HEARTLUNG TRANSPLANTATION Adult Recipients 2019 JHLT 2019 Oct

HEART-LUNG TRANSPLANTATION Adult Recipients 2019 JHLT. 2019 Oct; 38(10): 1015 -1066

Table of Contents < Donor and recipient characteristics: slides 3 -12 < Post transplant survival and other outcomes: slides 1320 < Induction and maintenance immunosuppression: slides 21 -24 < Post-transplant morbidities: slides 25 -32 < Focus theme – donor and recipient size match: slides 33 -50 • Select characteristic by size match: slides 34 -40 • Outcomes by size match: slides 41 -46 • Multivariable analysis: slides 47 -50 2019 JHLT. 2019 Oct; 38(10): 1015 -1066

Donor and Recipient Characteristics 2019 JHLT. 2019 Oct; 38(10): 1015 -1066

Adult Heart-Lung Transplants Number of Transplants Reported by Year 250 200 150 100 50 0 19 8 8 19 9 9 19 0 9 19 1 9 19 2 9 19 3 9 19 4 9 19 5 9 19 6 9 19 7 9 19 8 9 20 9 0 20 0 0 20 1 0 20 2 0 20 3 0 20 4 0 20 5 0 20 6 0 20 7 0 20 8 0 20 9 1 20 0 1 20 1 1 20 2 1 20 3 1 20 4 1 20 5 1 20 6 17 Number of Transplants 300 2019 JHLT. 2019 Oct; 38(10): 1015 -1066 NOTE: This figure includes only the heart-lung transplants that are reported to the ISHLT Transplant Registry. As such, this should not be construed as evidence that the number of heart-lung transplants worldwide has declined in recent years.

Adult Heart-Lung Transplants Average Center Volume by Location (Transplants: January 2010 – June 2018) Europe North America Other Percentage of Transplants 60 35 10 40 30 28 21 3 20 10 21 14 7 22 14 0 1 2 0 1 3 1 2 3 3 4 -9 Average number of heart-lung transplants per year 2019 JHLT. 2019 Oct; 38(10): 1015 -1066 7 0 % of Transplants Number of Centers 50 42

Adult Heart-Lung Transplants Diagnosis (Transplants: January 1988 – June 2018) Diagnosis N (%) PH-not IPAH 1, 142 (37. 7%) IPAH 860 (28. 4%) CF 452 (14. 9%) COPD 131 (4. 3%) IIP 117 (3. 9%) ILD-not IIP 60 (2. 0%) A 1 ATD 59 (1. 9%) Sarcoidosis 59 (1. 9%) Non CF-bronchiectasis 34 (1. 1%) Retransplant 24 (0. 8%) OB 21 (0. 7%) Other 68 (2. 2%) 2019 JHLT. 2019 Oct; 38(10): 1015 -1066

Adult Heart-Lung Transplants Diagnosis by Era (Transplants: January 1992 – June 2018) 120% Other Retransplant % of Transplants 100% Non CFbronchiectasis 80% IIP COPD 60% A 1 ATD 40% CF IPAH 20% PH-not IPAH 0% 1992 -2001 (N=1, 413) 2002 -2009 (N=595) 2019 JHLT. 2019 Oct; 38(10): 1015 -1066 2010 -6/2018 (N=377)

Adult Heart-Lung Transplants Major Diagnoses by Year (%) 100 PH-not IPAH CF COPD IIP 90 70 60 50 40 30 20 10 9 19 2 9 19 3 9 19 4 9 19 5 9 19 6 97 19 98 19 9 20 9 0 20 0 0 20 1 0 20 2 0 20 3 0 20 4 0 20 5 0 20 6 0 20 7 0 20 8 0 20 9 1 20 0 11 20 12 20 1 20 3 1 20 4 1 20 5 1 20 6 17 0 19 % of Transplants 80 Transplant Year 2019 JHLT. 2019 Oct; 38(10): 1015 -1066 Since only major indications are shown, sum of percentages for each year is less than 100%.

