Decline in Rejection in Decline in Rejection in the First Year Afterthe First Year AfterPediatric Cardiac Pediatric Cardiac Transplantation: Transplantation: A Multi-Institutional StudyA Multi-Institutional Study

Jeffrey G. Gossett, MD1, Charles E Canter, MD2, Jie Zheng3, Kenneth Schechtman3, Elizabeth D Blume, MD4, Sherrie Rodgers, MSN, CPNP1, David C Naftel, PhD5, James K Kirklin, MD5, Janet Scheel, MD6, F. J. Fricker, MD7,

Paul Kantor, MD8, Elfriede Pahl, MD1 and the PHTS Investigators

A Pediatric Heart Transplant Study A Pediatric Heart Transplant Study ProjectProject

1 Pediatric Cardiology, Children's Memorial Hospital, Chicago, IL; 2 Department of Pediatrics, Washington University, Saint Louis, MO; 3 Department of Biostatistics, Washington University, Saint Louis, MO; 4 Pediatric Cardiology, Children's Hospital Boston, Boston, MA; 5 Cardiac Surgery, University of Alabama, Birmingham, AL; 6 Pediatric Cardiology Johns Hopkins Hospital, Baltimore MD; 7 Pediatric Cardiology University of Florida, Gainesville, FL; 8 Paediatric Cardiology, Hospital for Sick Children, Toronto, ON

Conflict of Interest Conflict of Interest DisclosuresDisclosures

Grant/Grant/Research Research SupportSupport

Nothing to discloseNothing to disclose

ConsultantConsultant Nothing to discloseNothing to disclose

Speakers Speakers BureauBureau Nothing to discloseNothing to disclose

Stock Stock ShareholderShareholder Nothing to discloseNothing to disclose

Other Other (identify)(identify) Nothing to discloseNothing to disclose

• Mortality after pediatric Mortality after pediatric transplantation has improved over transplantation has improved over timetime11

• Clinical impression: overall incidence Clinical impression: overall incidence of rejection decreasedof rejection decreased– No data to confirm era effectNo data to confirm era effect

• Clinical importance:Clinical importance:– Survival decreased in patients with Survival decreased in patients with

rejection during first yearrejection during first year11

1. Boucek MM, et al. Registry of the International Society for Heart and Lung Transplantation: Tenth Official Pediatric Heart Transplantation Report--2007. The Journal of Heart and Lung Transplantation 2007;26(8):796-80

BackgroundBackground

• Primary objective:Primary objective:– To determine whether the incidence of To determine whether the incidence of

rejection in the first year after pediatric rejection in the first year after pediatric heart transplantation has changed over heart transplantation has changed over timetime

• Secondary objective:Secondary objective:– To explore factors associated with To explore factors associated with

changes in incidence of rejectionchanges in incidence of rejection

ObjectivesObjectives

• Pediatric Heart Transplant StudyPediatric Heart Transplant Study– Prospective multi-institutional event-driven Prospective multi-institutional event-driven

databasedatabase– From 1/1993 to 12/2006From 1/1993 to 12/2006

• Patients who died within one year of tx without rejection Patients who died within one year of tx without rejection excludedexcluded

• Primary outcome: Rejection in first year Primary outcome: Rejection in first year after transplantafter transplant– PHTS defines rejection as PHTS defines rejection as “an event leading “an event leading

to augmentation of immunotherapy”to augmentation of immunotherapy”

MethodsMethods

• 2049 patients met inclusion criteria2049 patients met inclusion criteria– Median age was 3.4 yrs (0-21)Median age was 3.4 yrs (0-21)

• Patients have changed over timePatients have changed over time– Increases in:Increases in:

• Age, African American race, prior sternotomies, mechanical assist, Age, African American race, prior sternotomies, mechanical assist, CMV+, PRA >10%, cardiomyopathy, females (p<0.05)CMV+, PRA >10%, cardiomyopathy, females (p<0.05)

