HEART TRANSPLANTATION Pediatric Recipients ISHLT 2005 J Heart Lung Transplant 2005;24: 945-982.

HEART TRANSPLANTATION

Pediatric Recipients

ISHLT 2005J Heart Lung Transplant 2005;24: 945-982

AGE DISTRIBUTION OF PEDIATRIC HEART RECIPIENTS (Transplants: January 1996 - June 2004)

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

Recipient Age (Years)

Nu

mb

er o

f T

ran

spla

nts


AGE DISTRIBUTION FOR DONORS OF PEDIATRIC HEART RECIPIENTS

(Transplants: January 1996 - June 2004)

0

100

200

300

400

500

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)

Nu

mb

er o

f T

ran

spla

nts


AGE DISTRIBUTION OF PEDIATRIC HEART RECIPIENTS

By Year of Transplant

0

100

200

300

40011-17 Years

1-10 Years

<1 Year

11 942

75109

130

194

254

325370367

388370385

359390

369360365

353365

Nu

mb

er o

f T

ran

spla

nts

355


NUMBER OF CENTERS REPORTING PEDIATRIC HEART TRANSPLANTS

0

20

40

60

80

100

120

Nu

mb

er o

f P

edia

tric

Cas

es R

epo

rtin

g


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

0

25

50

75

100

1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003

MyopathyCongenital

29%

65%

5%

1%

15%

81%2%

2%

Myopathy

Congenital

Other

ReTX

1988-1995 1/1996-6/2004

% o

f C

ases


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

0

25

50

75

100

1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003

Myopathy Congenital

52%

37%

5%6%52%

39%

5%

4%Myopathy

Congenital

Other

ReTX

1988-1995 1/1996-6/2004

% o

f C

ases


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

0

25

50

75

100

1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003

Myopathy Congenital

62%

27%

5%

6%

65%

25%

7%

3%

Myopathy

Congenital

Other

ReTX

1988-1995 1/1996-6/2004

% o

f C

ases


PEDIATRIC HEART TRANSPLANTATIONKaplan-Meier Survival (1/1982-6/2003)

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

Years

<1 Year (N = 1,375) 1-10 Years (N = 2,106)11-17 Years (N = 2,196) Overall (N = 5,677)

<1 year vs. 1-10 years: p = 0.0082

HALF-LIFE 1-10: 13.1 years; 11-17: 11.3 years

Su

rviv

al (

%)


PEDIATRIC HEART TRANSPLANTATIONConditional Kaplan-Meier Survival (1/1982-6/2003)

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

Years

<1 Year (N = 924) 1-10 Years (N = 1,559)11-17 Years (N = 1,644) Overall (N = 4,127)

0-1 vs. 1-10: p=0.0181Both comparisons with 11-17 years significant at p < 0.0001


Su

rviv

al (

%)


PEDIATRIC HEART TRANSPLANTATIONConditional 5-year Kaplan-Meier Survival (1/1982-6/2003)

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

Years

<1 Year (N = 521) 1-10 Years (N = 854)11-17 Years (N = 856) Overall (N = 2,231)

0-1 vs. 1-10: p=0.00070-1 vs. 11-17: p<0.00011-10 vs. 11-17: p=0.0025

HALF-LIFE not computable for any age group

Su

rviv

al (

%)


PEDIATRIC HEART TRANSPLANTATIONConditional Kaplan-Meier Survival for Recent Era

(1/1999-6/2003)

50

60

70

80

90

100

0 1 2 3 4 5

Years

<1 Year (N = 270) 1-10 Years (N = 464)11-17 Years (N = 464) Overall (N = 1,198)

No comparisons were statistically significant.Half-life for each age group not computable.

Su

rviv

al (

%)


PEDIATRIC HEART TRANSPLANTATION Kaplan-Meier Survival by Era (1/1982-6/2003)

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

Years

1982-1988 (N = 570) 1989-1993 (N = 1,704)

1994-1998 (N = 1,873) 1999-6/2003 (N = 1,620)

All p-values significant at < 0.05 except comparison of 1994-1998 vs. 1999-2003

HALF-LIFE 1982-1988: 9.7 years; 1989-1993: 11.5 years;

Su

rviv

al (

%)



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 16

Years

1982-1988 (N = 52) 1989-1993 (N = 516)

1994-1998 (N = 462) 2000-6/2003 (N = 370)