Adult Heart-Lung Transplants Major Diagnoses by Year (Number) 180 PH-not IPAH CF COPD IIP 140 120 100 80 60 40 20 9 19 2 9 19 3 9 19 4 9 19 5 9 19 6 9 19 7 9 19 8 9 20 9 0 20 0 0 20 1 0 20 2 0 20 3 0 20 4 05 20 06 20 0 20 7 0 20 8 0 20 9 1 20 0 1 20 1 1 20 2 1 20 3 1 20 4 1 20 5 1 20 6 17 0 19 Number of Transplants 160 Transplant Year 2019 JHLT. 2019 Oct; 38(10): 1015 -1066

Adult Heart-Lung Transplants Recipient Age Distribution (in Years) by Location (Transplants: January 2005 – June 2018) 18 -34 35 -49 50 -59 60+ 100% % of Transplants 80% 60% 40% 20% 0% Europe North America 2019 JHLT. 2019 Oct; 38(10): 1015 -1066 Other

Adult Heart-Lung Transplants Diagnosis Distribution by Location (Transplants: January 2005 – June 2018) 100% Other 90% Retransplant % of Transplants 80% Non CFbronchiectasis IIP 70% 60% 50% COPD 40% A 1 ATD 30% CF 20% IPAH 10% PH-not IPAH 0% Europe North America 2019 JHLT. 2019 Oct; 38(10): 1015 -1066 Other

Adult Heart-Lung Transplants Donor Age (in Years) Distribution by Location (Transplants: January 2005 – June 2018) 0 -5 6 -11 12 -17 18 -34 35 -49 50 -59 100% % of Donors 80% 60% 40% 20% 0% Europe North America 2019 JHLT. 2019 Oct; 38(10): 1015 -1066 Other 60+

Post-Transplant Survival and Other Outcomes 2019 JHLT. 2019 Oct; 38(10): 1015 -1066

Adult Heart-Lung Transplants Kaplan-Meier Survival (Transplants: January 1992 – June 2017) 100 Median survival = 4. 5 years; Conditional median survival = 11. 2 years Survival (%) 75 N = 2, 829 50 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 25 Years 2019 JHLT. 2019 Oct; 38(10): 1015 -1066

Adult Heart-Lung Transplants Kaplan-Meier Survival by Era (Transplants: January 1992 – June 2017) 100 Median survival (years): 1992 -2001=3. 7; 2002 -2009=5. 5; 2010 -6/2017=6. 5; Conditional median survival (years): 1992 -2001=10. 2; 2002 -2009=12. 8; 2010 -6/2017=NA Survival (%) 75 1992 -2001 (N=1, 619) 2002 -2009 (N=743) 50 2010 -6/2017 (N=467) 25 1992 -2001 vs. 2002 -2009: p=0. 031 1992 -2001 vs. 2010 -6/2017: p=0. 025 2002 -2009 vs. 2010 -6/2017: p=0. 691 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 2019 JHLT. 2019 Oct; 38(10): 1015 -1066

Adult Heart-Lung Transplants Kaplan-Meier Survival by Major Diagnosis (Transplants: January 1992 – June 2017) 100 PH-not IPAH (N=955) CF (N=305) IIP (N=81) IPAH (N=662) COPD (N=92) Survival (%) 75 Median survival (years): PH-not IPAH=5. 6; IPAH=5. 5; CF=6. 3; COPD=3. 9; IIP=1. 9 50 25 No pairwise comparisons were significant at p < 0. 05 except CF vs. IIP. 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Years 2019 JHLT. 2019 Oct; 38(10): 1015 -1066

Adult Heart-Lung Transplants Kaplan-Meier Survival by Major Diagnosis Conditional on Survival to 1 Year (Transplants: January 1992 – June 2017) 100 PH-not IPAH (N=623) CF (N=213) IIP (N=48) IPAH (N=452) COPD (N=57) Survival (%) 75 50 No pairwise comparisons were significant at p < 0. 05. 25 Median survival (years): PH-not IPAH=13. 0; IPAH=10. 7; CF=13. 1; COPD=7. 3; IIP=7. 3 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Years 2019 JHLT. 2019 Oct; 38(10): 1015 -1066

