SSA Hearing on Compassionate Allowances

Janet N Scheel MD

November 9,2010

Cardiomyopathy

• Restrictive cardiomyopathy

• Hypertrophic cardiomyopathy

• Dilated cardiomyopathy*

Frank Starling Curve

Causes of DCM in Children

• Genetic

• Infectious

• Metabolic

• Arrhythmias

Causes of DCM in Children

• Inflammatory

• Nutritional

• Structural heart disease

• Chemotherapy

CHF symptoms in Adults

CHF Symptoms in ChildrenRoss Classification

• Class I- no symptoms

• Class II-Mild tachypnea or diaphoresis with feedings/exertion. No growth failure

• Class III-Marked tachypnea or diaphoresis with feedings/exertion;prolonged feeding time;growth failure

• Class IV-Symptomatic at rest

Treatment options

• Oral medical therapy

• IV inotropes

• Pacing

• ECMO/VAD

• Transplant

ECMO

ECMO

Long – term devices specific for children

Selection for Pediatric Heart Transplant

• End stage congenital heart disease not amenable to surgical or medical therapy– Ross Classification III-IV– Failure to thrive– Protein losing enteropathy– Intractable arrhythmias– Plastic bronchitis

Selection for Pediatric Heart Transplant

• Dilated Cardiomyopathy –symptomatic on maximal medical therapy

• Restrictive Cardiomyopathy

Exclusion Criteria

• Genetic syndrome with poor long term prognosis

• Neurologic abnormalities with poor long term prognosis

• Irreversible end-organ damage

• Socio-economic factors leading to poor long term compliance

Exclusion Criteria

• Genetic syndrome with poor long term prognosis

• Neurologic abnormalities with poor long term prognosis

• Irreversible end-organ damage

• Socio-economic factors leading to poor long term compliance

Exclusion Criteria

• Pulmonary Hypertension (>5-6 woods units)– Unresponsive to oxygen or pulmonary vasodilators– Transpulmonary gradient > 15mmHg

• Pulmonary vein stenosis

• Active infection

• Active malignancy

AGE DISTRIBUTION OF PEDIATRIC HEART RECIPIENTS

By Year of Transplant

0

50

100

150

200

250

300

350

400

450

500

1982

1983

1984

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

11-17 Years

1-10 Years

<1 Year

Nu

mb

er

of

Tra

ns

pla

nts

ISHLT

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.

2009

PEDIATRIC HEART TRANSPLANTATIONKaplan-Meier Survival (Transplants: 1/1982-6/2007)

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 = 1,976) 1-10 Years (N = 2,788)

11-17 Years (N = 2,869) Overall (N = 7,633)

0-<1 vs. 1-10: p = 0.0007; 0-<1 vs. 11-17: p=0.4922; 1-10 vs. 11-17: p=0.0011.

Half-life <1: 18.4 Years; 1-10: 14.7 Years; 11-17: 11.1 Years

Su

rviv

al (

%)

ISHLT

2009

PEDIATRIC HEART TRANSPLANTATIONConditional Kaplan-Meier Survival

(Transplants: 1/1982-6/2007)

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 = 1,373) 1-10 Years (N = 2,163)11-17 Years (N =2,289) Overall (N = 5,825)

0-<1 vs. 1-10: p = 0.0044; 0-<1 vs. 11-17: p < 0.0001;1-10 vs. 11-17: p < 0.0001.

Half-life: <1: n.c.; 1-10: 18.5 Years; 11-17: 14.7 Years

Su

rviv

al (

%)

ISHLT

2009

PEDIATRIC HEART TRANSPLANTATIONConditional Kaplan-Meier Survival for Recent Era

(Transplants: 1/1999-6/2007)

50

60

70

80

90

100

0 1 2 3 4 5 6 7

Years

<1 Year (N = 606) 1-10 Years (N =1,033)

11-17 Years (N = 1,062) Overall (N = 2,701)

