HEARTLUNG TRANSPLANTATION Adult Recipients 2013 JHLT 2013 Oct

HEART-LUNG TRANSPLANTATION Adult Recipients 2013 JHLT. 2013 Oct; 32(10): 965 -978

Donor, Recipient and Center Characteristics 2013 JHLT. 2013 Oct; 32(10): 965 -978

Adult Heart-Lung Transplants Diagnosis (Transplants: January 1982 – June 2012) Idiopathic Pulmonary Fibrosis 4% Cystic Fibrosis 14% COPD/A 1 A 6% Idiopathic Pulmonary Arterial Hypertension 27% Re-Tx 2% Sarcoidosis 2% Other 5% Congenital 36% Acquired Heart Disease 5% 2013 JHLT. 2013 Oct; 32(10): 965 -978 NOTE: “Other” includes cancer, LAM, OB, bronchiectasis

Adult Heart-Lung Transplants Diagnosis (Transplants: January 1982 – June 2012) Diagnosis N (%) Congenital Heart Disease 1, 154 (35. 6%) Idiopathic Pulmonary Arterial Hypertension 890 (27. 5%) Cystic Fibrosis 453 (14. 0%) Acquired Heart Disease 165 (5. 1%) COPD/Emphysema 136 (4. 2%) Idiopathic Pulmonary Fibrosis 119 (3. 7%) Alpha-1 61 (1. 9%) Sarcoidosis 54 (1. 7%) Re-Transplant: Not Obliterative Bronchiolitis 37 (1. 1%) Re-Transplant: Obliterative Bronchiolitis 22 (0. 7%) Bronchiectasis 30 (0. 9%) Obliterative Bronchiolitis (not Re-Transplant) 24 (0. 7%) Other 96 (3. 0%) 2013 JHLT. 2013 Oct; 32(10): 965 -978

Adult Heart-Lung Transplants Diagnosis by Era (Transplants: January 1982 – June 2012) % of Transplants 100% 90% Other 80% Sarcoidosis Re-Tx 70% Idiopathic Pulmonary Fibrosis 60% COPD/A 1 A 50% Acquired Heart Disease 40% Cystic Fibrosis 30% IPAH 20% Congenital 10% 0% 1982 -1991 (N=959) 1992 -2001 (N=1, 453) 2013 JHLT. 2013 Oct; 32(10): 965 -978 2002 -6/2012 (N=829) NOTE: “Other” includes OB (non-Re-Tx) and Bronchiectasis.

Adult Heart-Lung Transplants Major Indications by Year (%) 100 Congenital Heart Disease IPAH Cystic Fibrosis COPD/Alpha-1 Retransplant Acquired Heart Disease 80 70 60 50 40 30 20 10 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 20 10 20 11 19 93 19 92 19 91 19 90 0 19 % of Transplants 90 Transplant Year 2013 JHLT. 2013 Oct; 32(10): 965 -978

Adult Heart-Lung Transplants Major Indications By Year (Number) IPAH Cystic Fibrosis COPD/Alpha-1 Retransplant Acquired Heart Disease 160 140 120 100 80 60 40 20 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 20 10 20 11 19 94 19 93 19 92 19 91 19 90 0 19 Number of Transplants 180 Congenital Heart Disease Transplant Year 2013 JHLT. 2013 Oct; 32(10): 965 -978

Adult Heart-Lung Transplants Age Distribution By Location (Transplants: January 2000 – June 2012) 18 - 34 years 35 - 49 years 50 - 59 years 60+ years 100% % of Transplants 80% 60% 40% 20% 0% Europe North America 2013 JHLT. 2013 Oct; 32(10): 965 -978 Other

Adult Heart-Lung Transplants Diagnosis Distribution By Location (Transplants: January 2000 – June 2012) Congenital heart disease IPAH Cystic Fibrosis Acquired heart disease IPF 100% % of Transplants 80% 60% 40% 20% 0% Europe North America 2013 JHLT. 2013 Oct; 32(10): 965 -978 Other

Adult Heart-Lung Transplants Donor Age Distribution By Location (Transplants: January 2000 – June 2012) 6 -11 12 -17 18 -34 35 -49 50 -59 60+ 100% % of Donors 80% 60% 40% 20% 0% Europe North America 2013 JHLT. 2013 Oct; 32(10): 965 -978 Other

Post-Transplant: Survival and Other Outcomes 2013 JHLT. 2013 Oct; 32(10): 965 -978

Adult Heart-Lung Transplants Kaplan-Meier Survival (Transplants: January 1982 – June 2011) 100 Median survival = 3. 3 years Conditional median survival = 10. 0 years Survival (%) 75 N = 3, 620 50 N at risk at 24 years = 17 25 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Years 2013 JHLT. 2013 Oct; 32(10): 965 -978

