HEART TRANSPLANTATION Pediatric Recipients ISHLT

HEART TRANSPLANTATION

Pediatric Recipients

ISHLT 2007 J Heart Lung Transplant 2007;26: 796-807

AGE DISTRIBUTION OF PEDIATRIC HEART RECIPIENTS (Transplants: January 1996 - June 2006)

0

100

200

300

400

500

600

700

800

900

1000

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Recipient Age (Years)

Nu

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er o

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ran

spla

nts


AGE DISTRIBUTION FOR DONORS OF PEDIATRIC HEART RECIPIENTS

(Transplants: January 1996 - June 2006)

Nu

mb

er o

f T

ran

spla

nts

ISHLT 2007

0

100

200

300

400

500

600

700

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18-25

26-30

31+

Donor Age (Years)

J Heart Lung Transplant 2007;26: 796-807

AGE DISTRIBUTION OF PEDIATRIC HEART RECIPIENTS

By Year of Transplant

0

50

100

150

200

250

300

350

400

45011-17 Years

1-10 Years

<1 Year

Nu

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spla

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ISHLT 2007

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.


NUMBER OF CENTERS REPORTING PEDIATRIC HEART TRANSPLANTS

0102030405060708090

100110

Nu

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er o

f P

edia

tric

Cas

es R

epo

rtin

g


AVERAGE CENTER VOLUMEPediatric Heart Transplants: January 1, 1997 - June 30, 2006

121

17

105

16 1490

10

20

30

40

50

60

70

80

90

100

110

120

1-4/yr 5-9/yr 10-19/yr

Average number of heart transplants per year

Nu

mb

er

of

cen

ters

.

1997-2001

2002-6/2006

ISHLT 2007J Heart Lung Transplant 2007;26: 796-807

DISTRIBUTION OF TRANSPLANTS BY CENTER VOLUME

Pediatric Heart Transplants: January 1, 1997 - June 30, 2006

35.328.8 30.629.3 25.9

44.7

0

10

20

30

40

50

1-4 5-9 10-19

Average number of heart transplants per year

% o

f tr

ansp

lan

ts .

1997-2001 2002-6/2006

ISHLT 2007J Heart Lung Transplant 2007;26: 796-807

PEDIATRIC HEART RE-TRANSPLANTSBy Transplant Year

Retransplants: January 1994 – December 2005

0

5

10

15

20

25

30

35

40

Nu

mb

er

of

tran

sp

lan

ts

Year of transplantISHLT 2007J Heart Lung Transplant 2007;26: 796-807

0

20

40

60

80

100

120

<1 month 1-<12 months 12-<36 months 36-<60 months 60+ months Not reported

Nu

mb

er o

f R

e-T

ran

spla

nts

PEDIATRIC HEART RE-TRANSPLANTSBy Intertransplant Interval

Retransplants: January 1994 - June 2005

ISHLT 2007

Time Between Previous and Current Transplant


50

60

70

80

90

100

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5

Su

rrviv

al (

%)

<1 month (N=24) 1-<12 months (N=14) 12-<36 months (N=27)

36+ months (N=132) Primary TX (N=4124)

Comparison of survival for re-transplant groups: p < 0.0001

KAPLAN-MEIER SURVIVAL RATES FOR PEDIATRIC HEART RETRANSPLANTS STRATIFIED BY INTER-TRANSPLANT INTERVAL


ISHLT 2007

Time (years) since most recent transplant


50

60

70

80

90

100

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5

Su

rrviv

al (

%)

<1 Year (N=38) 1-<3 Years (N=27) 3-<5 Years (N=36)

5+ Years (N=96) Primary TX (N=4124)

Comparison of survival for re-transplant groups: p = 0.0436

KAPLAN-MEIER SURVIVAL RATES FOR PEDIATRIC HEART RETRANSPLANTS STRATIFIED BY INTER-TRANSPLANT INTERVAL


ISHLT 2007

Time (years) since most recent transplant


DIAGNOSIS IN PEDIATRIC HEART TRANSPLANT RECIPIENTS (Age: < 1 Year)

02550

75100

Myopathy Congenital

30%

64%

0%

1%

4%

1%

16%

79%

0%

1%

2%

2%

Myopathy

Congenital

CAD

Malignancy

Other

ReTX1988-1995 1/1996-6/2006

% o

f C

ases


DIAGNOSIS IN PEDIATRIC HEART TRANSPLANT RECIPIENTS (Age: 1-10 Years)

0

2550

75

100Myopathy Congenital

52%

37%

6%

0%

1%

4%52%

40%

4%

0%

1%

3%Myopathy

Congenital

CAD

Malignancy

Other

ReTX1988-1995 1/1996-6/2006

% o

f C

ases


DIAGNOSIS IN PEDIATRIC HEART TRANSPLANT RECIPIENTS (Age: 11-17 Years)

0

2550

75

100Myopathy Congenital

62%

7%

5%

0%

25%

1%66%

2%

3%

0%

27%

2%

Myopathy

Congenital

CAD

Malignancy

Other

ReTX1988-1995 1/1996-6/2006

% o

f C

ases


PEDIATRIC HEART TRANSPLANTATIONKaplan-Meier Survival (1/1982-6/2005)

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Years

<1 Year (N= 1,682) 1-10 Years (N = 2,432)11-17 Years (N = 2,561) Overall (N= 6,675)

0-<1 vs. 1-10: p = 0.0017; 0-<1 vs. 11-17: p=0.1104; 1-10 vs. 11-17: p=0.0653

Half-life <1: 15.8 Years; 1-10: 14.2 Years; 11-17: 11.4 Years

Su

rviv

al (

%)


PEDIATRIC HEART TRANSPLANTATIONConditional Kaplan-Meier Survival (1/1982-6/2005)

