1. Evaluation of morbidity and mortality outcomes in heart transplant patients with and without diabetes after implementation of a tacrolimus monotherapy protocol Maryanne Kim, PharmD PGY1 Pharmacy Resident 1

2. Triple Immunosuppressive Therapy Standard of care in heart transplant patients Calcineurin inhibitor (tacrolimus or cyclosporine) Antimetabolite (mycophenolate mofetil) Corticosteroid Successful in preventing rejection Several adverse outcomes from multiple immunosuppressive medications NODAT (New Onset Diabetes After Transplant) Renal impairment Cardiovascular events 2 1. Chakkera HA, Weil EJ, Pham PT, et al. Can new-onset diabetes after kidney transplant be prevented? Diabetes Care. 2013;36(5):1406-1412 2. Baran DA, Zucker MJ, Arroyo LH, et al. A prospective, randomized trial of sin-gle-drug versus dual-drug immunosuppression in heart transplantation: the tacrolimus in combination, tacrolimus alone compared (TICTAC) trial. Circ Heart Fail. 2011;4(2):129-137 3. Marchetti P. New-onset diabetes after transplantation. J Heart Lung Transplant. 2004; 23(5 Suppl):S194-201

3. Tacrolimus Monotherapy Protocol 3 Tacrolimus MMF Corticosteroid Week 0-4Week 4-8Indefinite Tacrolimus MMF Corticosteroid Tacrolimus Heart transplant Add appropriate anti-rejection medication based on biopsy results Rebiopsy based on rejection timing/grade

4. Study Rationale The average survival of post-orthotopic heart transplant (OHT) patients is 10 years Early detection and management of comorbidities such as diabetes is becoming more important Long-term morbidity and mortality data are available after implementation of the unique tacrolimus monotherapy but have never been evaluated to date 4 5. Mastrobuoni S, Dell'Aquila AM, Azcarate PM, et al. Long-term survival (>20 years) following heart transplantation. J Cardiovasc Surg (Torino).2012;53(5):677-684.

5. Study Objective To evaluate the incidence of pre-defined morbidity and mortality outcomes in post-orthotopic heart transplant patients with and without diabetes after implementation of the unique tacrolimus protocol 5

6. Study Endpoints 6 -----------------------------------Transplant------------------------------------ Group 1 Pre-existing DM Group 2 NODAT Group 3 No DM Number and percent of patients who were screened for NODAT at 3, 6, 12 months and yearly after transplantation

7. Methods Design: Retrospective chart analysis Approved by the Institutional Review Board 7 Inclusion Criteria Age >18 years Received a heart transplant between January 1, 2008 and December 31, 2009 Exclusion Criteria Patients with more than 1 organ transplant Patients requiring immunosuppressive therapy for non- transplant reasons

8. Methods Electronic Medical Records Cerner® Solutions Software OTTR: Organ Transplant Tracking Record Data collected Patient demographics At 3, 6, 12 months then yearly post-transplant All-cause mortality NODAT NF-MACE Renal disease progression Hospitalizations Outcomes analysis Descriptive statistics, one-way ANOVA, and Kaplan-Meier Curves using JMP ® Software 8

9. Study Subjects 9 Included (N=71) Adult pt who received heart transplant between 1/1/08-12/31/09 Group 1 (n=23) Pre-existing DM Group 2 (n=24) NODAT Group 3 (n=17) No DM Excluded n= 7 >1 organ transplant (n=3) On steroid for non- transplant reasons (n=4) Previously non-diabetic patients (n=41)

10. Baseline Characteristics 10 Mean (95% CI) Pre-existing DM Group 1 (n=23) NODAT Group 2 (n=24) No DM Group 3 (n=17) P value Age at time of transplant (yr) 56.6 (52.0-61.2)58.1 (53.6-62.3)53.5 (48.2-58.8)0.4115 Race (%) 0.0436* Caucasian73.954.258.8 African American 8.716.735.3 Hispanic4.3250 Gender-Female (%)8.720.835.30.1177 Scr (mg/dl)1.12 (0.97-1.26)1.14 (0.1-1.28)1.18 (1.02-1.35)0.8357 GFR (ml/min/1.73m 2 ) 72.5 (54.0-91.1)70.3 (52.1-88.5)85.3 (63.7-106.9)0.5386

