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Immunosuppressive Agents in Heart Transplantation.ppt

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  • 1. Immunosuppressive Agents in Heart Transplantation Intern 許育偉 2008.02.04
  • 2. Questions Before This Topic
    • 常見的免疫抑制劑,分成哪幾類 ?
    • Monoclonal 和 Polyclonal Ab 有什麼差別 ?
    • 何時要用 Induction Therapy ?
    • AZA 和 MMF 哪一個比較好 ?
    • CsA 和 Tacrolimus 哪一個比較好 ?
    • 在腎功能惡化的情況下的用藥原則 ?
    • 什麼是 Rescue Therapy ?
  • 3. Outlines of Today’s Topic
    • Immuno-suppression mechanism
    • (1) Induction therapy
    • (2) Maintenance therapy
    • Immunosuppressive agents in renal function impairment
    • Rescue therapy
    • Current regimens worldwide
  • 4. Kobashigawa JA and Patel JK (2006) Immunosuppression for heart transplantation: where are we now? Nat Clin Pract Cardiovasc Med 3: 203–212 doi:10.1038/ncpcardio0510 Corticosteroids 1. Nonspecific anti-inflammatory agents 2. Block T cell and APC derived cytokine and cytokine-receptor expression Calcineurin Inhibitors 1. (1) Cyclosporine (CsA)  Neoral (2) Tacrolimus (FK-506)  Prograf 2. Binds to calcineurin 3. Key function in current immunosuppressive agents 4. Nephrotoxicity !!! Anti-proliferative Agents 1. (1) Azathioprine  Imuran (2) Mycophenolate Mofetil (MMF)  Cellcept 2. Block the cell cycle (De Novo synthesis) Proliferation Signal Inhibitors 1. (1) Sirolimus  Rapamycin (Rapa) (2) Everolimus  Certican 2. Block signaling downstream IL-2R Monoclonal Antibodies 1. (1) Muromonab  OKT3 (2) Basiliximab  Simulect (3) Daclizumab  Zenapax 2. Block TCR, CD3, CD4, or IL-2R Polyclonal Antibodies 1. (1) Rabbit antithymocytes globulin  RATG (2) Horse antithymocytes globulin  ATGAM 2. Various amounts of specific Ab against T cells
  • 5. Induction Therapy
    • Upstream Ab  Immunologic ablation
    Division of Cardiology, Department of Medicine, University Of Maryland, Baltimore, Maryland. J Heart Lung Transplant 2007;26:205–9.
  • 6. Polyclonal vs. Monoclonal Ab Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario, K1Y-4W7, Canada Interact CardioVasc Thorac Surg 2005;4:415-419 Average mean time to first rejection
  • 7. Polyclonal vs. Monoclonal Ab Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario, K1Y-4W7, Canada Interact CardioVasc Thorac Surg 2005;4:415-419 Graft Rejection Infection One-Year Survival
  • 8. Polyclonal vs. Monoclonal Ab
    • Side-effects more in monoclonal Ab (OKT3)
    • ☆ Fever
    • ☆ Headaches
    • ☆ Acute respiratory distress
    • ☆ Hypotension
    Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario, K1Y-4W7, Canada Interact CardioVasc Thorac Surg 2005;4:415-419
  • 9. Monoclonal Ab : OKT3 vs. IL-2R
    • 2006, SIMCOR Study
    • Randomized Multicenter Comparison of Basiliximab and Muromonab (OKT3) in Heart Transplantation
    • 99 heart transplant recipients
    • No difference in
    • (1) Severity of acute rejection episodes
    • (2) Timing of acute rejection episodes
    • (3) Incidence of infection
    • (4) Actuarial survival.
    • OKT3 had a higher incidence of adverse events such as fever, pulmonary edema, and hypotension
    A randomized multicenter comparison of basiliximab and muromonab (OKT3) in heart transplantation: SIMCOR study. Transplantation 2006;81:1542–8.
  • 10. Induction Therapy : Who ?
    • Mehra MR, Uber PA, Uber WE, Scott RL Curr Opin Cardiol 2003;18:153–8 .
    • 1. Multiparous women
    • 2. Reoperative sternotomy patients
    • 3. Posttransfusions patients
    • 4. Supported with left ventricular assist devices.
    • Higgins R, Kirklin JK, Brown RN, et al ;
    • Cardiac Transplant Research Database (CTRD).
    • 1990~2001, enrolled 6553 patients J Heart Lung Transplant 2005;24:392–400 .
    • 1. Ventricular assist device
    • 2. Black ethnicity,
    • 3. Extensive human leukocyte antigen mismatching
    Division of Cardiology, Department of Medicine, University Of Maryland, Baltimore, Maryland. J Heart Lung Transplant 2007;26:205–9.