Adult Heart-Lung Transplants Functional Status of Surviving Recipients by Karnofsky Score (Follow-ups: March 2005 – June 2018) 100% Moribund, fatal processes progressing rapidly Very sick, hospitalization necessary: active treatment necessary 80% Severely disabled: hospitalization is indicated, death not imminent Disabled: requires special care and assistance 60% Requires considerable assistance and frequent medical care Requires occasional assistance but is able to care for needs 40% Cares for self: unable to carry on normal activity or active work Normal activity with effort: some symptoms of disease 20% Able to carry on normal activity: minor symptoms of disease 0% 1 Year (N=272) 2 Year (N=217) 3 Year (N=194) 2019 JHLT. 2019 Oct; 38(10): 1015 -1066 Normal, no complaints, no evidence of disease

Adult Heart-Lung Transplants Surviving Recipients Working Post-Transplant by Era (Follow-ups: January 1995 – June 2018) 70% 60% 50% 40% 30% 20% 10% 0% 1 Year (N=227) 3 Years (N=188) 5 Years (N=167) 1995 -2004 1 Year (N=243) 3 Years (N=175) 2005 -6/2018 2019 JHLT. 2019 Oct; 38(10): 1015 -1066 5 Years (N=146)

Adult Heart-Lung Transplants Rehospitalization Post-transplant of Surviving Recipients (Follow-ups: January 1995 – June 2018) 100% 80% 60% 40% 20% No Hospitalization Hospitalized, Not Rejection/Not Infection Hospitalized, Rejection Only Hospitalized, Infection Only Hospitalized, Rejection and Infection 0% Up to 1 Year (N=599) Between 2 -3 Years (N=449) Between 4 -5 Years (N=383) 2019 JHLT. 2019 Oct; 38(10): 1015 -1066

Induction and Maintenance Immunosuppression 2019 JHLT. 2019 Oct; 38(10): 1015 -1066

Adult Heart-Lung Transplants Induction Immunosuppression (Transplants: January 2005 – June 2018) 70 N = 311 % of Patients 60 50 40 30 20 10 0 Any Induction Polyclonal ALG/ATG 2019 JHLT. 2019 Oct; 38(10): 1015 -1066 IL-2 R Antagonist Analysis is limited to patients who were alive at the time of discharge.

Adult Heart-Lung Transplants Induction Immunosuppression (Transplants: January 2005 – December 2017) 100 90 Any induction Polyclonal ALG/ATG IL-2 R Antagonist 80 60 50 40 30 20 10 0 20 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 17 % of Patients 70 2019 JHLT. 2019 Oct; 38(10): 1015 -1066 Analysis is limited to patients who were alive at the time of discharge.

Adult Heart-Lung Transplants Maintenance Immunosuppression Drug Combinations at Time of 1 Year Follow-up (Follow-ups: January 2005 – June 2018) 100% Other Sirolimus/Everolimus + Calcineurin Inhibitor + Cell Cycle Inhibitor 80% Sirolimus/Everolimus + Calcineurin Inhibitor 60% Tacrolimus + MMF/MPA 40% Tacrolimus + AZA Cyclosporine + MMF/MPA 20% Cyclosporine + AZA 0% Year 1 (N=260) 2019 JHLT. 2019 Oct; 38(10): 1015 -1066 Analysis is limited to patients who were alive at the time of follow-up.

Post-Transplant Morbidities 2019 JHLT. 2019 Oct; 38(10): 1015 -1066

Adult Heart-Lung Transplants Cumulative Post-Transplant Morbidity Rates in Survivors within 1 and 5 Years (Transplants: January 1995 – June 2017) Outcome Severe Renal Dysfunction* Within 1 Year Total number with known response Within 5 Years Total number with known response 7. 1% (N=480) 12. 4% (N=250) Creatinine > 2. 5 mg/dl (221 µmol/L) 3. 1% 8. 8% Chronic Dialysis 3. 8% 3. 2% Renal Transplant 0. 2% 0. 4% Diabetes 17. 3% (N=486) 27. 2% (N=250) Cardiac Allograft Vasculopathy 3. 1% (N=386) 7. 3% (N=124) Bronchiolitis Obliterans Syndrome 7. 1% (N=449) 31. 6% (N=206) 2019 JHLT. 2019 Oct; 38(10): 1015 -1066 * Severe renal dysfunction = Creatinine > 2. 5 mg/dl (221 μmol/L), dialysis or renal transplant