0-<1 vs. 1-10: p = 0.1610;0-<1 vs. 11-17: p = 0.0014; 1-10 vs. 11-17: p < 0.0001

Su

rviv

al (

%)

ISHLT

2009

PEDIATRIC HEART TRANSPLANTS (1/1995-6/2007)

Risk Factors For 1 Year Mortality

N=3,756

VARIABLE N Relative

Risk P-value

95% Confidence Interval

Congenital diagnosis, age = 0, on ECMO 74 2.70 0.0003 1.57 -4.63

Congenital diagnosis, age > 0 893 2.17 <0.0001 1.67 -2.83

Retransplant 225 2.09 0.0002 1.42 -3.07

On ventilator 706 1.80 <0.0001 1.45 -2.23

On dialysis 91 1.62 0.021 1.08 -2.43

Year of Transplant: 1995-96 vs. 2001-2002 506 1.55 0.0049 1.14 -2.09

PRA > 10% 344 1.37 0.0228 1.04 -1.79

Infection requiring IV drug therapy (with 2wk/TX) 565 1.29 0.0267 1.03 -1.62

Donor cause of death = anoxia vs. head trauma 863 0.80 0.0468 0.64 -1.00

Not ABO identical 843 0.79 0.0384 0.63 -0.99

Diagnosis other than congenital, no ECMO, age = 0 295 0.46 0.0042 0.27 -0.78

ISHLT

Reference diagnosis = cardiomyopathy2009

PEDIATRIC HEART RECIPIENTS Functional Status of Surviving Recipients

(Follow-ups: April 1994 - June 2008)

0%

20%

40%

60%

80%

100%

1 Year (N = 2,146) 5 Year (N = 1,418) 10 Year (N = 557)

No Activity Limitations Performs with Some Assistance Requires Total Assistance

ISHLT

2009

PEDIATRIC HEART RECIPIENTS Functional Status of Surviving Recipients

(Follow-ups: April 1994 - June 2008)For the Same Patients

0%

20%

40%

60%

80%

100%

1 Year (N = 758) 3 Year (N = 758) 5 Year (N = 758)

No Activity Limitations Performs with Some Assistance Requires Total Assistance

ISHLT

2009

PEDIATRIC HEART RECIPIENTS Rehospitalization Post-transplant of Surviving Recipients

(Follow-ups: April 1994 - June 2008)

0%

20%

40%

60%

80%

100%

1 Year (N = 3,431) 5 Years (N =2,143) 10 Years (N = 944)

No Hospitalization Hospitalized, Not Rejection/Not Infection

Hospitalized, Rejection Hospitalized, Infection Only

Hospitalized, Rejection + Infection

ISHLT

2009

PEDIATRIC HEART RECIPIENTS Maintenance Immunosuppression at Time of Follow-up

for Same Patients at Each Time Point(Follow-ups: January 2001 - June 2008)

% o

f Pa

tien

ts

ISHLT

0%

20%

40%

60%

80%

100%

Year 1 (N = 631) Year 5 (N = 631)

None

Other

Tacrolimus

Tacrolimus + MMF

Tacrolimus + AZA

Cyclosporine

Cyclosporine + MMF

Cyclosporine + AZA

Analysis is limited to patients who were alive at the time of the follow-up2009

FREEDOM FROM CORONARY ARTERY VASCULOPATHY For Pediatric Heart Recipients (Follow-ups: April 1994 - June 2008)

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10

Years

% F

ree

do

m f

rom

CA

V

ISHLT

2009

GRAFT SURVIVAL FOLLOWING REPORT OF CORONARY ARTERY VASCULOPATHY

For Pediatric Heart Recipients (Follow-ups: April 1994 - June 2008)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 4

Time since Report of CAV (Years)

<1 Year (N = 80)

1-10 Years (N = 135)

11-17 Years (N = 176)

p = 0.8363

Su

rviv

al s

ince

Rep

ort

of

CA

V (

%)

ISHLT

2009

FREEDOM FROM SEVERE RENAL DYSFUNCTION*For Pediatric Heart Recipients (Follow-ups: April 1994 - June 2008)