Adult Heart-Lung Transplants Kaplan-Meier Survival by Era (Transplants: January 1982 – June 2011) 100 Median survival (years): 1982 -1991=1. 9; 1992 -2001=3. 6; 2002 -6/2011=5. 9 Conditional median survival (years): 1982 -1991=9. 0; 1992 -2001=10. 0; 2002 -6/2011=NA Survival (%) 75 1982 -1991 (N=1, 210) 1992 -2001 (N=1, 598) 2002 -6/2011 (N=812) 50 25 1982 -1991 vs. 1992 -2001: p < 0. 0001 1982 -1991 vs. 2002 -6/2011: p < 0. 0001 1992 -2001 vs. 2002 -6/2011: p = 0. 0100 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Years 2013 JHLT. 2013 Oct; 32(10): 965 -978

Adult Heart-Lung Transplants Kaplan-Meier Survival By Diagnosis (Transplants: January 1990 – June 2011) 100 Other Congenital (N = 331) Eisenmenger's Syndrome (N = 630) Survival (%) 75 IPAH (N = 653) Median survival (years): Congenital=3. 3; Eisenmenger's=5. 5; IPAH=4. 6 50 25 No pair-wise comparisons were significant at p < 0. 05 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Years 2013 JHLT. 2013 Oct; 32(10): 965 -978

Adult Heart-Lung Transplants Kaplan-Meier Survival By Diagnosis Conditional on Survival to 1 Year (Transplants: January 1990 – June 2011) 100 Other Congenital (N = 194) Eisenmenger's Syndrome (N = 420) IPAH (N = 442) Survival (%) 75 50 Median survival (years): Congenital=13. 6; Eisenmenger's=11. 1; IPAH=10. 1 25 No pair-wise comparisons were significant at p < 0. 05 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Years 2013 JHLT. 2013 Oct; 32(10): 965 -978

Adult Heart-Lung Transplants Functional Status of Surviving Recipients (Follow-ups: March 2005 – June 2012) 100% 10% 20% 80% 30% 40% 60% 50% 60% 40% 70% 80% 90% 20% 100% 0% 1 Year (N = 172) 2 Years (N = 129) 2013 JHLT. 2013 Oct; 32(10): 965 -978 3 Years (N = 110)

Adult Heart-Lung Transplants Employment Status of Surviving Recipients (Follow-ups: April 1994 – June 2012) 100% 80% Working (FT/PT status unknown) Retired 60% Not Working Part Time 40% Working Full Time 20% 0% 1 Year (N = 363) 3 Years (N = 257) 2013 JHLT. 2013 Oct; 32(10): 965 -978 5 Years (N = 228)

Adult Heart-Lung Transplants Employment Status of Surviving Recipients by Era (Follow-ups: April 1994 – June 2012) 100% Working (FT/PT status unknown) 80% Retired 60% Not Working 40% Working Part Time Working Full Time 20% 0% 3 years 1 year 5 years (N = 162) (N = 109) (N = 97) 4/1994 - 1999 3 years 5 years 1 year (N = 148) (N = 131) (N = 201) 2000 - 6/2012 2013 JHLT. 2013 Oct; 32(10): 965 -978

Adult Heart-Lung Transplants Rehospitalization Post-transplant of Surviving Recipients (Follow-ups: April 1994 – June 2012) 100% 80% 60% 40% 20% 0% No Hospitalization Hospitalized, Rejection Only Hospitalized, Rejection and Infection Up to 1 Year (N = 491) Hospitalized, Not Rejection/Not Infection Hospitalized, Infection Only Between 2 and 3 Years (N = 341) 2013 JHLT. 2013 Oct; 32(10): 965 -978 Between 4 and 5 Years (N = 286)

Induction and Maintenance Immunosuppression 2013 JHLT. 2013 Oct; 32(10): 965 -978

Adult Heart-Lung Transplants Induction Immunosuppression (Transplants: January 2001 – June 2012) 70 % of Patients 60 50 40 30 20 10 0 Any Induction (N=202) Polyclonal ALG/ATG (N=68) 2013 JHLT. 2013 Oct; 32(10): 965 -978 OKT 3 (N=5) IL-2 R Antagonist (N=109) Analysis is limited to patients who were alive at the time of the discharge

Adult Heart-Lung Transplants Induction Immunosuppression (Transplants: January 2000 – December 2011) 100 Any Induction Polyclonal ALG/ATG OKT 3 IL-2 R Antagonist % of Patients 80 60 40 2001 2002 2003 2004 2005 2013 JHLT. 2013 Oct; 32(10): 965 -978 2006 2007 2008 2009 2010 2011 Analysis is limited to patients who were alive at the time of the discharge