  • 11. Maintenance Therapy
    • Three-combined regimen
    • --- Glucocorticosteroids (1~2 mg/kg/day)
    • --- Calcineurin inhibitors (5 mg/ kg/ day)
    • Ex : CsA, Tacrolimus (FK-506)
    • --- Purine inhibitors
    • Ex : AZA, MMF
    • or added Sirolimus, Everolimus
    Department of Surgery, Louisiana State University Health Sciences Center CRITICAL CARE NURSING QUARTERLY/JANUARY–MARCH 2004
  • 12. Maintenance Therapy~CNI
    • Calcineurin inhibitors
    • Cornerstone of immunosuppressive therapy
    • High doses of CsA, Keep trough level : 250~350 μ g/L in initial 6~12 months
    • Trough 150~250 ≒250~350 μ g/L
    Department of Cardiovascular Surgery, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada Ann Thorac Surg 2004;77:363–71
  • 13. Maintenance ~ MMF and AZA
    • MMF 3000 mg/ day
    • AZA 1.5~3 mg/kg/day
    • MMF vs. AZA
    • Reduction of mortality at 1 year (p=0.03)
    • Less requirement for treatment of rejection within the first 6-months after transplantation (p=0.03)
    • Rejection free at 6 months (p=0.04)
    Department of Cardiovascular Surgery, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada Ann Thorac Surg 2004;77:363–71
  • 14. Maintenance Therapy
    • Cohort study, included 317 HT patients.
    • (1) OKT3 7 days + CsA + MMF + S
    • (2) OKT3 7 days + CsA + AZA + S
    • (3) OKT3 10 days + CsA + MMF + S
    • (4) OKT3 10 days + CsA + AZA + S
    • (5) IL-2 antagonists + CsA + MMF + S
    • (6) IL-2 antagonists + tacrolimus + MMF + S
    • (Daclizumab)
    Transplantation Proceedings, 38, 2550–2552 (2006)
  • 15. Maintenance Therapy Transplantation Proceedings, 38, 2550–2552 (2006)
  • 16. Maintenance Therapy
    • (5) IL-2 antagonists + CsA + MMF + S (91.2 %)
    • (6) IL-2 antagonists + tacrolimus + MMF + S (84.6 %)
    • (1) OKT3 7 days + CsA + MMF + S (75.8 %)
    • (3) OKT3 10 days + CsA + MMF + S (63.6 %)
    • (2) OKT3 7 days + CsA + AZA + S (51.2 %)
    • (4) OKT3 10 days + CsA + AZA + S (25.3 %)
    • (5) > (6)  CsA >FK-506 (???)
    • (1) > (2) and (3) > (4)  MMF > AZA
    • (5) > (1)  IL-2 ant > OKT3
    • (1) > (3)  OKT 7 days > 10 days
    Transplantation Proceedings, 38, 2550–2552 (2006)
  • 17. Tacrolimus vs. Cyclosporine
    • Europe : Favored Cyclosporine
    • America : Favored Tacrolimus
    J Heart Lung Transplant 2007;26:769–81.
  • 18. Tacrolimus vs. Cyclosporine
    • A large, prospective study
    • Randomized Clinical Trial
    • Tacrolimus vs. Cyclosporine (each 157)
    American Journal of Transplantation 2006; 6: 1387–1397
  • 19. Tacrolimus vs. Cyclosporine
    • Tacrolimus 0.075 mg/kg/day
    • Cyclosporine 4~6 mg/kg/day
    • ★ Target trough level
    • Tacrolimus 10~20 ng/mL for 1~3 months, followed by 5~15 ng/mL
    • Cyclosporine 200~350 ng/mL, followed by 100~200 ng/mL
    American Journal of Transplantation 2006; 6: 1387–1397
  • 20. Tacrolimus vs. Cyclosporine American Journal of Transplantation 2006; 6: 1387–1397
  • 21. Tacrolimus vs. Cyclosporine American Journal of Transplantation 2006; 6: 1387–1397 Creatinine Lipid (TG) SBP DBP
  • 22. Tacrolimus vs. Cyclosporine American Journal of Transplantation 2006; 6: 1387–1397
  • 23. Tacrolimus vs. Cyclosporine American Journal of Transplantation 2006; 6: 1387–1397
  • 24. Studies in Renal Impairments
    • Calcineurin inhibitors is the cornerstone of immunosuppressive therapy
    • Nephrotoxicity !!!
    • Odium et al : the level of pre-transplantation renal dysfunction that would lead to an increase in postoperative renal failure and mortality  Ccr< 40 ml/min
    • Goal : To minimize the usage of CNI
    Division of Cardiology, Department of Medicine, University Of Maryland, Baltimore, Maryland. J Heart Lung Transplant 2007;26:205–9.