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Years

<1 Year (N = 1,148) 1-10 Years (N = 1,845)11-17 Years (N = 1,968) Overall (N = 4,961)

0-<1 vs. 1-10: p = 0.0029; 0-<1 vs. 11-17: p=<.0001;1-10 vs. 11-17: p=<.0001

Half-life: <1: n.c.; 1-10: 17.5 Years; 11-17: 15.2 Years

Su

rviv

al (

%)


PEDIATRIC HEART TRANSPLANTATIONConditional 5-year Kaplan-Meier Survival (1/1982-6/2005)

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Years

<1 Year (N = 675) 1-10 Years (N = 1,074)11-17 Years (N = 1,047) Overall (N = 2,796)

0-<1 vs. 1-10: p = <.0001; 0-<1 vs. 11-17: p=<.0001; 1-10 vs. 11-17: p=0.0020

Su

rviv

al (

%)


PEDIATRIC HEART TRANSPLANTATIONConditional Kaplan-Meier Survival for Recent Era

(1/1999-6/2005)

50

60

70

80

90

100

0 1 2 3 4 5 6

Years

<1 Year (N = 418) 1-10 Years (N = 738)11-17 Years (N = 757) Overall (N = 1,913)

0-<1 vs. 1-10: p = 0.8889;0-<1 vs. 11-17: p=0.0063; 1-10 vs. 11-17: p=0.0014

Su

rviv

al (

%)


PEDIATRIC HEART TRANSPLANTATIONKaplan-Meier Survival by Era (1/1982-6/2005)

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Years

1982-1989 (N = 860) 1990-1994 (N=1,842)

1995-1999 (N=1,877) 2000-6/2005 (N=2,096)

All p-values significant at p< 0.0001 except comparison of 1995-1999 vs. 2000-6/2005

Half-life 1982-1989: 10.8 years; 1990-1994: 12.0 years; 1995-1999: n.c.; 2000-6/2005: n.c.

Su

rviv

al (

%)


PEDIATRIC HEART TRANSPLANTATION Kaplan-Meier Survival by Era (1/1982-6/2005)

Age: < 1 Year

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16Years

1982-1989 (N=167) 1990-1994 (N=562)

1995-1999 (N=480) 2000-6/2005 (N =473)

P-values for era comparisons82-89 vs. 90-94: 0.3879; 82-89 vs. 95-99: <.0001; 82_90 vs. 00-6/05: <.000190-94 vs. 95-99: <.0001; 90-94 vs. 00-6/05: <.0001; 95-99 vs. 00-6/05: 0.7892

Half-life 1982-1989: 10.8 years; 1990-1994: 10.6 years; 1995-1999: n.c. ; 2000-6/2005: n.c.S

urv

ival

(%

)



Age: 1-10 Years

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Years

1982-1989 (N = 266) 1990-1994 (N=652)

1995-1999 (N=724) 2000-6/2005 (N=790)

P-values for era comparisons82-89 vs. 90-94: 0.0270; 82-89 vs. 95-99: <.0001; 82-89 vs. 00-6/05: <.0001 90-94 vs. 95-99: 0.0021;89-94 vs. 00-6/05: <.0001; 95-99 vs. 00-6/05: 0.2005

Half-life 1982-1989: 10.9; 1990-1994: 12.5; 1995-1999: . ; 2000-6/2005: n.a.

Su

rviv

al (

%)



Age: 11-17 Years

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Years

1982-1989 (N=427) 1990-1994 (N=628)

1995-1999 (N=673) 2000-6/2005 (N=833)

P-values for era comparisons82-89 vs. 90-94: 0.0465; 82-89 vs. 95-99: 0.0860; 82_90 vs. 88-6/05: <.0001; 90-94 vs. 95-99: 0.6394; 90-94 vs. 00-6/05: 0.0577; 95-99 vs. 00-6/05: 0.2086

Half-life 1982-1989: 9.9; 1990-1994: 11.5; 1995-1999: 10.1; 2000-6/2005: n.a.

Su

rviv

al (

%)


0%

20%

40%

60%

80%

100%

Europe North America Other

% o

f T

ran

spla

nts

<1 years 1-10 years 11-17 years

PEDIATRIC HEART TRANSPLANTS:AGE DISTRIBUTION BY LOCATION

Transplants between January 2000 and June 2006


0%

20%

40%

60%

80%

100%


% o

f T

ran

sp

lan

ts

Other

Re-TX/GraftFailure

Malignancy

Coronary ArteryDisease

Congenital

Cardiomyopathy

PEDIATRIC HEART TRANSPLANTS:DIAGNOSIS DISTRIBUTION BY LOCATION



0%

20%

40%

60%

80%

100%


% o

f D

on

ors

<1 1-10 11-17 18-34 35-49 50-64

PEDIATRIC HEART TRANSPLANTS:DONOR AGE DISTRIBUTION BY LOCATION



PEDIATRIC HEART TRANSPLANTS (1/1995-6/2005)

Risk Factors For 1 Year Mortality

N=3,209

VARIABLE N

Relative Risk

P-value 95% Confidence Interval

Congenital diagnosis, age = 0, on ECMO 51 5.66 <.0001 3.54 -9.06

Congenital diagnosis, age > 0, on ECMO 48 4.30 <.0001 2.58 -7.14

Congenital diagnosis, age > 0, no ECMO 710 2.23 <.0001 1.70 -2.91

Congenital diagnosis, age=0, on PGE 201 2.12 .0003 1.40 -3.20

Retransplant 179 1.91 .0029 1.25 -2.92

Congenital diagnosis, age = 0, no PGE or ECMO 336 1.90 .0004 1.33 -2.70

On ventilator 581 1.45 .0033 1.13 -1.87

Year of Transplant: 1995-96 vs. 1999-2000 547 1.43 .0191 1.06 -1.94

ISHLT 2007

Reference diagnosis = cardiomyopathy



Borderline Significant Risk Factors For 1 Year Mortality

N=3,209

VARIABLE N Relative

Risk P-value

95% Confidence Interval

PRA > 10% 286 1.31 .0744 0.97 -1.77

Hospitalized (including ICU) 2147 1.25 .0781 0.98 -1.60

Female recipient 1401 1.18 .0933 0.97 -1.42


PEDIATRIC HEART TRANSPLANTS (1/1995-6/2005) Risk Factors for 1 Year Mortality

Continuous Factors (see figures) Donor Age

Bilirubin (borderline)