– Decreases in:Decreases in:• Tx for congenital indications, prior thoractomies (p<0.05)Tx for congenital indications, prior thoractomies (p<0.05)

• Increases in published risk factors for rejection Increases in published risk factors for rejection – AA race, Age, PRA>10%AA race, Age, PRA>10%1-31-3

• The use of ECHO to diagnose rejection decreased over timeThe use of ECHO to diagnose rejection decreased over time

1. Webber SA et al. Late rejection episodes more than 1 year after pediatric heart transplantation: risk factors and outcomes. Journal of Heart & Lung Transplantation 2003;22(8):869-75 2. Chin C, et al. Risk factors for recurrent rejection in pediatric heart transplantation: a multicenter experience. Journal of Heart & Lung Transplantation 2004;23(2):178-85 3. Itescu, S, Tung TC, Burke EM et al Preformed IgG Antibodies Against Major Histocompatibility Complex Class II Antigens are Major Risk Factors for High-Grade Cellular Rejection in Recipients of

Heart Transplantation Circulation 1998;98:786-93

Results- Results- DemographicsDemographics

Rejection Rate Within 1st year after HTx (Average slope of rate / year: -2.97 ± 0.43, P<0.001)

65

73

6866

70

6365

63

59

50

45

4143

25

Perc

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tag

e (

%)

0

10

20

30

40

50

60

70

80

Year

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006

Change in Rejection Mortality in 1st Year (Average slope of rate /year: -0.22 ± 0.1,

P=0.045)

3.1

6.5

3.1

0.8

2.1 1.90.7

0.00.7

1.91.4

3.1

0.6 0.5

Per

cen

tag

e (%

)

0

10

20

Year

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006

Rejection Rate by Histology at 1st Episode

BIOPSY NEGATIVE REJECTION1R2R3RNO REJECTIONREJECTION WITHOUT BIOPSY

Pe

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ge

(%

)

0

10

20

30

40

50

60

70

80

Year

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006

GroupGroupAverage slope Average slope

of rate of rate /year/year

P valueP value

1R1R -0.84 ± 0.20-0.84 ± 0.20 0.0010.001

2R2R -0.81 ± 0.43-0.81 ± 0.43 0.0830.083

2R after 19962R after 1996 -2.08 ± 0.39-2.08 ± 0.39 <0.00<0.0011

Rjxn without Rjxn without bxbx -1.15 ± 0.26-1.15 ± 0.26 <0.00<0.00

11

No rjxnNo rjxn 2.97 ± 0.432.97 ± 0.43 <0.00<0.0011

Bx Neg and 3R not analyzed due to Bx Neg and 3R not analyzed due to small numbersmall number

• Variables associated with rejection in Variables associated with rejection in the first year after adjusting for year of the first year after adjusting for year of transplantation (era effect) (P<0.05)transplantation (era effect) (P<0.05)– Increased incidence of rejection:Increased incidence of rejection:

• Older ageOlder age• Higher number of sternotomies Higher number of sternotomies • Positive donor specific crossmatch Positive donor specific crossmatch • PRA >10% PRA >10% • Cardiomyopathy vs. congenital disease Cardiomyopathy vs. congenital disease

– Decreased incidence of rejection:Decreased incidence of rejection:• Initial induction therapyInitial induction therapy

Univariate AnalysisUnivariate Analysis

Multivariate Associations with Multivariate Associations with Rejection Within 1Rejection Within 1stst yr after yr after HTx HTx

Odds Ratio EstimatesOdds Ratio Estimates

EffectEffect Point EstimatePoint Estimate 95% Wald95% Wald

Confidence LimitsConfidence Limits

P valueP value

Induction therapyInduction therapy 0.7710.771 0.6030.603 0.9860.986 0.03800.0380

Year of transplantYear of transplant 0.8570.857 0.8310.831 0.8840.884 <.0001<.0001