11. Onset of NODAT 11 No DM (Group 3) n=17 Pre-existing DM (Group 1) n=23 NODAT (Group 2) n=24 37%

12. Mortality and Morbidity Outcomes 12 Percent of patients

13. Median Time to Event 13 6.59(0.72-7.33) 6.65 (6.29-7.41) 6.28 (6.07-6.84) 1.69 (1.25-4.1) 4.49 (3.4-5.2) 4.1 (3.8-4.9) 0.25 (0.25-0.25) 0.38 (0.25-0.5) 0.25(0.25-1.6) Years to Date (IQR)

14. Kaplan-Meier Survival Analysis 14 *Log-Rank test: p = 0.0257 o Intention-to-treat protocol o Group 1 (n=23) – pre-existing DM (red) o Group 2 (n=24) – NODAT (blue) o Group 3 (n=17) – No DM (green)

15. NODAT Screening 15

16. Discussion New diabetes patients post-transplant are likely under-represented Missing lab values resulting in missed diagnosis of NODAT No diabetes group (Group 3) may be over-represented Missed diagnosis People who expired before month 3 were included in Group 3 HbA1C was assessed in less than 30% of yearly post-transplant visits on average 16

17. Conclusion Approximately 60% of non-diabetic patients developed diabetes post-transplant Comorbidities were more common and seen earlier in pre-existing DM patients Current results highlight the need for timely screening of NODAT 17

18. Future Directions Opportunity for outpatient transplant pharmacists in screening for long-term comorbidities After diagnosis, pharmacist s can play a role in the proper management of diabetes in all transplant patients in outpatient setting Further study with larger N will be conducted to investigate correlation between diabetes status and outcomes 18

19. Assessment Question Which of the 3 study groups showed the highest incidence and the shortest time-to-event for NF-MACE (non-fatal major adverse cardiac events) and renal disease progression outcomes? A)Group 1: Pre-existing diabetes group B)Group 2: New Onset Diabetes After Transplant group (NODAT) C)Group 3: No diabetes group D)There was no difference between groups 19

20. Acknowledgement Leena Kansagra, PharmD, BCPS, Critical Care Clinical Specialist Sheetal Patel, PharmD, BCPS, Residency Program Director and Clinical Coordinator Rouel Guiang, RPh, Transplant Clinical Specialist David A. Baran, MD, FACC, FSCAI, Director of Heart Failure and Transplant Research 20

21. Questions? 21

22. References 1.Chakkera HA, Weil EJ, Pham PT, et al. Can new-onset diabetes after kidney transplant be prevented? Diabetes Care.2013;36(5):1406-1412. 2.Baran DA, Zucker MJ, Arroyo LH, et al. A prospective, randomized trial of sin-gle-drug versus dual-drug immunosuppression in heart transplantation: the tacrolimus in combination, tacrolimus alone compared (TICTAC) trial. Circ Heart Fail. 2011;4(2):129-137. 3.Marchetti P. New-onset diabetes after transplantation. J Heart Lung Transplant. 2004; 23(5 Suppl):S194-201 4.Barnabas Health Heart Failure and Transplant. Retrieved from http://www.barnabashealth.org/Newark-Beth-Israel-Medical-Center/Giving/What- Your-Gift-Can-Do/Heart-Failure-Transplantation-Program-Dr-Zucker.aspx. Accessed Nov 4, 2015 5.Mastrobuoni S, Dell'Aquila AM, Azcarate PM, et al. Long-term survival (>20 years) following heart transplantation. J Cardiovasc Surg (Torino).2012;53(5):677-684. 22

23. Methods 23 NODATNF-MACE Renal disease progression Hospitalization Satisfying at least one of the following: 2 Fasting Blood Glucose (FBG) ≥ 126 mg/dl Hemoglobin A1C (A1C) ≥ 6.5% Use of insulin Use of non-insulin antihyperglycemic agents First occurrence of: Nonfatal myocardial infarction Congestive heart failure Percutaneous cardiac intervention Coronary artery bypass grafting Cardiac defibrillator placement Cerebral vascular accident Peripheral vascular disease Decrease in estimated glomerular filtration rate (GFR) over two consecutive visits The groups are defined as: GFR ≥ 60 GFR 30-59 GFR <30 (ml/min/1.73m 2 ) Any inpatient admission resulting in an inpatient status. Definitions