Creatinine

Weight ratio

Pediatric transplant volume

ISHLT 2007

N=3,209



Donor Age

0

0.5

1

1.5

2

0 10 20 30 40

Donor Age (Years)

Rela

tive R

isk o

f 1 Y

ear

Mo

rtality

p = 0.0007

ISHLT 2007 N=3,209J Heart Lung Transplant 2007;26: 796-807


Pre-Transplant Bilirubin

0

0.5

1

1.5

2

0 1 2 3 4 5 6 7 8

Recipient Bilirubin (mg/dl)

Rela

tive R

isk o

f 1 Y

ear

Mo

rtality

p = 0.071



Pre-Transplant Creatinine

0

0.5

1

1.5

2

0 0.5 1 1.5 2 2.5

Recipient serum creatinine (mg/dl)

Rela

tive R

isk o

f 1 Y

ear

Mo

rtality

p = 0.0002



Weight Ratio

0

0.5

1

1.5

2

2.5

0.5 1 1.5 2 2.5 3

Weight ratio (donor weight/recipient weight)

Rela

tive R

isk o

f 1 Y

ear

Mo

rtality

p = 0.018



Center Volume for Pediatric Transplants

0

0.5

1

1.5

2

2.5

0 2 4 6 8 10 12 14 16 18 20

Center Volume (cases per year)

Rela

tive R

isk o

f 1 Y

ear

Mo

rtality

p = 0.0055


PEDIATRIC HEART TRANSPLANTS (1/1995-6/2005) Factors Not Significant for 1 Year Mortality

Recipient Factors:IV inotropes, sternotomy, thoracotomy, history of malignancy, height, recent infection, age

Donor Factors:Gender, history of hypertension, height, clinical infection, history of diabetes

Transplant Factors:CMV mismatch, ABO identical/compatible, ischemia time, HLA mismatch


PEDIATRIC HEART TRANSPLANTS (1/1995-6/2005) 1-Year Predicted Survival Model

80%

85%

90%

95%

100%

0 0.2 0.4 0.6 0.8 1

Time (years)

Recipient: 15 y.o., male, wgt = 40kg, on FK506, PRA > 10%, creatinine = 2.0 mg/dl, dx = retransplant w/ 2.5 years between txDonor: 65 kg, female, 35 y.o. Transplant: 3 hrs ischemia time

Recipient: 15 y.o., male, wgt = 40kg, on FK506, PRA < 10%, creatinine = 1.0 mg/dl, Dx = cardiomyopathy, IV inotropesDonor: 50 kg, male, 15 y.o.Transplant : 3 hrs ischemia time

Pre

dic

ted

Su

rviv

al

ISHLT 2007


Risk Factors For 5 Year Mortality

N=1,896

VARIABLE N Relative

Risk P-

value 95% Confidence

Interval

Congenital diagnosis, age = 0, ECMO 21 3.11 .0020 1.51 -6.39

Congenital diagnosis, age > 0, ECMO 23 2.72 .0127 1.24 -5.96

Congenital diagnosis, age > 0, no ECMO 434 2.30 <.0001 1.66 -3.18

Re-transplant 104 2.17 .0062 1.25 -3.77

Ventilator 311 1.59 .0026 1.18 -2.16

Hospitalized (including ICU) 1224 1.49 .0108 1.10 -2.03

Year of Transplant: 1995-96 vs. 1999-6/2001 547 1.43 .0139 1.08 -1.91

Female recipient 808 1.27 .0489 1.00 -1.62

Female donor 800 1.27 .0494 1.00 -1.60



Borderline Significant Risk Factors For 5 Year Mortality

VARIABLE N Relative

Risk P-

value 95% Confidence

Interval

Other diagnosis (not congenital, cardiomyopathy or retransplant)

56 1.94 .0594 0.97 -3.88

ISHLT 2007

N=1,896J Heart Lung Transplant 2007;26: 796-807


Continuous Factors (see figure)

Recipient age Bilirubin (borderline)

Pediatric transplant volume

ISHLT 2007



Recipient Age

0

0.5

1

1.5

2

2.5

0 2 4 6 8 10 12 14 16 18

Recipient Age (Years)

Rela

tive R

isk o

f 5 Y

ear

Mo

rtality

p = 0.014

ISHLT 2007



Pre-Transplant Bilirubin

0

0.5

1

1.5

2

0 1 2 3 4 5 6 7 8

Recipient Bilirubin (mg/dl)

Rela

tive R

isk o

f 5 Y

ear

Mo

rtality

p = 0.057



Center Volume for Pediatric Transplants

0

0.5

1

1.5

2

0 2 4 6 8 10 12 14 16 18 20

Center Volume (cases per year)

Rela

tive R

isk o

f 5 Y

ear

Mo

rtality

p = 0.043

ISHLT 2007



Recipient Factors:History of malignancy, PRA, height, weight, creatinine, diabetes, repeat transplant, transfusions



Donor Factors:Cause of death, history of hypertension, weight, height, age, clinical infection

