis4 demonstrated that induction therapy did not increase the risk of CMV disease or post-transplant lymphoproliferative disease.
Malignancy A malignancy developed in 2% patients in the first year after transplant, with at least 1 cancer developing in 12% by 12 years (Figure 13). Almost all malignancies were lymphomas. The use of induction therapy did not increase the risk of lymphoma.
Maintenance Most immunosuppressive regimens included a combination of a calcineurin inhibitor and cell-cycle inhibitor, and a
Retransplantation Retransplants now account for 5% of transplant operations (Figure 14). The interval between the initial transplant and the retransplant operation was quite variable (Figure 15), and survival was decreased when the inter-transplant interval was less than 3 years (Figure 16). Retransplantation had increased risks for mortality both at 1 year (RR, 1.96; Table 1) and 5 years (RR, 1.48) but not at 10 years (Table 2).
% Freedom from Malignancy
100
95
90
85 All malignancy
Lymph
Skin
Other
80 0
1
2
3
4
5
6
7
8
9
10
11
12
Years
Figure 13 Freedom from malignancy for follow-ups April 1994 –June 2009.
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2010 Pediatric Heart Transplant Registry Report
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40
Number of transplants
35 30 25 20 15 10 5
20 08
20 07
20 06
20 05
20 04
20 03
20 02
20 01
20 00
19 99
19 98
19 97
19 96
19 95
19 94
0
Year of re-transplant Only patients who were less than 18 years old at the time of re-transplant are included.
Figure 14
Retransplants according to retransplant year.
significant number of patients also received corticosteroids. At the 1-year follow-up, slightly more than 33% of patients received cyclosporine and 66% received tacrolimus. Cellcycle inhibitors were used by 86% of patients, including 22% azathioprine, 66% mycophenolate mofetil (MMF), and
50
% of Re-Transplants
0-10 Years
11-17 Years
40
30
20
10
0 <1 month
1-<12 months
12-<36 months
36-<60 months
60+ months Not reported
Time Between Previous and Current Transplant Only patients who were less than 18 years old at the time of re-transplant are included. Analysis is based on the age at the time of re-transplant
Figure 15 Retransplants according to intertransplant interval for retransplants performed January 1994 –June 2009. <1 Year (N=48)
1-<3 Years (N=34)
5+ Years (N=145)
Primary TX (N=5,417)
3-<5 Years (N=48)
70
2001 2002 2003 2004 2005 2006 2007 2008 2009
60
100
% of Patients
Comparison of survival for re-transplant groups: p = 0.0019
90
Surrvival (%)
2% on both azathioprine and MMF. Sixty-six percent received prednisone and 9% received a mammalian target of rapamycin (mTOR) inhibitor. A cohort of 789 patients was tracked from 1 to 5 years after transplant to see how their immunosuppression regimens changed (Figure 18). Overall, the proportion of patients on cyclosporine-based regimens decreased from 46% to 30%, whereas the proportion on tacrolimus-based regimens rose from 50% to 63%. Most of those changing from cyclosporine regimens changed to tacrolimus regimens, with the remainder going onto other combinations of therapy. The proportion receiving cyclosporine and a cell-cycle inhibitor halved during the 5 years, whereas those receiving a combination of tacrolimus and a cell-cycle inhibitor did not change significantly. Only a very few patients were reported to receive no immunosuppression (3 in Year 1 and 8 in Year 5). The use of tacrolimus compared with cyclosporine appeared to reduce the incidence of rejection between hospital discharge and 1 year after transplantation (Figure 19), but conferred no overall survival advantage. In conclusion, this Registry report continues to document the outcomes of pediatric heart transplant recipients. It is a
80 70
50 40 30 20
60
10
50
0 Any Induction
40 0
1
2
3
4
5
Time (years) since most recent transplant Only patients who were less than 18 years old at the time of re-transplant are included.
Figure 16 Survival rates for retransplants, stratified by intertransplant interval, for retransplants performed January 1994 –June 2008.
Polyclonal ALG/ATG
IL2R-antagonist
Test of increasing trend over time: Any induction p < 0.0001 Polyclonal p < 0.0001 IL2 p < 0.0001
Analysis is limited to patients who were alive at the time of the follow-up
Figure 17 Induction immunosuppression for transplants performed January 2001–June 2009. ALG, anti-lymphocyte globulin; ATG, anti-thymocyte globulin; IL-2R, interleukin-2 receptor.
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The Journal of Heart and Lung Transplantation, Vol 29, No 10, October 2010 100% None
% of Patients
80%
Other Tacrolimus
60% Tacrolimus + MMF Tacrolimus + AZA
40%
Cyclosporine Cyclosporine + MMF
20%
Cyclosporine + AZA
0% Year 1 (N = 789)
Year 5 (N = 789) Analysis is limited to patients who were alive at the time of the follow-up
% experiencing acute rejection within 1 year
Figure 18 Maintenance immunosuppression at time of follow-up, for January 2001–June 2009 follow-ups. AZA, azathioprine; MMF, mycophenolate mofetil.
70 60
CyA + No induction, Treatment CyA + Induction (no OKT3), Treatment TAC + No induction, Treatment TAC + Induction (no OKT3), Treatment
CyA + No induction, No Treatment CyA + Induction (no OKT3), No Treatment TAC + No induction, No Treatment TAC + Induction (no OKT3), No Treatment
50 40 30 20 10 0 Overall
<1
1-10
10-17
Overall: all comparisons were statistically significant at 0.05 except CyA + no induction vs. CyA + induction and TAC + no induction vs. TAC + induction <1 year: CyA + no induction vs. TAC + no induction ( p=0.0268); 1-10 years: all comparisons were statistically significant at 0.05 except CyA + no induction vs. CyA + induction and TAC + no induction vs. TAC + induction 11-17 years: CyA + no induction vs. TAC + no induction (p = 0.0005); CyA + induction vs. TAC + no induction (p < 0.0001); CyA + induction vs. TAC + induction ( p =0.0025) Analysis is limited to patients who were alive at the time of the follow-up
Treated rejection = Recipient was reported to (1) have at least one acute rejection episode that was treated with an anti-rejection agent; or (2) have been hospitalized for rejection. No rejection = Recipient had (i) no acute rejection episodes and (ii) was reported either as not hospitalized for rejection or did not receive anti-rejection agents.
Figure 19 Percentage of recipients experiencing acute rejection between transplant discharge and 1-year follow-up, stratified by maintenance immunosuppression and induction for July 2004 –June 2009 follow-ups.
registry report and not a double-blind randomized trial of treatment options and outcomes. The information is therefore imperfect; nonetheless, it is a wonderful resource recording management and outcomes in pediatric cardiac transplantation over time.
Disclosure statement All relevant disclosures for the Registry Director, Executive Committee members and authors are on file with ISHLT and can be made available for review by contacting the Executive Director of ISHLT.
References 1. Organ Procurement and Transplantation Network. http://optn.transplant. hrsa.gov/latestData/viewDataReports.asp. 2. Ganesh JS, Rogers CA, Banner NR, et al. Donor cause of death and medium-term survival after heart transplantation: a United Kingdom national study. J Thorac Cardiovasc Surg 2005;129:1153-9. 3. Weiss ES, Allen JG, Patel ND, et al. The impact of donor-recipient sex matching on survival after orthotopic heart transplantation analysis of 18 000 transplants in the modern era. Circ Heart Fail 2009; 2:401-8. 4. Kirk R, Edwards LB, Aurora P, et al. Registry of the International Society for Heart and Lung Transplantation: twelfth official pediatric heart transplantation report—2009. J Heart Lung Transplant 2009;28: 993-1006.