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10

Years

% F

ree

do

m f

rom

Se

ve

re

Re

na

l Dy

sfu

nc

tio

n

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

ISHLT

2009

MALIGNANCY POST-HEART TRANSPLANTATION FOR PEDIATRICSCumulative Prevalence in Survivors (Follow-ups: April 1994 - June 2008)

Malignancy/Type 1-Year Survivors

5-Year Survivors

10-Year Survivors

No Malignancy 3,361 (98.1%) 1,343 (95.2%) 332 (92.2%)

Malignancy (all types combined) 64 (1.9%) 68 (4.8%) 28 (7.8%)

Malignancy Type

Lymph 59 64 26

Other 4 5 2

Skin 1

Type Not Reported 1

ISHLT

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

2009

FREEDOM FROM MALIGNANCYFor Pediatric Heart Recipients (Follow-ups: April 1994 - June 2008)

80

85

90

95

100

0 1 2 3 4 5 6 7 8 9 10

Years

All malignancy Lymph Skin Other% F

ree

do

m f

rom

Ma

lign

an

cy

ISHLT

2009

PEDIATRIC HEART RECIPIENTS Incidence of Hypertension between 1 and 3 Years

(Transplants: April 1993 - June 2005)

Maintenance Immunosuppression at discharge and 1 year

% HTN reported between 1 and 3 years

P-valueFor Patients

on drugFor Patients not on drug

Azathioprine 22.0 26.0 0.1643

Cyclosporine 21.4 26.2 0.1083

MMF 23.4 22.7 0.8049

Prednisone 29.6 10.7 <.0001

Rapamycin 37.5 22.5 - 

Tacrolimus 28.8 20.3 0.0039

ISHLT

2009

PEDIATRIC HEART RECIPIENTS Incidence of Hypertension between 3 and 8 Years

(Transplants: April 1993 - June 2000)

Maintenance Immunosuppression at discharge and 1 year

% HTN reported between 3 and 8 years

P-valueFor Patients

on drugFor Patients not on drug

Azathioprine 37.5 48.9 0.1623

Cyclosporine 36.5 43.8 0.4302

MMF 41.4 37.6 0.6949

Prednisone 47.1 20.2 <.0001

Rapamycin . 37.6 - 

Tacrolimus 42.3 34.8 0.4484

ISHLT

2009

PEDIATRIC HEART TRANSPLANT RECIPIENTS: Cause of Death (Deaths: January 1992 - June 2008)

CAUSE OF DEATH 0-30 Days (N = 461)

31 Days - 1 Year (N =

421)

>1 Year - 3 Years (N = 307)

>3 Years - 5 Years (N = 226)

>5 Years - 10 Years (N = 350)

>10 Years (N = 172)

CORONARY ARTERY VASCULOPATHY

5 (1.1%) 30 (7.1%) 62 (20.2%) 69 (30.5%) 98 (28.0%) 49 (28.5%)

ACUTE REJECTION 44 (9.5%) 100 (23.8%) 71 (23.1%) 31 (13.7%) 45 (12.9%) 10 (5.8%)

LYMPHOMA 10 (2.4%) 12 (3.9%) 6 (2.7%) 33 (9.4%) 11 (6.4%)

MALIGNANCY, OTHER 4 (1.0%) 2 (0.7%) 1 (0.4%) 5 (1.4%) 11 (6.4%)

CMV 1 (0.2%) 11 (2.6%) 1 (0.3%)

INFECTION, NON-CMV 54 (11.7%) 65 (15.4%) 20 (6.5%) 8 (3.5%) 17 (4.9%) 13 (7.6%)

PRIMARY FAILURE 102 (22.1%) 23 (5.5%) 10 (3.3%) 15 (6.6%) 18 (5.1%) 5 (2.9%)

GRAFT FAILURE 97 (21.0%) 45 (10.7%) 62 (20.2%) 53 (23.5%) 74 (21.1%) 44 (25.6%)