Transplant Factors:CMV mismatch, ischemia time, HLA mismatch


PEDIATRIC HEART TRANSPLANTS (1/1995-6/2001) Conditional 5-Year Predicted Survival Model

50%

60%

70%

80%

90%

100%

0 1 2 3 4 5

Time (years)

Recipient: 4 m.o., cardiomyopathy, creatinine=0.5 mg/dl, wgt = 5 kg, cyclosporine, no rejection within 1st yearDonor: 8 m.o., wgt = 6 kgTransplant: 3 hrs ischemia time, center volume = 16 pediatric txs/year

Recipient: 4 m.o., congenital heart disease, creatinine=1.4 mg/dl, wgt = 5 kg, ECMO, cyclosporine, rejection within 1st yearDonor: 18 m.o., wgt = 14 kgTransplant : 95 minutes ischemia time, center volume = 3 pediatric txs/year

Pre

dic

ted

Su

rviv

al

ISHLT 2007

PEDIATRIC HEART RECIPIENTS Functional Status of Surviving Recipients

(Follow-ups: April 1994 - June 2006)

0%

20%

40%

60%

80%

100%

1 Year (N = 2,070) 5 Year (N = 1,382) 10 Year (N = 7)

No Activity Limitations Performs with Some Assistance Requires Total Assistance


PEDIATRIC HEART RECIPIENTS Rehospitalization Post-transplant of Surviving Recipients


0%

20%

40%

60%

80%

100%

1 Year (N = 2,784) 5 Years (N = 1,737) 10 Years (N = 749)

No Hospitalization Hospitalized, Not Rejection/Not Infection

Hospitalized, Rejection Hospitalized, Infection Only

Hospitalized, Rejection + Infection


0

10

20

30

40

50

Any Induction (N = 865) Polyclonal ALG/ATG (N= 579)

OKT3 (N = 39) IL2R-antagonist (N =283)

PEDIATRIC HEART RECIPIENTS Induction Immunosuppression


% o

f P

atie

nts


0

10

20

30

40

50

60

Any Induction Polyclonal ALG/ATG IL2R-antagonist

% o

f P

ati

en

ts

200120022003200420052006

PEDIATRIC HEART RECIPIENTSInduction Immunosuppression (Transplants: January 2001 - June 2006)

ISHLT 2007

Test of increasing trend over time:Any induction p < 0.0001Polyclonal p < 0.0001IL2 p = 0.0722


PEDIATRIC HEART TRANSPLANTATION Kaplan-Meier Survival by Induction Group

(Transplants: January 2000 – June 2005) Conditional on Survival to 14 Days

50

60

70

80

90

100

0 1 2 3 4

Years

No induction (N =891)

Polyclonal induction (N = 509)

IL2R-antagonist (N =185)

Su

rviv

al (

%)

No comparisons were statistically significant.


PEDIATRIC HEART TRANSPLANTATION Kaplan-Meier Survival by Induction Group and Treated for Rejection Between

Transplant Discharge and 1-Year Follow-up (Transplants: January 2000 – June 2004) Conditional on Survival to 1 Year

50

60

70

80

90

100

0 1 2 3 4

Years

No induction/No rejection (N = 287)

Polyclonal induction/No rejection (N = 124)

IL2R-antagonist/No rejection (N = 53)

No induction/Rejection (N = 178)

Polyclonal induction/Rejection (N = 105)

IL2R-antagonist/Rejection (N = 38)

Su

rviv

al (

%)

No pair-wise comparisons of survival by induction were statistically significant within either rejection grouping.


PEDIATRIC HEART TRANSPLANTATIONKaplan-Meier Survival by Induction Group (Transplants: January 2000 – June 2005)

Conditional on Survival to 14 DaysAge: < 1 Year

50

60

70

80

90

100

0 1 2 3 4

Years

No induction (N = 185)Polyclonal induction (N = 191)IL2R-antagonist (N = 23)


Su

rviv

al (

%)


PEDIATRIC HEART TRANSPLANTATIONKaplan-Meier Survival by Induction Group (Transplants: January 2000 – June 2005)

Conditional on Survival to 14 DaysAge: 1-10 Years

50

60

70

80

90

100

0 1 2 3 4

Years

No induction (N = 358)Polyclonal induction (N = 177)IL2R-antagonist (N = 66)

Su

rviv

al (

%)

ISHLT 2007



PEDIATRIC HEART TRANSPLANTATION Kaplan-Meier Survival by Induction Group (Transplants: January 2000 – June 2005)

Conditional on Survival to 14 DaysAge: 11-17 Years

50

60

70

80

90

100

0 1 2 3 4

Years

No induction (N = 348)

Polyclonal induction (N = 141)

IL2R-antagonist (N = 96)


Su

rviv

al (

%)


0

20

40

60

80

100

Cyclosporine Tacrolimus Rapamycin MMF Azathioprine Prednisone

Year 1 (N = 1,471) Year 5 (N = 1,034)

PEDIATRIC HEART RECIPIENTS Maintenance Immunosuppression at Time of Follow-up

(Follow-ups: January 2001 - June 2006)

NOTE: Different patients are analyzed in Year 1 and Year 5

% o

f P

atie

nts


PEDIATRIC HEART RECIPIENTS Maintenance Immunosuppression at Time of Follow-up

for Same Patients at Each Time Point(Follow-ups: January 2001 - June 2006)

% o

f P

atie

nts

ISHLT 2007

0%

20%

40%

60%

80%

100%

Year 1 (N = 311) Year 5 (N = 314)

None

Other

Tacrolimus

Tacrolimus + MMF

Tacrolimus + AZA

Cyclosporine

Cyclosporine + MMF

Cyclosporine + AZA


PEDIATRIC HEART TRANSPLANTATIONKaplan-Meier Survival Based on Prednisone Use

Conditional on Survival to 1 Year (Transplants: April 1994 - June 2005)