P-values for era comparisons1982-88 vs. 1999-03: p = 0.0052; 1989-93 vs. 1994-98: p = 0.00041989-93 vs. 1999-03: p < 0.0001; 1994-98 vs. 1999-03: p = 0.0071

HALF-LIFE 1982-1988: 12.0 years; 1989-1993: 11.4 yearsSu

rviv

al (

%)



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 17 18

Years

1982-1988 (N = 182) 1989-1993 (N = 599)

1994-1998 (N = 742) 1999-6/2003 (N = 616)

P-values for era comparisons1982-88 vs. 1989-93: p < 0.05; 1982-88 vs. 1994-98: p < 0.0001; 1982-88 vs. 1999-03: p < 0.0001; 1989-93 vs. 1994-1998: p = 0.0008; 1989-94 vs. 1999-03: p < 0.0001


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

Years

1982-1988 (N = 336) 1989-1993 (N = 589)

1994-1998 (N = 669) 1999-6/2003 (N = 634)

P-values for era comparisons1982-89 vs. 1995-99: p = 0.0328; 1982-89 vs. 2000-2003: p < 0.0001;

HALF-LIFE 1982-1988: 8.3 years; 1989-1993: 11.1 years;

Su

rviv

al (

%)


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

(Transplants: April 1994 - June 2002)

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9

Years

Free from Rejection during 1st Year (N = 762)Rejection within 1st Year (N = 899)

p = 0.0002

Su

rviv

al (

%)


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

(Transplants: January 1998 – June 2002)

50

60

70

80

90

100

0 1 2 3 4 5 6

Years

Free from Rejection during 1st Year (N = 454)Rejection within 1st Year (N = 526)

p = 0.0001

Su

rviv

al (

%)


PEDIATRIC HEART TRANSPLANTS (1/1995-6/2003)

Risk Factors For 1 Year Mortality

N=3,014

VARIABLE N

Relative Risk

P-value 95% Confidence

Interval

Congenital diagnosis, on ECMO 69 4.16 <0.0001 2.66 -6.51

Congenital diagnosis, no ECMO 974 2.19 <0.0001 1.74 -2.77

ECMO, diagnosis other than congenital 68 1.9 0.0211 1.10 -3.28

Year of Transplant: 1995 vs. 1998 362 1.9 0.001 1.30 -2.77


Hospitalized (including ICU) 2132 1.55 0.0007 1.20 -2.00


On ventilator 448 1.35 0.0239 1.04 -1.76

Female recipient 1300 1.22 0.0409 1.01 -1.48



Borderline Significant Risk Factors For 1 Year Mortality

N=3,014

VARIABLE N

Relative Risk

P-value 95% Confidence

Interval Other diagnosis (not congenital, retransplant or cardiomyopathy)

106 1.64 0.0634 0.97 -2.75

Recipient on dialysis 48 1.57 0.0884 0.93 -2.63

Re-transplant 142 1.5 0.0903 0.94 -2.39

Year of transplant: 1999 vs. 1998 353 1.47 0.0587 0.99 -2.20


PEDIATRIC HEART TRANSPLANTS (1/1995-6/2003) Risk Factors for 1 Year Mortality

Continuous Factors (see figures) Donor Age

Bilirubin

Creatinine

Weight ratio



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 = 0.0014



Pre-Transplant Bilirubin

0

0.5

1

1.5

2

0 1 2 3 4 5 6 7 8 9 10

Recipient Bilirubin (mg/dl)

Rela

tive R

isk o

f 1 Y

ear

Mo

rtality

.

p = 0.006



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 < 0.0001



Weight Ratio

0

0.5

1

1.5

2

0.5 1 1.5 2 2.5 3 3.5

Weight ratio (donor weight/recipient weight)

Rela

tive R

isk o

f 1 Y

ear

Mo

rtality

.

p = 0.024


PEDIATRIC HEART TRANSPLANTS (1/1995-6/2003) Factors Not Significant for 1 Year Mortality

Recipient Factors:IV inotropes, sternotomy, thoracotomy, history of malignancy, height, recent infection, age, PA pressure, cardiac output, pulmonary vascular resistance, PRA



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

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


PEDIATRIC HEART TRANSPLANTS (1/1995-6/2003) 1-Year Predicted Survival – Hypothetical Cases #1 and #2

50%

60%

70%

80%

90%

100%

0 30 60 90 120 150 180 210 240 270 300 330 360

Time (days)

Pre

dic

ted

Su

rviv

al .