Adult Heart-Lung Transplants Freedom from Cardiac Allograft Vasculopathy and Bronchiolitis Obliterans Syndrome (Transplants: January 1995 – June 2017) Freedom from CAV and BOS (%) 100 75 50 25 Freedom from CAV (N=407) Freedom from BOS (N=474) 0 0 1 2 3 4 5 6 7 Years 2019 JHLT. 2019 Oct; 38(10): 1015 -1066 8 9 10 11 12 13 14

Adult Heart-Lung Transplants Freedom from Severe Renal Dysfunction (Transplants: January 1995 – June 2017) Freedom from Severe Renal Dysfunction (%) 100 N=504 75 50 25 *Severe renal dysfunction = Creatinine > 2. 5 mg/dl (221 μmol/L), dialysis, or renal transplant 0 0 1 2 3 4 5 6 7 8 Years 2019 JHLT. 2019 Oct; 38(10): 1015 -1066 9 10 11 12 13 14 15

Adult Heart-Lung Transplants Cumulative Post Transplant Malignancy Rates in Survivors (Transplants: January 1995 – June 2017) 1 -Year Survivors Malignancy/Type No Malignancy (all types combined) Malignancy Type* 5 -Year Survivors 10 -Year Survivors 466 (94. 7%) 234 (89. 3%) 103 (83. 1%) 26 (5. 3%) 28 (10. 7%) 21 (16. 9%) Skin 3 14 13 Lymphoma 18 8 3 Other 4 6 6 Type Not Reported 1 0 0 * Recipients may have experienced more than one type of malignancy so the sum of individual malignancy types may be greater than the total number with malignancy. 2019 JHLT. 2019 Oct; 38(10): 1015 -1066

Adult Heart-Lung Transplants Freedom from Malignancy (Transplants: January 1995 - June 2017) Freedom from Malignancy (%) 100 90 80 70 All malignancy Lymphoma 60 Skin Other 50 0 1 2 3 4 5 6 7 8 Years 2019 JHLT. 2019 Oct; 38(10): 1015 -1066 9 10 11 12 13 14 15

Adult-Heart Lung Transplants Cause of Death (Deaths: January 1995 – June 2018) Cause Of Death OB/BOS 0 -30 Days (N=371) 31 Days - 1 Year >1 Year - 3 Years >3 Years - 5 Years (N=301) (N=251) (N=143) >5 Years (N=570) 0 7 (2. 3%) 58 (23. 1%) 28 (19. 6%) 116 (20. 4%) 3 (0. 8%) 6 (2. 0%) 6 (2. 4%) 1 (0. 7%) 3 (0. 5%) 0 5 (1. 7%) 10 (4. 0%) 6 (4. 2%) 13 (2. 3%) 1 (0. 3%) 5 (1. 7%) 12 (4. 8%) 7 (4. 9%) 43 (7. 5%) 0 1 (0. 3%) 2 (0. 8%) 0 1 (0. 2%) Infection, Non-CMV 58 (15. 6%) 101 (33. 6%) 66 (26. 3%) 32 (22. 4%) 121 (21. 2%) Graft Failure 81 (21. 8%) 53 (17. 6%) 36 (14. 3%) 30 (21. 0%) 80 (14. 0%) Cardiovascular 34 (9. 2%) 17 (5. 6%) 22 (8. 8%) 16 (11. 2%) 58 (10. 2%) Technical 98 (26. 4%) 13 (4. 3%) 2 (0. 8%) 2 (1. 4%) 7 (1. 2%) Multiple Organ Failure 49 (13. 2%) 56 (18. 6%) 16 (6. 4%) 7 (4. 9%) 40 (7. 0%) Other 47 (12. 7%) 37 (12. 3%) 21 (8. 4%) 14 (9. 8%) 88 (15. 4%) Acute Rejection Lymphoma Malignancy, Other CMV 2019 JHLT. 2019 Oct; 38(10): 1015 -1066