Adult Heart-Lung Transplants Induction Immunosuppression (Transplants: January 2000 – December 2011) 90 80 60 50 40 30 20 10 0 20 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 11 % of Patients 70 Any Induction Polyclonal ALG/ATG OKT 3 2013 JHLT. 2013 Oct; 32(10): 965 -978 IL-2 R Antagonist Analysis is limited to patients who were alive at the time of the discharge

Adult Heart-Lung Transplants Maintenance Immunosuppression at Time of Follow-up (Follow-ups: January 2001 – June 2012) 100 90 Year 1 (N = 238) Year 5 (N = 146) % of Patients 80 70 60 50 40 30 20 10 0 Cyclosporine Tacrolimus Sirolimus/ MMF/MPA Azathioprine Everolimus NOTE: Different patients are analyzed in Year 1 and Year 5 2013 JHLT. 2013 Oct; 32(10): 965 -978 Prednisone Analysis is limited to patients who were alive at the time of the follow-up

Adult Heart-Lung Transplants Maintenance Immunosuppression Drug Combinations at Time of Follow-up (Follow-ups: January 2001 – June 2012) 100% Other None 80% Sirolimus/Everolimus + Calcineurin + Cellcycle Sirolimus/Everolimus + Calcineurin 60% Tacrolimus 40% Tacrolimus + MMF/MPA Tacrolimus + AZA 20% Cyclosporine + MMF/MPA 0% Cyclosporine + AZA Year 1 (N = 238) Year 5 (N = 146) NOTE: Different patients are analyzed in Year 1 and Year 5 2013 JHLT. 2013 Oct; 32(10): 965 -978 Analysis is limited to patients who were alive at the time of the follow-up

Post-transplant Morbidities 2013 JHLT. 2013 Oct; 32(10): 965 -978

Adult Heart-Lung Transplants Cumulative Morbidity Rates in Survivors within 1 and 5 Years Post-Transplant (Follow-ups: April 1994 – June 2012) Within 1 Year Total number with known response Within 5 Years Total number with known response Hypertension 59. 1% (N = 421) 87. 8% (N = 148) Renal Dysfunction 18. 2% (N = 466) 45. 3% (N = 181) Outcome 11. 2% 31. 5% Creatinine > 2. 5 mg/dl 2. 8% 10. 5% Chronic Dialysis 4. 1% 2. 2% Renal Transplant 0. 2% 1. 1% Abnormal Creatinine ≤ 2. 5 mg/dl Hyperlipidemia 26. 6% (N = 443) 69. 2% (N = 156) Diabetes 18. 8% (N = 469) 27. 9% (N = 179) Coronary Artery Vasculopathy 3. 0% (N = 371) 7. 6% (N = 92) Bronchiolitis Obliterans Syndrome 8. 6% (N = 441) 28. 3% (N = 152) 2013 JHLT. 2013 Oct; 32(10): 965 -978

Adult Heart-Lung Transplants Freedom from Coronary Artery Vasculopathy and Bronchiolitis Obliterans Syndrome % Free from CAV and Bronchiolitis Obliterans Syndrome (Follow-ups: April 1994 – June 2012) 100 80 60 40 Freedom from Coronary Artery Vasculopathy 20 Freedom from Bronchiolitis Obliterans Syndrome 0 0 1 2 3 4 5 Years 2013 JHLT. 2013 Oct; 32(10): 965 -978 6 7 8 9 10

Adult Heart-Lung Transplants Freedom from Coronary Artery Vasculopathy By Diagnosis Type (Follow-ups: April 1994 – June 2012) 100 % Free from CAV 90 80 70 Heart (N=203) Lung (N=60) 60 Heart/Lung (N=99) p-value comparing all = 0. 7222 50 0 1 2 3 Years 2013 JHLT. 2013 Oct; 32(10): 965 -978 4 5

Adult Heart-Lung Transplants % Free from Bronchiolitis Obliterans Syndrome Freedom from Bronchiolitis Obliterans Syndrome By Diagnosis Type (Follow-ups: April 1994 – June 2012) 100 Heart (N=236) Lung (N=74) 90 Heart/Lung (N=122) 80 70 60 p-value comparing all = 0. 9993 50 0 1 2 3 Years 2013 JHLT. 2013 Oct; 32(10): 965 -978 4 5

Adult Heart-Lung Transplants Freedom from Severe Renal Dysfunction* % Free from Severe Renal Dysfunction (Follow-ups: April 1994 – June 2012) 100 90 80 70 *Severe renal dysfunction = Creatinine > 2. 5 mg/dl (221 μmol/L), dialysis or renal transplant 60 50 0 1 2 3 4 5 Years 2013 JHLT. 2013 Oct; 32(10): 965 -978 6 7 8 9