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9

Years

Prednisone use at discharge and 1 year (N = 1,614)

No Prednisone at discharge or at 1 year (N = 297)

Prednisone at discharge/not at 1 year (N = 339)

p = 0.0102

Su

rviv

al (

%)


PEDIATRIC HEART TRANSPLANTATIONKaplan-Meier Survival Based on Prednisone Use for a Recent Era

Conditional on Survival to 1 Year (Transplants: January 1998 – June 2005)

50

60

70

80

90

100

0 1 2 3 4 5 6

Years

Prednisone use at discharge and 1 year (N = 1,282)

No Prednisone at discharge or at 1 year (N = 216)

Prednisone at discharge/not at 1 year (N = 277)

p = 0.1326

Su

rviv

al (

%)


PEDIATRIC HEART TRANSPLANTATIONKaplan-Meier Survival Stratified by Tacrolimus vs. Cyclosporine Use at Discharge

(Transplants: January 1998 - June 2005) Conditional on Survival to 14 Days

50

60

70

80

90

100

0 1 2 3 4 5 6 7

Years

Tacrolimus use at discharge (N = 803)

Cyclosporine use at discharge (N = 1,419)

Su

rviv

al (

%)

ISHLT 2007

p = 0.3486


PEDIATRIC HEART TRANSPLANTATIONKaplan-Meier Survival Based on Rejection within 1st Year

(Transplants: April 1994 - June 2004)

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10

Years

Free from Rejection during 1 year (N = 890)Rejection within 1st Year (N =1,089)

p = <.0001

Su

rviv

al (

%)



for Recent Transplants

(Transplants: January 2000 – June 2004)

50

60

70

80

90

100

0 1 2 3 4 5 6

Years

Free from Rejection during 1st Year (N = 407)Rejection within 1st Year (N = 478)

p = 0.0034

Su

rviv

al (

%)



Stratified by Calcineurin Use at Discharge (Transplants: April 1994 - June 2005)

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8

Years

CyA: Free from Rejection during 1 year (N = 362)

CyA: Rejection within 1st Year (N = 442)

TAC: Free from Rejection during 1 year (N = 203)

TAC: Rejection within 1st Year (N = 232)

Free from Rejection: CyA vs. TAC p = 0.0262Rejection: CyA vs. TAC p = 0.2743 CyA: Rejection vs. no rejection p = 0.0010TAC: Rejection vs. no rejection p = 0.1610

Su

rviv

al (

%)



Stratified by Calcineurin Use at Discharge: Age = 0-10 Years (Transplants: April 1994 - June 2005)

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8

Years





Free from Rejection: CyA vs. TAC p = 0.02230Rejection: CyA vs. TAC p = 06632 CyA: Rejection vs. no rejection p = 0.0003TAC: Rejection vs. no rejection p = 0.2545

Su

rviv

al (

%)



Stratified by Calcineurin Use at Discharge: Age = 11-17 Years (Transplants: April 1994 - June 2005)

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8

Years


CyA: Rejection within 1st Year (N =180)




Su

rviv

al (

%)



for Recent TransplantsStratified by Calcineurin Use at Discharge (Transplants: January 2000 - June 2005)

50

60

70

80

90

100

0 1 2 3 4 5

Years






Su

rviv

al (

%)


0%

20%

40%

60%

80%

100%

Year 1 (N = 1,471) Year 5 (N = 1034)

None

Other

Tacrolimus

Tacrolimus + MMF

Tacrolimus + AZA

Cyclosporine

Cyclosporine + MMF

Cyclosporine + AZA

PEDIATRIC HEART RECIPIENTS Maintenance Immunosuppression Drug Combinations at Time of Follow-up

(Follow-ups: January 2001 - June 2006)

NOTE: Different patients are analyzed in Year 1 and Year 5

% o

f P

atie

nts


PERCENTAGE OF PEDIATRIC HEART TRANSPLANT RECIPIENTS TREATED FOR REJECTION IN 1ST YEARStratified by Induction (Transplants: January 2000 - June 2005)

0

10

20

30

40

50

60

70

Overall <1 1-10 11-17 F M

No induction Used Induction Used (no OKT3)

Age group Gender

% t

reat

ed f

or

reje

ctio

n w

ith

in 1

yea

r

No within age group or gender comparisons were significant except 1-10 years (p=0.005).


NUMBER OF REJECTION EPISODES FOR PEDIATRIC HEART TRANSPLANT RECIPIENTS TREATED FOR REJECTION IN 1ST YEAR

Stratified by Induction (Transplants: January 2000 - June 2005)

0

0.5

1

1.5

2

2.5

Overall <1 1-10 11-17 F M

No induction Used Induction Used (no OKT3)

No within age group or gender comparisons were significant.

Age group Gender

Ave

rag

e n

um

ber

of

reje

ctio

n e

pis

od

es


PERCENTAGE OF PEDIATRIC HEART TRANSPLANT RECIPIENTS TREATED FOR REJECTION IN 1ST YEAR

Stratified by Type of Induction (Transplants: January 2000 - June 2005)

0

10

20

30

40

50

60

70

80

90

Overall <1 1-10 11-17 F M

No induction PolyclonalIL2R-antagonist OKT3

% t

reat

ed f

or

reje

ctio

n w

ith

in 1

yea

r

Overall: No induction vs. OKT3 (p = 0.0032); polyclonal vs. OKT3 (p = 0.024); IL2 vs. OKT3 (p = 0.035). 1-10: No induction vs. polyclonal (p = 0.0047); 11-17: No induction vs. OKT3 (p = 0.0097); polyclonal vs. OKT3 (p = 0.028); IL2R vs. OKT3 (p = 0.013)Female: No induction vs. OKT3 (p = 0.015); polyclonal vs. OKT3 (p = 0.041)



Stratified by Type of Induction (Transplants: January 2000 - June 2005)

0

0.5

1

1.5

2

2.5

Overall <1 1-10 11-17 F M

No induction Polyclonal IL2R-antagonist OKT3

11-17 years: No induction vs. OKT3 (p = 0.04). No other comparisons were significant.