Adult Heart-Lung Transplants Relative Incidence of Leading Causes of Death (Deaths: January 1995 – June 2018) OB/BOS Graft Failure Infection (non-CMV) Cardiovascular Technical % of Deaths 40 30 20 10 0 0 -30 Days (N=371) 31 Days - 1 Year (N=301) >1 -3 Years (N=251) 2019 JHLT. 2019 Oct; 38(10): 1015 -1066 >3 -5 Years (N=143) >5 Years (N=570)

Focus Theme: Donor and Recipient Size Match (Donor -Recipient Height Difference) 2019 JHLT. 2019 Oct; 38(10): 1015 -1066

Select Characteristics by Donor and Recipient Size Match 2019 JHLT. 2019 Oct; 38(10): 1015 -1066

Adult Heart-Lung Transplants Mean Donor-Recipient Height Difference (cm) by Transplant Year N Mean (cm) 2005 48 -0. 1 2006 47 2. 3 2007 35 1. 4 2008 31 0. 6 2009 44 -2. 7 2010 28 3. 5 2011 37 1. 1 2012 19 0. 3 2013 24 2. 9 2014 13 3. 2 2015 20 -0. 5 2016 33 3. 3 2017 16 1. 4 2018 48 -0. 1 2019 JHLT. 2019 Oct; 38(10): 1015 -1066

Adult Heart-Lung Transplants Donor-Recipient Height Difference by Recipient Diagnosis Category (Transplants: January 1992 – June 2018) <-15 cm - <-5 cm - 5 cm >5 cm - 15 cm >15 cm 100% % of Transplants 80% 60% 40% 20% 0% IIP/ILD-not IIP (N=82) IPAH/PH-not IPAH (N=1068) 2019 JHLT. 2019 Oct; 38(10): 1015 -1066 CF (N=202) Other (N=180)

Adult Heart-Lung Transplants Donor-Recipient Height Difference by Donor-Recipient Gender Combination (Transplants: January 1992 – June 2018) <-15 cm - <-5 cm - 5 cm >5 cm - 15 cm >15 cm 100% % of Transplants 80% 60% 40% 20% 0% Female-to-Female (N=767) Female-to-Male (N=250) 2019 JHLT. 2019 Oct; 38(10): 1015 -1066 Male-to-Female (N=272) Male-to-Male (N=580)

Adult Heart-Lung Transplants Donor-Recipient Height Difference by Ischemic Time (Transplants: January 1992 – June 2018) <-15 cm - <-5 cm - 5 cm >5 cm - 15 cm >15 cm 100% % of Transplants 80% 60% 40% 20% 0% <2 hours (N=41) 2 -<4 hours (N=486) 2019 JHLT. 2019 Oct; 38(10): 1015 -1066 4+ hours (N=441)

Adult Heart-Lung Transplants Donor-Recipient Height Difference by Donor Age (Transplants: January 1992 – June 2018) 15 cm - <-5 cm - 5 cm 18 -34 years (N=744) 35 -44 years (N=399) >5 cm - 15 cm >15 cm 100% % of Transplants 80% 60% 40% 20% 0% <18 years (N=304) 2019 JHLT. 2019 Oct; 38(10): 1015 -1066 45 -54 years (N=346) 55+ years (N=76)

Adult Heart-Lung Transplants Donor-Recipient Height Difference by Geographic Location (Transplants: January 1992 – June 2018) <-15 cm - <-5 cm - 5 cm >5 cm - 15 cm >15 cm 100% % of Transplants 80% 60% 40% 20% 0% Europe (N=943) North America (N=788) 2019 JHLT. 2019 Oct; 38(10): 1015 -1066 Other (N=138)

Post-Transplant Outcomes by Donor and Recipient Size Match 2019 JHLT. 2019 Oct; 38(10): 1015 -1066