Adult Heart-Lung Transplants Post Transplant Malignancy (Follow-ups: April 1994 – June 2012) Cumulative Morbidity Rates in Survivors 1 -Year Survivors Malignancy/Type No Malignancy (all types combined) Malignancy Type* 5 -Year Survivors 10 -Year Survivors 449 (94. 5%) 166 (88. 8%) 58 (84. 1%) 26 (5. 5%) 21 (11. 2%) 11 (15. 9%) Skin 2 8 9 Lymphoma 18 6 1 Other 4 5 2 Type Not Reported 2 2 0 * Recipients may have experienced more than one type of malignancy so sum of individual malignancy types may be greater than total number with malignancy. 2013 JHLT. 2013 Oct; 32(10): 965 -978

Adult Heart-Lung Transplants Freedom from Malignancy (Follow-ups: April 1994 – June 2012) % Free from Malignancy 100 90 80 70 All malignancy Lymphoma 60 Skin Other 50 0 1 2 3 4 5 Years 2013 JHLT. 2013 Oct; 32(10): 965 -978 6 7 8 9 10

Adult-Heart Lung Transplants Cause of Death (Deaths: January 1992 – June 2012) CAUSE OF DEATH BRONCHIOLITIS 0 -30 Days 31 Days - 1 Year >1 Year - 3 Years >3 Years - 5 (N = 415) (N = 322) (N = 263) Years (N = 163) >5 Years (N = 426) 0 13 (4. 0%) 64 (24. 3%) 36 (22. 1%) 92 (21. 6%) 7 (1. 7%) 9 (2. 8%) 5 (1. 9%) 2 (1. 2%) 3 (0. 7%) 0 8 (2. 5%) 13 (4. 9%) 8 (4. 9%) 9 (2. 1%) 1 (0. 2%) 7 (2. 2%) 12 (4. 6%) 5 (3. 1%) 27 (6. 3%) 0 2 (0. 6%) 1 (0. 4%) 1 (0. 6%) 1 (0. 2%) INFECTION, NON-CMV 74 (17. 8%) 113 (35. 1%) 75 (28. 5%) 42 (25. 8%) 102 (23. 9%) GRAFT FAILURE 112 (27. 0%) 68 (21. 1%) 36 (13. 7%) 29 (17. 8%) 59 (13. 8%) CARDIOVASCULAR 32 (7. 7%) 14 (4. 3%) 19 (7. 2%) 16 (9. 8%) 37 (8. 7%) TECHNICAL 91 (21. 9%) 9 (2. 8%) 3 (1. 1%) 3 (1. 8%) 3 (0. 7%) OTHER 98 (23. 6%) 79 (24. 5%) 35 (13. 3%) 21 (12. 9%) 93 (21. 8%) ACUTE REJECTION LYMPHOMA MALIGNANCY, OTHER CMV 2013 JHLT. 2013 Oct; 32(10): 965 -978

Adult Heart-Lung Transplants Relative Incidence of Leading Causes of Death (Deaths: January 1992 – June 2012) 50 Bronchiolitis Infection (non-CMV) Cardiovascular Technical Graft Failure % of Deaths 40 30 20 10 0 0 -30 Days 31 Days – 1 >1 Year – 3 >3 Years – 5 (N = 415) Year (N = 322) Years (N = 263) Years (N = 163) 2013 JHLT. 2013 Oct; 32(10): 965 -978 >5 Years (N = 426)

Multivariable Analysis 2013 JHLT. 2013 Oct; 32(10): 965 -978

Adult Heart-Lung Transplants (January 1995 – June 2011) Risk Factors For 1 Year Mortality VARIABLE Diagnosis: IPAH vs. Other* N Hazard Ratio P-value 446 0. 78 0. 0171 95% Confidence Interval 0. 63 - 0. 96 Continuous factors (see figures) Donor age Transplant center volume (borderline) N = 1, 681 2013 JHLT. 2013 Oct; 32(10): 965 -978 * Other = All diagnoses other than IPAH and Congenital

Adult Heart-Lung Transplants (January 1995 – June 2011) Risk Factors For 1 Year Mortality with 95% Confidence Limits Donor Age Hazard Ratio of 1 Year Mortality 2. 0 p = 0. 0195 1. 0 0. 5 0. 0 15 20 25 30 35 Donor Age 2013 JHLT. 2013 Oct; 32(10): 965 -978 40 45 50

Adult Heart-Lung Transplants (January 1995 – June 2011) Risk Factors For 1 Year Mortality with 95% Confidence Limits Transplant Center Volume Hazard Ratio of 1 Year Mortality 2. 0 p = 0. 0519 1. 5 1. 0 0. 5 0. 0 5 10 15 20 25 30 35 Center Volume (cases per year) 2013 JHLT. 2013 Oct; 32(10): 965 -978 40 45 50