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Induction and maintenance of immunosuppressive therapy in cardiac transplantation

Michael X Pham, MD, MPH
Section Editor
Sharon A Hunt, MD
Deputy Editor
Susan B Yeon, MD, JD, FACC


The goal of immunosuppression is to prevent or treat cardiac allograft rejection while minimizing drug toxicities as well as the major sequelae of immune suppression, namely infection and malignancy. Most clinically used immunosuppressive regimens consist of a combination of several agents used concurrently and the regimen design follows several general principles.

Immunosuppressive regimens can be classified as induction, maintenance, or anti-rejection. Induction regimens provide intense early postoperative immune suppression while maintenance regimens are used throughout the patient's life to prevent both acute and chronic rejection. This topic will review the induction and maintenance immunosuppressive regimens used in heart transplantation. The management of acute allograft rejection and the diagnosis and allograft vasculopathy are discussed separately. (See "Acute cardiac allograft rejection: Treatment" and "Prevention and treatment of cardiac allograft vasculopathy".)


Three general principles govern induction and maintenance immunosuppressive therapy regimens. The first principle is that immune reactivity and tendency toward graft rejection are highest early (within the first three to six months) after graft implantation and decrease with time. Thus, most regimens employ the highest intensity of immunosuppression immediately after surgery and decrease the intensity of therapy over the first year, eventually settling on the lowest maintenance levels of immunosuppression that are compatible with preventing graft rejection while minimizing drug toxicities in an individual patient. The second principle is to use low doses of several drugs with non-overlapping toxicities in preference to higher (and more toxic) doses of fewer drugs whenever feasible. The third principle is to avoid over-immunosuppression, because it leads to a myriad of undesirable effects including susceptibility to infection and malignancy. (See "Infection in the solid organ transplant recipient" and "Development of malignancy following solid organ transplantation" and "Treatment and prevention of post-transplant lymphoproliferative disorders".)


The overall strategy of deciding whether to use induction therapy and identifying an optimal regimen to achieve a state of early intense immunosuppression remains controversial. Approximately 50 percent of heart transplant programs currently do employ a strategy of augmented immunosuppression, or induction therapy, during the early postoperative period [1]. Several anti-lymphocyte antibodies that target specific epitopes on the surface of both B and T cells have been used as part of induction therapy.

The goal of induction therapy is to provide intense immunosuppression when the risk of allograft rejection is highest. From a clinical perspective, the main advantages of induction therapy are to allow delayed initiation of nephrotoxic immunosuppressive drugs in patients with compromised renal function prior to or following surgery and to provide some flexibility with respect to early glucocorticoid weaning or use of glucocorticoid-sparing baseline regimens after transplantation [2-4].