CASE #1: Recipient: male with congenital diagnosis, 3 months old, 3 kg, creatinine=0.6, not hospitalized; Donor: male, 6 months old, 5 kg

CASE #2: Recipient : male with congenital diagnosis, 3 months old, 3.5 kg, creatinine=1.5, ECMO, PGE, ventilator; Donor: male, 18 months old, 10 kg


PEDIATRIC HEART TRANSPLANTS (1/1995-6/2003) 1-Year Predicted Survival – Hypothetical Case #3

50%

60%

70%

80%

90%

100%

0 30 60 90 120 150 180 210 240 270 300 330 360

Time (days)

Pre

dic

ted

Su

rviv

all

CASE #3: Recipient: female with congenital diagnosis, 6 years old, 12 kg, creatinine=1.0, not hospitalized; Donor: female, 9 years old, 18 kg


PEDIATRIC HEART TRANSPLANTS (1/1995-6/2003) 1-Year Predicted Survival – Hypothetical Cases #4 and #5

50%

60%

70%

80%

90%

100%

0 30 60 90 120 150 180 210 240 270 300 330 360

Time (days)

Pre

dic

ted

Su

rviv

all

CASE #4: Recipient: male with cardiomyopathy, 14 years old, 30 kg, creatinine=1.0, hospitalized; Donor: male, 16 years old, 40 kg

CASE #5: Recipient: male with congenital diagnosis, 14 years old, 40 kg, creatinine=1.8, hospitalized; Donor: male, 22 years old, 65 kg



Risk Factors For 5 Year Mortality

N=1,598

VARIABLE N Relative

Risk P-value

95% Confidence Interval

Recipient on dialysis 17 2.64 .0038 1.37 -5.09

Congenital diagnosis, on ECMO 24 2.53 .0039 1.35 -4.77

Re-transplant 63 1.81 .0110 1.15 -2.86

Congenital diagnosis, age=0, PGE 124 1.72 .0095 1.14 -2.59

Congenital diagnosis, no ECMO 522 1.69 <0.0001 1.34 -2.13

Female donor 667 1.28 .0158 1.05 -1.55

IV inotropes 633 1.26 .0366 1.01 -1.57



Continuous Factors (see figures)

Recipient weight Creatinine (borderline)


PEDIATRIC HEART TRANSPLANTS (1/1995-6/1999) Risk Factors for 5 Year Mortality Pre-Transplant Recipient Weight

0

1

2

3

0 15 30 45 60 75

Recipient Weight (kg)

Rela

tive R

isk o

f 5 Y

ear

Mo

rtality

.

p = 0.0067



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 5 Y

ear

Mo

rtality

.

p = 0.071



Recipient Factors:History of malignancy, recent infection, bilirubin, age, hospitalized at time of transplant, PRA, pulmonary vascular resistance, gender, PA pressures, cardiac output, sternotomy, height



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

Transplant Factors:Donor/recipient weight ratio, year of transplant, CMV mismatch, ischemia time, HLA mismatch, transplant center volume


PEDIATRIC HEART TRANSPLANTS (1/1995-6/1999) 5-Year Predicted Survival – Hypothetical Cases #1,2 and 3

50%

60%

70%

80%

90%

100%

0 1 2 3 4 5

Time (years)

Pre

dic

ted

Su

rviv

all

CASE #1: Recipient: male with congenital diagnosis, 3 months old, 3 kg, creatinine=0.6, not hospitalized; Donor: male, 6 months old, 5 kg

CASE #2: Recipient: female with congenital diagnosis, 6 years old, 12 kg, creatinine=1.0, not hospitalized; Donor: female, 9 years old, 18 kg

CASE #3: Recipient: male with congenital diagnosis, 14 years old, 40 kg, creatinine=1.8, hospitalized, on inotropes; Donor: male, 22 years old, 65 kg


PEDIATRIC HEART TRANSPLANTS (1/1995-6/1999) 5-Year Predicted Survival – Hypothetical Cases #4 and 5

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 1 2 3 4 5

Time (years)

Pre

dic

ted

Su

rviv

all

CASE #4: Recipient: male with congenital diagnosis, 3 months old, 3.5 kg, creatinine=1.5, ECMO, PGE, ventilator; Donor: male, 18 months old, 10 kg