Adult Heart-Lung Transplants Kaplan-Meier Survival Within 1 Year by Donor-Recipient Height Difference (Transplants: January 1992 – June 2017) 100 Survival (%) 75 50 No pairwise comparisons were significant at p < 0. 05. 25 <-15 cm (N=48) -15 cm - <-5 cm (N=302) >5 cm - 15 cm (N=495) >15 cm (N=79) -5 cm - 5 cm (N=888) 0 0 1 2 3 4 5 6 Months 2019 JHLT. 2019 Oct; 38(10): 1015 -1066 7 8 9 10 11 12

Adult Heart-Lung Transplants Kaplan-Meier Survival Within 1 Year by Donor-Recipient Weight Difference (Transplants: January 1992 – June 2017) 100 Survival (%) 75 50 No pairwise comparisons were significant at p < 0. 05 except -15 kg - < -5 kg vs. > 5 kg - 15 kg. 25 <-15 kg (N=182) -15 kg - < -5 kg (N=328) > 5 kg - 15 kg (N=477) > 15 kg (N=402) -5 kg - 5 kg (N=521) 0 0 1 2 3 4 5 6 Months 2019 JHLT. 2019 Oct; 38(10): 1015 -1066 7 8 9 10 11 12

Adult Heart-Lung Transplants Kaplan-Meier Survival Within 5 Years by Donor-Recipient Height Difference (Transplants: January 1992 – June 2013) 100 No pairwise comparisons were significant at p < 0. 05. Survival (%) 75 50 25 <-15 cm (N=44) -15 cm - <-5 cm (N=281) >5 cm - 15 cm (N=452) >15 cm (N=75) -5 cm - 5 cm (N=832) 0 0 1 2 3 Years 2019 JHLT. 2019 Oct; 38(10): 1015 -1066 4 5

Adult Heart-Lung Transplants Kaplan-Meier Survival Within 5 Years by Donor-Recipient Weight Difference (Transplants: January 1992 – June 2013) 100 No pairwise comparisons were significant at p < 0. 05 except -15 kg - < -5 kg vs. -5 kg - 5 kg , > 5 kg - 15 kg and >15 kg. Survival (%) 75 50 25 0 0 <-15 kg (N=172) -15 kg - < -5 kg (N=312) > 5 kg - 15 kg (N=443) > 15 kg (N=369) 1 2 2019 3 Years JHLT. 2019 Oct; 38(10): 1015 -1066 -5 kg - 5 kg (N=486) 4 5

Adult Heart-Lung Transplants Kaplan-Meier Freedom from BOS within 5 Years by Donor. Recipient Height Difference (Transplants: January 1992 – June 2013) 100 Survival (%) 75 50 No pairwise comparisons were significant at p < 0. 05. 25 <-15 cm (N=17) -15 cm - <-5 cm (N=84) >5 cm - 15 cm (N=134) >15 cm (N=26) -5 cm - 5 cm (N=175) 0 0 1 2 3 Years 2019 JHLT. 2019 Oct; 38(10): 1015 -1066 4 5

Multivariable Analysis 2019 JHLT. 2019 Oct; 38(10): 1015 -1066

Adult Heart-Lung Transplants (2000 -6/2017) Statistically Significant Risk Factors For 1 Year Mortality with 95% Confidence Limits 2019 JHLT. 2019 Oct; 38(10): 1015 -1066 (N = 1, 421)

Adult Heart-Lung Transplants (2000 -6/2017) Statistically Significant Risk Factors For 1 Year Mortality Continuous Factor (see figure) Donor age (years) Note: Recipient age and donor-recipient height difference were retained in the final model but were not statistically significant (p-values > 0. 05). 2019 JHLT. 2019 Oct; 38(10): 1015 -1066

Adult Heart-Lung Transplants (2000 -6/2017) Risk Factors For 1 Year Mortality with 95% Confidence Limits Donor age (years) Hazard Ratio of 1 Year Mortality 2. 5 p = 0. 0080 2. 0 1. 5 1. 0 0. 5 0. 0 15 20 25 30 35 40 45 50 55 Donor age (years) 2019 JHLT. 2019 Oct; 38(10): 1015 -1066 (N = 1, 421) 60