Age at transplantAge at transplant 1.0451.045 1.0241.024 1.0661.066 <.0001<.0001

Positive cross Positive cross

matchmatch

1.7451.745 1.1591.159 2.6292.629 0.00770.0077

• Over a dozen immunosuppressive Over a dozen immunosuppressive combinationscombinations– 1993-1998: mostly CSA +/- steroid1993-1998: mostly CSA +/- steroid– 1998-2005: mainly CSA+ AZA +/- steroid, 1998-2005: mainly CSA+ AZA +/- steroid,

or CSA+ MMF+ steroidor CSA+ MMF+ steroid– Since 2005: most common TAC+ MMF + Since 2005: most common TAC+ MMF +

steroidsteroid

• No single combination explained our No single combination explained our effecteffect– Only year of transplant remained significantOnly year of transplant remained significant

ImmunosuppressivImmunosuppressiveses

• Our a-priori definition of rejectionOur a-priori definition of rejection– Potential changes in practice over time and Potential changes in practice over time and

within institutionswithin institutions

• Voluntary database submissionVoluntary database submission– Potential changes in submissions over time Potential changes in submissions over time

• Pre-determined database fields Pre-determined database fields • Variability in practice of immunotherapyVariability in practice of immunotherapy

– Institutions specificInstitutions specific– Limited power for causal relationshipsLimited power for causal relationships

LimitationsLimitations

• Decline in rejection and death from Decline in rejection and death from rejection in first year after pediatric rejection in first year after pediatric HTxHTx

• Prior published risk factor of AA race Prior published risk factor of AA race notnot predictive of rejection predictive of rejection

• Changes in demographics, co-Changes in demographics, co-morbidities and immunosuppression morbidities and immunosuppression may be related to reduction in may be related to reduction in rejectionrejection

ConclusionsConclusions

Pediatric Heart Transplant Pediatric Heart Transplant StudyStudyParticipating Centers (36 Sites)Participating Centers (36 Sites)Arkansas Children’s Hospital, Little Rock, AR

Cardinal Glennon Children’s Hospital, St. Louis, MOChildren’s Healthcare of Atlanta, Atlanta, GAChildren’s Hospital Medical Center, Cincinnati, OHChildren’s Hospital of Michigan, Detroit, MIChildren’s Hospital of Philadelphia, Philadelphia, PAChildren’s Hospital of Pittsburgh, Pittsburgh, PAChildren’s Hospital of Wisconsin, Milwaukee, WIChildren’s Hospital, Boston, MAChildren’s Medical Center, Dallas, TXChildren’s Memorial Hospital, Chicago, ILCleveland Clinic Children’s Hospital, Cleveland, OHColumbia University-Babies Hospital, New York, NYColumbus Children’s, Columbus, Ohio Freeman Hospital, Newcastle on Tyne, United KingdomHospital of Sick Children, Toronto, ONJackson Memorial Hospital, Miami, FLLoma Linda University Medical Center, Loma Linda, CA Medical University of South Carolina, Charleston, SC**Montefiore Medical Center, New York, NY**

Primary Children’s Medical Center, Salt Lake City, UTRiley Children’s Hospital, Indianapolis, INSeattle Children’s Medical Center, Seattle, WashingtonSt. Louis Children’s Hospital, St. Louis, MOStanford University Medical Center, Palo Alto, CAThe Children’s Hospital, Denver, COUniversity of Alabama at Birmingham, Birmingham, ALUniversity of Alberta, Alberta, Ontario, CanadaUniversity of California Los Angeles, Los Angeles, CAUniversity of Florida/Shands Hospital, Gainesville, FLUniversity of Iowa Hospitals and Clinics, Iowa City, IAUniversity of Louisville, Louisville, Kentucky**University of Michigan/Mott Children’s Hospital, Ann Arbor, MIUniversity of North Carolina, Chapel Hill, NCUniversity of South Florida-All Children’s Hospital, St. Petersburg, FL**new institutions

NOYES

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Year

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006

Rejection Rate With or Without Induction

Odds Ratio 0.64 (0.54-0.77) p<0.001