CASE #5: Recipient: male with cardiomyopathy, 14 years old, 30 kg, creatinine=1.0, hospitalized, on inotropes; Donor: male, 16 years old, 40 kg


PEDIATRIC HEART TRANSPLANTS (1/1995-6/1999)Risk Factors For 5 Year Mortality Conditional on 1 Year Survival

N=1,276

VARIABLE N Relative

Risk P-value

95% Confidence Interval

ECMO, diagnosis other than congenital

22 2.94 0.0126 1.26 -6.86

Re-transplant 50 2.41 0.004 1.32 -4.37

Congenital diagnosis, age=0, PGE 93 2.28 0.0198 1.14 -4.55

Treated for rejection (after transplant hospitalization)

328 2.19 <0.0001 1.57 -3.03

Female recipient 536 1.45 0.0282 1.04 -2.01


PEDIATRIC HEART TRANSPLANTS (1/1995-6/1999) Risk Factors For 5 Year Mortality Conditional on 1 Year Survival

Continuous Factors (see figures)

Recipient weight Ischemia time



Recipient Weight

0

0.5

1

1.5

2

0 15 30 45 60 75

Recipient Weight (kg)

Re

lati

ve

Ris

k o

f 5

Ye

ar

Mo

rta

lity p = 0.002



Ischemia Time

0

0.5

1

1.5

2

1 2 3 4 5 6 7

Ischemia time (hours)

Rela

tive R

isk o

f 5 Y

ear

Mo

rtality

.

p = 0.002


PEDIATRIC HEART TRANSPLANTS (1/1995-6/1999) Factors Not Significant for Conditional 5 Year Mortality

Recipient Factors:History of malignancy, recent infection, hospitalized at time of transplant, bilirubin, creatinine, cardiac output, pulmonary vascular resistance, PRA, sternotomy, ventilator, VAD, age, PA pressures


PEDIATRIC HEART TRANSPLANTS (1/1995-6/1999) Factors Not Significant for Conditional 5 Year Mortality

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

Transplant Factors:Donor/recipient weight ratio, year of transplant, CMV mismatch, transplant center volume, induction use, treated for infection prior to discharge, dialysis prior to discharge


PEDIATRIC HEART TRANSPLANTS (1/1995-6/1999) 5-Year Predicted Survival Conditional on Survival to 1 Year –

Hypothetical Case #1

50%

60%

70%

80%

90%

100%

1 2 3 4 5

Time (years)

Pre

dic

ted

Su

rviv

all

Not treated for rejection

Treated for rejection

Recipient: male with congenital diagnosis, 3 months old, 3 kg, creatinine=0.6, not hospitalized;

Donor: male, 6 months old, 5 kg




50%

60%

70%

80%

90%

100%

1 2 3 4 5

Time (years)

Pre

dic

ted

Su

rviv

all



Recipient: male with congenital diagnosis, 3 months old, 3.5 kg, creatinine=1.5, ECMO, PGE, ventilator;

Donor: male, 18 months old, 10 kg




50%

60%

70%

80%

90%

100%

1 2 3 4 5

Time (years)

Pre

dic

ted

Su

rviv

all



Recipient: female with congenital diagnosis, 6 years old, 12 kg, creatinine=1.0, not hospitalized;

Donor: female, 9 years old, 18 kg




50%

60%

70%

80%

90%

100%

1 2 3 4 5

Time (years)

Pre

dic

ted

Su

rviv

all



Recipient: male with cardiomyopathy, 14 years old, 30 kg, creatinine=1.0, hospitalized, on inotropes;

Donor: male, 16 years old, 40 kg




50%

60%

70%

80%

90%

100%

1 2 3 4 5

Time (years)

Pre

dic

ted

Su

rviv

all



Recipient: male with congenital diagnosis, 14 years old, 40 kg, creatinine=1.8, hospitalized, on inotropes;

Donor: male, 22 years old, 65 kg


PEDIATRIC HEART RECIPIENTS Functional Status of Surviving Recipients

(Follow-ups: April 1994 - June 2004)

0%

20%

40%

60%

80%

100%

1 Year (N = 1,947) 3 Years (N = 1,621) 5 Years (N = 1,305) 7 Years (N = 924)

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%

Up to 1 Year (N = 2,236)