TECHNICAL 27 (5.9%) 3 (0.7%) 2 (0.7%) 2 (0.9%) 4 (1.1%) 1 (0.6%)

OTHER 25 (5.4%) 26 (6.2%) 29 (9.4%) 24 (10.6%) 30 (8.6%) 10 (5.8%)

MULTIPLE ORGAN FAILURE

46 (10.0%) 54 (12.8%) 11 (3.6%) 6 (2.7%) 10 (2.9%) 8 (4.7%)

RENAL FAILURE 1 (0.2%) 4 (1.0%) 1 (0.3%) 1 (0.4%) 1 (0.3%) 3 (1.7%)

PULMONARY 29 (6.3%) 30 (7.1%) 15 (4.9%) 8 (3.5%) 8 (2.3%) 5 (2.9%)

CEREBROVASCULAR 30 (6.5%) 16 (3.8%) 9 (2.9%) 2 (0.9%) 7 (2.0%) 2 (1.2%)

ISHLT

2009

PEDIATRIC HEART TRANSPLANT RECIPIENTS: Cause of Death (Deaths: January 1998 - June 2008)

CAUSE OF DEATH 0-30 Days (N = 213)

31 Days - 1 Year (N = 241)

>1 Year - 3 Years (N = 192)

>3 Years - 5 Years (N = 153)

>5 Years - 10 Years (N = 286)

>10 Years (N =165)

CAV 2 (0.9%) 14 (5.8%) 33 (17.2%) 43 (28.1%) 77 (26.9%) 47 (28.5%)

ACUTE REJECTION 22 (10.3%) 45 (18.7%) 36 (18.8%) 23 (15.0%) 36 (12.6%) 10 (6.1%)

LYMPHOMA 6 (2.5%) 7 (3.6%) 4 (2.6%) 28 (9.8%) 11 (6.7%)

MALIGNANCY, OTHER

1 (0.4%) 1 (0.5%) 4 (1.4%) 10 (6.1%)

CMV 7 (2.9%) 1 (0.5%)

INFECTION, NON-CMV

26 (12.2%) 31 (12.9%) 11 (5.7%) 3 (2.0%) 13 (4.5%) 11 (6.7%)

PRIMARY FAILURE 44 (20.7%) 9 (3.7%) 4 (2.1%) 6 (3.9%) 10 (3.5%) 5 (3.0%)

GRAFT FAILURE 31 (14.6%) 25 (10.4%) 48 (25.0%) 44 (28.8%) 66 (23.1%) 42 (25.5%)

TECHNICAL 14 (6.6%) 2 (1.0%) 4 (1.4%) 1 (0.6%)

OTHER 19 (8.9%) 20 (8.3%) 24 (12.5%) 17 (11.1%) 26 (9.1%) 10 (6.1%)

MULTIPLE ORGAN FAILURE

27 (12.7%) 40 (16.6%) 10 (5.2%) 5 (3.3%) 8 (2.8%) 8 (4.8%)

RENAL FAILURE 4 (1.7%) 1 (0.5%) 1 (0.7%) 1 (0.3%) 3 (1.8%)

PULMONARY 11 (5.2%) 27 (11.2%) 10 (5.2%) 6 (3.9%) 7 (2.4%) 5 (3.0%)

CEREBROVASCULAR 17 (8.0%) 12 (5.0%) 4 (2.1%) 1 (0.7%) 6 (2.1%) 2 (1.2%)

ISHLT

2009

PEDIATRIC HEART TRANSPLANT RECIPIENTS: Relative Incidence of Leading Causes of Death

(Deaths: January 1998 - June 2008)

0

10

20

30

40

0-30 Days (N= 213)

31 Days – 1Year (N =

241)

>1 Year – 3Years (N =

192)

>3 Years – 5Years (N =

153)

>5 Years – 10Years (N =

286 )

>10 Years (N= 165)

CAV Acute Rejection Infection (non-CMV)

Primary Failure Graft Failure

Pe

rce

nta

ge

of

De

ath

s

ISHLT

2009