Ave

rag

e n

um

ber

of

reje

ctio

n e

pis

od

es



Stratified by Maintenance Immunosuppression and Induction (Transplants: January 2000 - June 2005)

0

10

20

30

40

50

60

70

Overall <1 1-10 11-17

CyA + No induction Used CyA + Induction Used (no OKT3)TAC + No induction Used TAC + Induction Used (no OKT3)

Age group% t

reat

ed f

or

reje

ctio

n w

ith

in 1

yea

r

Overall: CyA + induction vs. TAC + no induction: p = 0.0179<1: CyA + no induction vs. TAC + no induction: p = 0.0471-10 years: CyA + induction vs. TAC + induction: p = 0.017; CyA + induction vs. TAC + no induction: p = 0.0003; CyA + no induction vs. CyA + induction: 0.011.

No other age group differences were significant.



Stratified by Maintenance Immunosuppression and Induction (Transplants: January 2000 - June 2005)

0

0.5

1

1.5

2

2.5

Overall <1 1-10 11-17

CyA + No induction Used CyA + Induction Used (no OKT3)TAC + No induction Used TAC + Induction Used (no OKT3)

<1 years: CyA + no induction vs. TAC + no induction: p = 0.048.No other age group comparisons were significant.

Age group

Ave

rag

e n

um

ber

of

reje

ctio

n e

pis

od

es



Stratified by Maintenance Immunosuppression (Transplants: January 2000 - June 2005)

0

10

20

30

40

50

60

70

Overall <1 1-10 11-17

Cyclosporine + MMF Cyclosporine + AZATacrolimus + MMF Tacrolimus + AZA

% t

reat

ed f

or

reje

ctio

n w

ith

in 1

yea

r

Overall: CyA +MMF vs. TAC + AZA (p = 0.0027); CyA + AZA vs. TAC + AZA (p = 0.013).<1: CyA + MMF vs. TAC + MMF ( p = 0.024); CyA + AZA vs. TAC + MMF (p = 0.021). 1-10: CyA + MMF vs. TAC + AZA (p = 0.0014); TAC + MMF vs. TAC + AZA (p = 0.011); CyA + AZA vs. TAC + AZA (p = 0.016).


NUMBER OF REJECTION EPISODES FOR PEDIATRIC HEART TRANSPLANT RECIPIENTS TREATED FOR REJECTION IN 1ST YEAR Stratified by Maintenance Immunosuppression (Transplants: January 2000 - June 2005)

0

0.5

1

1.5

2

2.5

Overall <1 1-10 11-17

Cyclosporine + MMF Cyclosporine + AZATacrolimus + MMF Tacrolimus + AZA

Ave

rag

e n

um

ber

of

reje

ctio

n e

pis

od

es

<1 years: CyA + AZA vs. TAC + MMF (p=0.0027); CyA + AZA vs. TAC + AZA (p=0.45). No other age group comparisons were significant.


PERCENTAGE OF PEDIATRIC HEART TRANSPLANT RECIPIENTS TREATED FOR REJECTION IN 1ST YEARStratified by Calcineurin Inhibitor Use at Discharge


0

10

20

30

40

50

60

Overall <1 1-10 11-17

Cyclosporine Tacrolimus

Age group

% t

reat

ed f

or

reje

ctio

n w

ith

in 1

yea

r

Overall: CyA vs. TAC (p = 0.0084) 1-10: CyA vs. TAC (p = 0.0079)



Stratified by Calcineurin Inhibitor Use at Discharge (Transplants: January 2000 - June 2005)

0

0.5

1

1.5

2

2.5

Overall <1 1-10 11-17

Cyclosporine Tacrolimus

No comparisons were significant other than <1 years (p = 0.031).

Age group

Ave

rag

e n

um

ber

of

reje

ctio

n e

pis

od

es


POST-HEART TRANSPLANT MORBIDITY FOR PEDIATRICS

Cumulative Prevalence in Survivors within 1 Year Post-Transplant (Follow-ups: April 1994 - June 2006)

Outcome Within 1

Year Total number with known response

Hypertension 46.7% (N = 2,704)

Renal Dysfunction 6.0% (N = 2,710)

Abnormal Creatinine < 2.5 mg/dl 4.0% Creatinine > 2.5 mg/dl 1.2% Chronic Dialysis 0.8% Renal Transplant 0.0%

Hyperlipidemia 11.1% (N = 2,838)

Diabetes 3.5% (N = 2,716)

Coronary Artery Vasculopathy 2.5% (N = 2,495)


POST-HEART TRANSPLANT MORBIDITY FOR PEDIATRICS Cumulative Prevalence in Survivors within 5 Years Post-Transplant


Outcome Within 5

Years Total number with known response

Hypertension 63.2% (N = 980)

Renal Dysfunction 9.3% (N = 1,021)

Abnormal Creatinine < 2.5 mg/dl 7.5% Creatinine > 2.5 mg/dl 1.0% Chronic Dialysis 0.6% Renal Transplant 0.2%

Hyperlipidemia 25.6% (N = 1,062)

Diabetes 5.0% (N = 981)

Coronary Artery Vasculopathy 10.9% (N = 724)