Between 2 and 3Years (N = 1,762)



No Hospitalization Hospitalized, Not Rejection/Not Infection

Hospitalized, Rejection Hospitalized, Infection Only

Hospitalized, Rejection + Infection


0

10

20

30

40

50

Any Induction (N = 472) Polyclonal ALG/ATG (N = 295)

OKT3 (N = 29) IL2R-antagonist (N = 167)

PEDIATRIC HEART RECIPIENTS Induction Immunosuppression (Follow-ups: January 2001 - June 2004)

% o

f P

atie

nts


0

10

20

30

40

50

60

Any Induction Polyclonal ALG/ATG OKT3 IL2R-antagonist

% o

f P

atien

ts

2001 2002

2003 1/2004-6/2004

PEDIATRIC HEART RECIPIENTSInduction Immunosuppression (Follow-ups: January 2001 - June 2004)


0

20

40

60

80

100

Cyclosporine Tacrolimus Rapamycin MMF Azathioprine Prednisone

Year 1 (N = 822) Year 5 (N = 558)

PEDIATRIC HEART RECIPIENTS Maintenance Immunosuppression at Time of Follow-up

(Follow-ups: January 2001 - June 2004)

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

% o

f P

atie

nts


0%

20%

40%

60%

80%

100%

Year 1 (N = 815) Year 5 (N = 571)

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 2004)

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 2003)

0

10

20

30

40

50

60

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.


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

Stratified by Induction (Transplants: January 2000 - June 2003)

0

0.5

1

1.5

2

2.5

Overall <1 1-10 11-17 F M

No induction Used Induction Used (no OKT3)


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 2003)

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 = 0.0003); polyclonal vs. OKT3 (p = 0.0017); IL2 vs. OKT3 (p = 0.0010). 1-10: No induction vs. polyclonal (p = 0.04); 11-17: No induction vs. OKT3 (p = 0.003); polyclonal vs. OKT3 (p = 0.007); IL2R vs. OKT3 (p = 0.002)Female: No induction vs. OKT3 (p = 0.003); polyclonal vs. OKT3 (p = 0.01); IL2R vs. OTK3 (p = 0.03)Male: No induction vs. OKT3 (p=0.03); polyclonal vs. OKT3 (p < 0.05); IL2R vs. OKT3 (p = 0.01)



Stratified by Type of Induction (Transplants: January 2000 - June 2003)

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 2003)

0

10

20

30

40

50

60

Overall <1 1-10 11-17 F M

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

Age group Gender% t

reat

ed f

or

reje

ctio

n w

ith

in 1

yea

r

Overall: CyA + no induction vs. TAC + no induction: p = 0.0045; CyA + induction vs. TAC + induction: p = 0.0188; CyA + induction vs. TAC + no induction: p = 0.0204; CyA + no induction vs. TAC +induction: p = 0.0071; 1-10 years: CyA + no induction vs. TAC + no induction: p = 0.0313; CyA + induction vs. TAC + induction: p = 0.0144; CyA + induction vs. TAC + no induction: p = 0.0011.Female: CyA + no induction vs. TAC + no induction: p=0.008; CyA + induction vs. TAC + induction: p = 0.0163; CyA + induction vs. TAC + no induction: p = 0.0166; CyA + no induction vs. TAC + induction: p = 0.0097.No other age group or gender differences were significant.



Stratified by Maintenance Immunosuppression and Induction (Transplants: January 2000 - June 2003)

0

0.5

1

1.5

2

2.5

Overall <1 1-10 11-17 F M

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 = 0.0477.No other age group or gender comparisons were significant.

Age group Gender

Ave

rag

e n

um

ber

of

reje

ctio

n e

pis

od

es



Stratified by Maintenance Immunosuppression (Transplants: January 2000 - June 2003)