  • 25. Induction Therapy with Delayed CNI
    • 1. High risk patients (Ccr 33~50 mL/min)
    • Basiliximab + CsA (Day 4 ) + MMF + S
    • 2. Low risk patients (Ccr > 50 mL/min)
    • Basiliximab + CsA (Day 0) + MMF + S
    • 3. High risk patients
    • Basiliximab + CsA (Day 0) + MMF + S
    •  Ccr : 2 ≒> 1 >> 3
    • Basiliximab vs. RATG  No difference
    Division of Cardiology, Department of Medicine, University Of Maryland, Baltimore, Maryland. J Heart Lung Transplant 2007;26:205–9.
  • 26. Sirolimus
    • Retrospective study, enroll 38 patients
    • Sirolimus loading dose : 2.0 mg
    • Sirolimus level : 8.0 ng/mL
    • P<0.01
    University Health Network, Toronto General Hospital, Toronto, Ontario, Canada. J Heart Lung Transplant 2007;26:998–1003. 28.8 25.6 25.9 22.9 Ccr 6 3 1 0 Months
  • 27. Everolimus
    • 2007 Prospective study
    • 5 medical centers
    • Enrolled 60 patients, 6-month follow-up
    • Loading dose : 0.75 mg BID
    • + CNI, MMF, Steroids in the first week
    • In the second week  CNI ↓ 30 %
    • After second week  DC CNI
    J Heart Lung Transplant 2007;26:250–7.
  • 28. Everolimus J Heart Lung Transplant 2007;26:250–7.
  • 29. Everolimus J Heart Lung Transplant 2007;26:250–7. Tremor Peripheral edema Hirsutism Gingival hyperplasia
  • 30. Rescue Therapy
    • Rescue treatment involves any type of therapy introduced once the first-line treatment has failed.
    • Corticosteroids
    • Polyclonal and monoclonal Ab
    • Mycophenolate Mofetil
    • Tacrolimus
    Department of Cardiovascular Surgery, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada Ann Thorac Surg 2004;77:363–71
  • 31. Rescue Therapy~ Corticosteroids
    • High doses corticosteroids
    • First choice for first-line rescue therapy
    • A pulse of 1g methylpredisolone iv for 3 days.( 500mg or 250 mg/day maybe ok )
    • Keep low dose oral form 0.5~1 mg/kg/d
    Department of Cardiovascular Surgery, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada Ann Thorac Surg 2004;77:363–71
  • 32. Rescue Therapy~ Antibodies
    • Steroid resistant  Ab
    • OKT3 in rescue therapy  10~14 days
    • Basilizumab and Daclizumab  not study well yet
    Department of Cardiovascular Surgery, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada Ann Thorac Surg 2004;77:363–71
  • 33. Rescue Therapy~ MMF
    • Steroids + Cyclosporine + Azathioprine
    •  Steroids + Cyclosporine + MMF
    • MMF oral dose : 1000~3000 mg/ day
    • Rescue  2000 mg~3000mg /day
    Department of Cardiovascular Surgery, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada Ann Thorac Surg 2004;77:363–71
  • 34. Rescue Therapy~ Tacrolimus
    • Cyclosporine  Tacrolimus (FK-506)
    • 139 patients, 15 of Grade III or above
    •  Conversion rate : 14 in 15 patients
    Department of Cardiovascular Surgery, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada Ann Thorac Surg 2004;77:363–71
  • 35. Transplantation worldwide
    • ISHLT, >76000 heart transplantation patients
    J Heart Lung Transplant 2007;26:769–81.
  • 36. World Trends ~ Induction J Heart Lung Transplant 2007;26:769–81. 42 52 20 <3 31 16 0
  • 37. World Trends ~ Maintenance (1) J Heart Lung Transplant 2007;26:769–81. 40 54 13 63 MMF dominant
  • 38. World Trends ~ Maintenance (5) J Heart Lung Transplant 2007;26:769–81. 39 33
  • 39. World Trends ~ Maintenance J Heart Lung Transplant 2007;26:769–81.
  • 40. Questions After This Topic
    • 常見的免疫抑制劑,分成哪幾類 ?
    • Monoclonal 和 Polyclonal Ab 有什麼差別 ?
    • 何時要用 Induction Therapy ?
    • AZA 和 MMF 哪一個比較好 ?
    • CsA 和 Tacrolimus 哪一個比較好 ?
    • 在腎功能惡化的情況下的用藥原則 ?
    • 什麼是 Rescue Therapy ?
  • 41. Thanks For Your Attention