Outcome Within 8



Renal Dysfunction 10.3% (N = 427) Abnormal Creatinine < 2.5 mg/dl 8.0% Creatinine > 2.5 mg/dl 0.5% Chronic Dialysis 1.4% Renal Transplant 0.5%

Hyperlipidemia 31.4% (N = 446)

Diabetes 5.0% (N = 404)





Outcome Within 10



Renal Dysfunction 17.4% (N = 190) Abnormal Creatinine < 2.5 mg/dl 13.2% Creatinine > 2.5 mg/dl 1.6% Chronic Dialysis 1.6% Renal Transplant 1.1%

Hyperlipidemia 38.2% (N = 199)

Diabetes 4.5% (N = 179)



FREEDOM FROM CORONARY ARTERY VASCULOPATHY For Pediatric Heart Recipients (Follow-ups: April 1994 - June 2006)

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8

Years

% F

reed

om

fro

m C

AV


FREEDOM FROM CORONARY ARTERY VASCULOPATHY For Pediatric Heart Recipients (Follow-ups: April 1994 - June 2006)

Stratified by Induction

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8

Years

Induction (N =844)

No Induction (N = 1,343)% F

ree

do

m f

rom

CA

V

p = 0.8381


FREEDOM FROM CORONARY ARTERY VASCULOPATHYFor Pediatric Heart Recipients (Follow-ups: April 1994 - June 2006)

Stratified by Age Group

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8

Years

<1 Year (N =576)

1-10 Years (N = 826)

11-17 Years (N = 793)

p < 0.0001

% F

ree

do

m f

rom

CA

V


FREEDOM FROM CORONARY ARTERY VASCULOPATHYFor Pediatric Heart Recipients (Follow-ups: January 1999-June 2006)

Stratified by Age Group

50

60

70

80

90

100

0 1 2 3 4 5 6

Years

<1 Year (N = 475)

1-10 Years (N = 727)

11-17 Years (N = 744)

p = <.0001

% F

ree

do

m f

rom

CA

V



Stratified by Ischemia Time

50

60

70

80

90

100

0 1 2 3 4 5 6 7

Years

0-<2 hours (N=232)

2-<4 hours (N=1,123)

4+ hours (N=693)

p = 0.0090

% F

ree

do

m f

rom

CA

V


FREEDOM FROM CORONARY ARTERY VASCULOPATHYFor Pediatric Heart Recipients (Follow-ups: January 1999 - June 2006)

Stratified by Ischemia Time for Recent Era

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8

Years

0-<2 hours (N=149)

2-<4 hours (N=823)

4+ hours (N=501)

p = 0.0081

% F

ree

do

m f

rom

CA

V



Stratified by Ischemia Time and Recipient Age

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9

Years

0-<2 hours/0-10 years (N=129)

2+ hours/0-10 years (N=665)

0-<2 hours/11-17 years (N=91)

2+ hours/11-17 years (N=409)

0-10 years: p = 0.0124;11-17 years: p = 0.1837

% F

ree

do

m f

rom

CA

V


GRAFT SURVIVAL FOLLOWING REPORT OF CORONARY ARTERY VASCULOPATHY

For Pediatric Heart Recipients (Follow-ups: April 1994 - June 2006)Stratified by Age Group

0

10

20

30

40

50

60

70

80

90

100

0 0.5 1 1.5 2 2.5 3 3.5

Time since Report of CAV (Years)

<1 Year (N = 50)

1-10 Years (N = 94)

11-17 Years (N = 122)

p = 0.0234

Su

rviv

al s

ince

Rep

ort

of

CA

V (

%)


FREEDOM FROM SEVERE RENAL DYSFUNCTION*For Pediatric Heart Recipients (Follow-ups: April 1994 - June 2006)

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9

Years

* Severe renal dysfunction = Creatinine > 2.5 mg/dl (221 μmol/L), dialysis or renal transplant

% F

reed

om

fro

m S

ever

e

Ren

al D

ysfu

nct

ion


MALIGNANCY POST-HEART TRANSPLANTATION FOR PEDIATRICSCumulative Prevalence in Survivors (Follow-ups: April 1994 - June 2006)

Malignancy/Type 1-Year Survivors

5-Year Survivors

10-Year Survivors

No Malignancy 2771 (98.1%) 1010 (95%) 186 (93%)

Malignancy (all types combined) 55 (1.9%) 53 (5%) 14 (7%)

Malignancy Type

Lymph 51 48 13

Other 3 6

Skin 1

Type Not Reported 1 1

ISHLT 2007

NOTE: Multiple types may be reported; sum of types may be greater than total number with malignancy.


FREEDOM FROM MALIGNANCYFor Pediatric Heart Recipients (Follow-ups: April 1994 - June 2006)

80

85

90

95

100

0 1 2 3 4 5 6 7 8 9 10

Years

All malignancy Lymph Skin Other

% F

reed

om

fro

m M

alig

nan

cy


PEDIATRIC HEART RECIPIENTS Incidence of Hypertension between 1 and 3 Years


Maintenance Immunosuppression at discharge and 1 year

% HTN reported between 1 and 3 years

P-valueFor Patients

on drugFor Patients not on drug

Azathioprine 21.9 24.2 0.4675

Cyclosporine 20.7 25.0 0.2225

MMF 20.7 22.1 0.6763

Prednisone 29.3 8.0 <.0001

Rapamycin 100.0 21.1 -

Tacrolimus 29.1 19.1 0.0045


PEDIATRIC HEART RECIPIENTS Incidence of Hypertension between 3 and 8 Years


Maintenance Immunosuppression at discharge and 1 year

% HTN reported between 3 and 8 years

P-valueFor Patients

on drugFor Patients not on drug

Azathioprine 37.0 42.3 0.6119

Cyclosporine 34.7 41.7 0.5062

MMF 38.5 37.4 0.9407

Prednisone 47.8 19.1 0.0002

Rapamycin - 35.8 -

Tacrolimus 38.9 33.1 0.6234

ISHLT 2007

N=204


PEDIATRIC HEART RECIPIENTSRelationship of Rejection and Coronary Artery Vasculopathy