0

10

20

30

40

50

60

70

Overall <1 1-10 11-17 F M

Cyclosporin + MMF Cyclosporin + AZATacrolimus + MMF Tacrolimus + AZA

% t

reat

ed f

or

reje

ctio

n w

ith

in 1

yea

r

Overall: CyA+MMF vs. TAC+MMF (p = 0.0071); CyA +MMF vs. TAC + AZA (p = 0.0018); CyA + AZA vs. TAC + MMF (p = 0.0026); CyA + AZA vs. TAC + AZA (p = 0.0009).<1: CyA + MMF vs. TAC + MMF ( p = 0.03); CyA + AZA vs. TAC + MMF (p = 0.005). 1-10: Cya + MMF vs. TAC + AZA (p = 0.005); CyA + AZA vs. TAC + AZA (p = 0.004).11-17: CyA + AZA vs. TAC + MMF (p = 0.01). Female: CyA + MMF vs. TAC + AZA (p = 0.002); CyA + AZA vs. TAC + MMF (p = 0.01); CyA + AZA vs. TAC + AZA (p=0.0006); TAC + MMF vs. TAC + AZA (p = 0.03). Male: CyA + MMF vs. TAC + MMF (p < 0.05)


NUMBER OF REJECTION EPISODES FOR PEDIATRIC HEART TRANSPLANT RECIPIENTS TREATED FOR REJECTION IN 1ST YEAR Stratified by Maintenance Immunosuppression (Transplants: January 2000 - June 2003)

0

0.5

1

1.5

2

2.5

3

Overall <1 1-10 11-17 F M

Cyclosporin + MMF Cyclosporin + 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=0.004). No other age group or gender comparisons were significant.



Stratified by Tacrolimus vs. Cyclosporine Use at Discharge Conditional on Survival to 14 Days

(Transplants: January 2000 - June 2003)

0

10

20

30

40

50

60

Overall <1 1-10 11-17 F M

Cyclosporine Tacrolimus

Age group Gender

% t

reat

ed f

or

reje

ctio

n w

ith

in 1

yea

r

<1: CyA vs. TAC (p = 0.0156)1-10: CyA vs. TAC (p = 0.0013)Females: CyA vs. TAC (p = 0.0001)


NUMBER OF REJECTION EPISODES FOR PEDIATRIC HEART TRANSPLANT RECIPIENTS TREATED FOR REJECTION IN 1ST YEAR Stratified by Tacrolimus vs. Cyclosporine Use at Discharge

Conditional on Survival to 14 Days (Transplants: January 2000 - June 2003)

0

0.5

1

1.5

2

2.5

Overall <1 1-10 11-17 F M

Cyclosporine Tacrolimus


Age group Gender

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


Outcome Within 1

Year Total number with known response

Hypertension 46.7% (N = 2,184)

Renal Dysfunction 5.8% (N = 2,183)

Abnormal Creatinine < 2.5 mg/dl 3.8% Creatinine > 2.5 mg/dl 1.3% Chronic Dialysis 0.6% Renal Transplant 0.0%

Hyperlipidemia 10.1% (N = 2,285)

Diabetes 3.2% (N = 2,188)

Coronary Artery Vasculopathy 2.5% (N = 1,996)


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 61.4% (N = 696)

Renal Dysfunction 9.4% (N = 715)

Abnormal Creatinine < 2.5 mg/dl 8.0% Creatinine > 2.5 mg/dl 0.8% Chronic Dialysis 0.4% Renal Transplant 0.1%

Hyperlipidemia 21.4% (N = 746)

Diabetes 4.6% (N = 694)

Coronary Artery Vasculopathy 11.0% (N = 480)


POST-HEART TRANSPLANT MORBIDITY FOR PEDIATRICS Cumulative Prevalence in Survivors within 7 Years Post-Transplant


Outcome Within 7

Years Total number with known response

Hypertension 65.8% (N = 357)

Renal Dysfunction 11.4% (N = 370) Abnormal Creatinine < 2.5 mg/dl 7.8% Creatinine > 2.5 mg/dl 2.2% Chronic Dialysis 0.5% Renal Transplant 0.8%

Hyperlipidemia 26.3% (N = 388)

Diabetes 3.9% (N = 358)

Coronary Artery Vasculopathy 15.2% (N = 217)


FREEDOM FROM CORONARY ARTERY VASCULOPATHY For Pediatric Heart Recipients (Follow-ups: April 1994 - June 2004)

50

60

70

80

90

100

0 1 2 3 4 5 6 7

Years

% F

reed

om

fro

m C

AV



Stratified by Induction

50

60

70

80

90

100

0 1 2 3 4 5 6 7

Years

Induction (N =806)

No Induction (N = 1,362)% F

ree

do

m f

rom

CA

V

p = 0.43



Stratified by Age Group

50

60

70

80

90

100

0 1 2 3 4 5 6 7

Years

<1 Year (N =574)

