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Immunosuppressive Agents in Heart Transplantation.ppt

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Immunosuppressive Agents in Heart Transplantation.ppt

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

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