(Follow-ups: April 1994 – June 2006)

Rejection During 1st Year

Reported CAV between 1st and 3rd years

post-transplant

Reported CAV between 3rd

and 5th years

post-transplant

Yes No All Yes No All

Yes 44

7.7%

529

92.3%

573

100%

23

7.7%

275

92.3%

298

100%

No 18

3.0%

588

97.0%

606

100%

15

4.8%

300

95.2%

315

100%p = 0.0003 p = 0.1293

NOTE: Only those recipients without CAV prior to 3 years were included in the last set of columnsISHLT 2007


PEDIATRIC HEART TRANSPLANT RECIPIENTS: Cause of Death (Deaths: January 1992 - June 2006)

CAUSE OF DEATH 0-30 Days (N = 387)

31 Days - 1 Year (N = 332)

>1 Year - 3 Years (N = 249)

>3 Years - 5 Years (N = 169)

>5 Years - 10 Years (N = 237)

>10 Years (N = 103)

CORONARY ARTERY VASCULOPATHY

4 (1.0%) 27 (8.1%) 50 (20.1%) 60 (35.5%) 72 (30.4%) 32 (31.1%)

ACUTE REJECTION 40 (10.3%) 83 (25.0%) 65 (26.1%) 23 (13.6%) 36 (15.2%) 7 (6.8%)

LYMPHOMA 7 (2.1%) 11 (4.4%) 3 (1.8%) 23 (9.7%) 6 (5.8%)

MALIGNANCY, OTHER

4 (1.2%) 2 (0.8%) 1 (0.6%) 3 (1.3%) 7 (6.8%)

CMV 1 (0.3%) 7 (2.1%) 1 (0.4%)

INFECTION, NON-CMV

53 (13.7%) 55 (16.6%) 17 (6.8%) 7 (4.1%) 14 (5.9%) 10 (9.7%)

PRIMARY FAILURE 73 (18.9%) 17 (5.1%) 8 (3.2%) 10 (5.9%) 11 (4.6%) 2 (1.9%)

GRAFT FAILURE 90 (23.3%) 35 (10.5%) 45 (18.1%) 38 (22.5%) 47 (19.8%) 25 (24.3%)

TECHNICAL 21 (5.4%) 2 (0.6%) 2 (0.8%) 1 (0.6%) 2 (0.8%)

OTHER 19 (4.9%) 15 (4.5%) 19 (7.6%) 14 (8.3%) 17 (7.2%) 2 (1.9%)

MULTIPLE ORGAN FAILURE

38 (9.8%) 45 (13.6%) 7 (2.8%) 3 (1.8%) 4 (1.7%) 6 (5.8%)

RENAL FAILURE 1 (0.3%) 5 (1.5%) 1 (0.4%) 1 (1.0%)

PULMONARY 24 (6.2%) 20 (6.0%) 13 (5.2%) 8 (4.7%) 4 (1.7%) 5 (4.9%)

CEREBROVASCULAR 23 (5.9%) 10 (3.0%) 8 (3.2%) 1 (0.6%) 4 (1.7%)


PEDIATRIC HEART TRANSPLANT RECIPIENTS: Cause of Death (Deaths: January 1998 - June 2006)

CAUSE OF DEATH 0-30 Days (N = 164)

31 Days - 1 Year (N = 159)

>1 Year - 3 Years (N = 144)

>3 Years - 5 Years (N = 104)

>5 Years - 10 Years (N = 184)

>10 Years (N = 96)

CAV 1 (0.6%) 11 (6.9%) 25 (17.4%) 36 (34.6%) 56 (30.4%) 30 (31.3%)

ACUTE REJECTION 19 (11.6%) 30 (18.9%) 32 (22.2%) 14 (13.5%) 27 (14.7%) 7 (7.3%)

LYMPHOMA 3 (1.9%) 6 (4.2%) 2 (1.9%) 19 (10.3%) 6 (6.3%)

MALIGNANCY, OTHER

1 (0.6%) 1 (0.7%) 2 (1.1%) 6 (6.3%)

CMV 3 (1.9%) 1 (0.7%)

INFECTION, NON-CMV

24 (14.6%) 22 (13.8%) 8 (5.6%) 2 (1.9%) 12 (6.5%) 8 (8.3%)

PRIMARY FAILURE 30 (18.3%) 5 (3.1%) 4 (2.8%) 3 (2.9%) 5 (2.7%) 2 (2.1%)

GRAFT FAILURE 29 (17.7%) 15 (9.4%) 30 (20.8%) 30 (28.8%) 38 (20.7%) 23 (24.0%)

TECHNICAL 8 (4.9%) . (.%) 2 (1.4%) 2 (1.1%)

OTHER 14 (8.5%) 10 (6.3%) 16 (11.1%) 9 (8.7%) 14 (7.6%) 2 (2.1%)

MULTIPLE ORGAN FAILURE

20 (12.2%) 31 (19.5%) 6 (4.2%) 2 (1.9%) 3 (1.6%) 6 (6.3%)

RENAL FAILURE 5 (3.1%) 1 (0.7%) 1 (1.0%)

PULMONARY 8 (4.9%) 17 (10.7%) 8 (5.6%) 6 (5.8%) 3 (1.6%) 5 (5.2%)

CEREBROVASCULAR 11 (6.7%) 6 (3.8%) 4 (2.8%) 3 (1.6%)


HEART TRANSPLANTATION Pediatric Recipients ISHLT

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