1-10 Years (N = 862)

11-17 Years (N = 838)

p = 0.0001

% 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 2004)Stratified by Age Group

0

10

20

30

40

50

60

70

80

90

100

0 0.5 1 1.5 2 2.5

Time since Report of CAV (Years)

<1 Year (N = 35)

1-10 Years (N = 69)

11-17 Years (N = 88)

p = 0.1108

Su

rviv

al s

ince

Rep

ort

of

CA

V (

%)


FREEDOM FROM SEVERE RENAL DYSFUNCTION*For Pediatric Heart Recipients (Follow-ups: April 1994 - June 2004)

50

60

70

80

90

100

0 1 2 3 4 5 6 7

Years

* Severe renal dysfunction = Creatinine > 2.5 mg/dl, 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 2004)

Malignancy/Type 1-Year Survivors

5-Year Survivors

7-Year Survivors

No Malignancy2230 (98.0%) 716 (95.9%) 365 (93.8%)

Malignancy (all types combined) 45 (2.0%) 31 (4.1%) 24 (6.2%)

Malignancy Type

Lymph 41 27 22

Other 3 3

Type Not Reported 1

Other types: Ewings, Large cell lymphoma


FREEDOM FROM MALIGNANCYFor Pediatric Heart Recipients (Follow-ups: April 1994 - June 2004)

50

60

70

80

90

100

0 1 2 3 4 5 6

Years

All malignancy Lymph Skin Other

% F

reed

om

fro

m M

alig

nan

cy


PEDIATRIC HEART TRANSPLANTATIONKaplan-Meier Survival Based on Prednisone Use


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 = 1,256)

No Prednisone at discharge or at 1 year (N = 215)

Prednisone at discharge/not at 1 year (N = 249)

p = 0.0006

Su

rviv

al (

%)


PEDIATRIC HEART TRANSPLANTATIONKaplan-Meier Survival Based on Prednisone Use

(Transplants: January 1998 – June 2003)

50

60

70

80

90

100

0 1 2 3 4 5 6

Years

Prednisone use at discharge and 1 year (N = 924)

No Prednisone at discharge or at 1 year (N = 139)

Prednisone at discharge/not at 1 year (N = 187)

p = 0.009

Su

rviv

al (

%)


PEDIATRIC HEART TRANSPLANTATION Kaplan-Meier Survival by Induction Group

(Transplants: January 2000 – June 2003) Conditional on Survival to 14 Days

50

60

70

80

90

100

0 1 2 3

Years

No induction (N = 604)

Polyclonal induction (N = 290)

IL2R-antagonist (N = 104)

OKT3 (N = 40)

Su

rviv

al (

%)

No comparisons were statistically significant.


PEDIATRIC HEART TRANSPLANTATIONKaplan-Meier Survival by Induction Group (Transplants: January 2000 – June 2003)

Conditional on Survival to 14 DaysAge: < 1 Year

50

60

70

80

90

100

0 1 2 3

Years

No induction (N = 123)Polyclonal induction (N = 109)IL2R-antagonist (N = 16)


Su

rviv

al (

%)


PEDIATRIC HEART TRANSPLANTATIONKaplan-Meier Survival by Induction Group (Transplants: January 2000 – June 2003)

Conditional on Survival to 14 DaysAge: 1-10 Years

50

60

70

80

90

100

0 1 2 3

Years

No induction (N = 252)Polyclonal induction (N = 102)IL2R-antagonist (N = 35)

No induction vs. polyclonal: p = 0.00182

Su

rviv

al (

%)


PEDIATRIC HEART TRANSPLANTATION Kaplan-Meier Survival by Induction Group (Transplants: January 2000 – June 2003)

Conditional on Survival to 14 DaysAge: 11-17 Years

50

60

70

80

90

100

0 1 2 3 4

Years

No induction (N = 229)Polyclonal induction (N =79)IL2R-antagonist (N = 53)OKT3 (N = 24)


Su

rviv

al (

%)


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

(Transplants: January 1998 - June 2003) Conditional on Survival to 14 Days

50

60

70

80

90

100

0 1 2 3 4 5 6

Years

Tacrolimus use at discharge (N = 449)

Cyclosporine use at discharge (N = 1,029)

Su

rviv

al (

%)


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 drug

For Patients not on drug

Azathioprine 21.6% 22.1% 0.9

Cyclosporine 20.5% 21.4% 0.8

MMF 19.9% 21.0% 0.8

Prednisone 28.9% 6.6% <0.0001

Rapamycin . 20.6%

Tacrolimus 24.8% 19.5% 0.2


PEDIATRIC HEART RECIPIENTSRelationship of Rejection and Coronary Artery Vasculopathy

(Follow-ups: April 1994 – June 2004)

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 36

8.1%

408

91.9%

444

100%

12

6.5%

174

93.5%

186

100%

No 13

3.0%

420

97.0%

433

100%

9

4.6%

188

95.4%

197

100%

p = 0.001 p = 0.4185NOTE: Only those recipients without CAV prior to 3 years were included in the last set of columnsISHLT 2005

J Heart Lung Transplant 2005;24: 945-982

PEDIATRIC HEART RECIPIENTS Growth Following Transplantation: Height

Stratified by Prednisone Use at Discharge and at 1 Year

-1.25

-1

-0.75

-0.5

-0.25

0

Immediately Pre-Transplant

1 Year Follow-up 2 Year Follow-up 3 Year Follow-up

Time of Measurement

Z-S

core

1-5 Years/No Prednisone 1-5 Years/Prednisone

11-17/No Prednisone 11-17/Prednisone


PEDIATRIC HEART RECIPIENTS Growth Following Transplantation: Weight

Stratified by Prednisone Use at Discharge and at 1 Year

-1.5

-1.25

-1

-0.75

-0.5

-0.25

0

0.25

0.5

Immediately Pre-Transplant

1 Year Follow-up 2 Year Follow-up 3 Year Follow-up

Time of Measurement

Z-S

core

1-5 Years/No Prednisone 1-5 Years/Prednisone

11-17/No Prednisone 11-17/Prednisone


PEDIATRIC HEART TRANSPLANT RECIPIENTS: Cause of Death (Deaths: January 1992 - June 2004)

CAUSE OF DEATH 0-30 Days (N = 335)

31 Days - 1 Year (N = 281)

>1 Year - 3 Years (N = 198)

>3 Years - 5 Years (N = 139)

>5 Years (N = 252)

CORONARY ARTERY VASCULOPATHY

3 (0.9%) 26 (9.3%) 36 (18.2%) 52 (37.4%) 72 (28.6%)

ACUTE REJECTION 27 (8.1%) 76 (27.0%) 54 (27.3%) 18 (12.9%) 32 (12.7%)

LYMPHOMA 6 (2.1%) 10 (5.1%) 3 (2.2%) 21 (8.3%)

MALIGNANCY, OTHER 4 (1.4%) 2 (1.0%) 1 (0.7%) 9 (3.6%)

CMV 1 (0.3%) 7 (2.5%) 1 (0.5%)

INFECTION, NON-CMV 47 (14.0%) 46 (16.4%) 17 (8.6%) 6 (4.3%) 16 (6.3%)

PRIMARY FAILURE 58 (17.3%) 11 (3.9%) 6 (3.0%) 8 (5.8%) 12 (4.8%)

GRAFT FAILURE 79 (23.6%) 31 (11.0%) 35 (17.7%) 27 (19.4%) 49 (19.4%)

TECHNICAL 21 (6.3%) 2 (0.7%) 2 (1.0%) 1 (0.7%) 1 (0.4%)

OTHER 15 (4.5%) 16 (5.7%) 16 (8.1%) 14 (10.1%) 24 (9.5%)

MULTIPLE ORGAN FAILURE

36 (10.7%) 29 (10.3%) 3 (1.5%) 2 (1.4%) 6 (2.4%)

RENAL FAILURE 1 (0.3%) 4 (1.4%) 1 (0.5%)

PULMONARY 24 (7.2%) 16 (5.7%) 9 (4.5%) 6 (4.3%) 7 (2.8%)

CEREBROVASCULAR 23 (6.9%) 7 (2.5%) 6 (3.0%) 1 (0.7%) 3 (1.2%)


HEART TRANSPLANTATION Pediatric Recipients ISHLT 2005 J Heart Lung Transplant 2005;24: 945-982.

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Transcript of HEART TRANSPLANTATION Pediatric Recipients ISHLT 2005 J Heart Lung Transplant 2005;24: 945-982.