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Literature review current through: Nov 2017. | This topic last updated: Jul 31, 2017.
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  1. Lund LH, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: Thirty-second Official Adult Heart Transplantation Report--2015; Focus Theme: Early Graft Failure. J Heart Lung Transplant 2015; 34:1244.
  2. Rosenberg PB, Vriesendorp AE, Drazner MH, et al. Induction therapy with basiliximab allows delayed initiation of cyclosporine and preserves renal function after cardiac transplantation. J Heart Lung Transplant 2005; 24:1327.
  3. Yamani MH, Taylor DO, Czerr J, et al. Thymoglobulin induction and steroid avoidance in cardiac transplantation: results of a prospective, randomized, controlled study. Clin Transplant 2008; 22:76.
  4. Cantarovich M, Giannetti N, Barkun J, Cecere R. Antithymocyte globulin induction allows a prolonged delay in the initiation of cyclosporine in heart transplant patients with postoperative renal dysfunction. Transplantation 2004; 78:779.
  5. Adamson R, Obispo E, Dychter S, et al. Long-term outcome with the use of OKT3 induction therapy in heart transplant patients: a single-center experience. Transplant Proc 1998; 30:1107.
  6. Johnson MR, Mullen GM, O'Sullivan EJ, et al. Risk/benefit ratio of perioperative OKT3 in cardiac transplantation. Am J Cardiol 1994; 74:261.
  7. Swinnen LJ, Costanzo-Nordin MR, Fisher SG, et al. Increased incidence of lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in cardiac-transplant recipients. N Engl J Med 1990; 323:1723.
  8. Opelz G, Döhler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant 2004; 4:222.
  9. Beniaminovitz A, Itescu S, Lietz K, et al. Prevention of rejection in cardiac transplantation by blockade of the interleukin-2 receptor with a monoclonal antibody. N Engl J Med 2000; 342:613.
  10. Prieto M, Lake KD, Pritzker MR, et al. OKT3 induction and steroid-free maintenance immunosuppression for treatment of high-risk heart transplant recipients. J Heart Lung Transplant 1991; 10:901.
  11. Rinaldi M, Pellegrini C, D'Armini AM, et al. Neoplastic disease after heart transplantation: single center experience. Eur J Cardiothorac Surg 2001; 19:696.
  12. Higgins R, Kirklin JK, Brown RN, et al. To induce or not to induce: do patients at greatest risk for fatal rejection benefit from cytolytic induction therapy? J Heart Lung Transplant 2005; 24:392.
  13. Penninga L, Møller CH, Gustafsson F, et al. Immunosuppressive T-cell antibody induction for heart transplant recipients. Cochrane Database Syst Rev 2013; :CD008842.
  14. Segovia J, Rodríguez-Lambert JL, Crespo-Leiro MG, et al. A randomized multicenter comparison of basiliximab and muromonab (OKT3) in heart transplantation: SIMCOR study. Transplantation 2006; 81:1542.
  15. Mattei MF, Redonnet M, Gandjbakhch I, et al. Lower risk of infectious deaths in cardiac transplant patients receiving basiliximab versus anti-thymocyte globulin as induction therapy. J Heart Lung Transplant 2007; 26:693.
  16. Mehra MR, Zucker MJ, Wagoner L, et al. A multicenter, prospective, randomized, double-blind trial of basiliximab in heart transplantation. J Heart Lung Transplant 2005; 24:1297.
  17. Hershberger RE, Starling RC, Eisen HJ, et al. Daclizumab to prevent rejection after cardiac transplantation. N Engl J Med 2005; 352:2705.
  18. Hardinger KL, Rhee S, Buchanan P, et al. A prospective, randomized, double-blinded comparison of thymoglobulin versus Atgam for induction immunosuppressive therapy: 10-year results. Transplantation 2008; 86:947.
  19. Brennan DC, Flavin K, Lowell JA, et al. A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients. Transplantation 1999; 67:1011.
  20. El-Hamamsy I, Stevens LM, Carrier M, et al. Incidence and prognosis of cancer following heart transplantation using RATG induction therapy. Transpl Int 2005; 18:1280.
  21. Carrier M, Leblanc MH, Perrault LP, et al. Basiliximab and rabbit anti-thymocyte globulin for prophylaxis of acute rejection after heart transplantation: a non-inferiority trial. J Heart Lung Transplant 2007; 26:258.
  22. Caillat-Zucman S, Blumenfeld N, Legendre C, et al. The OKT3 immunosuppressive effect. In situ antigenic modulation of human graft-infiltrating T cells. Transplantation 1990; 49:156.
  23. Norman DJ. Mechanisms of action and overview of OKT3. Ther Drug Monit 1995; 17:615.
  24. Michaels PJ, Espejo ML, Kobashigawa J, et al. Humoral rejection in cardiac transplantation: risk factors, hemodynamic consequences and relationship to transplant coronary artery disease. J Heart Lung Transplant 2003; 22:58.
  25. Jensen PB, Birkeland SA, Rohrp N, et al. Development of anti-OKT3 antibodies after OKT3 treatment. Scand J Urol Nephrol 1996; 30:227.
  26. Hammond EH, Wittwer CT, Greenwood J, et al. Relationship of OKT3 sensitization and vascular rejection in cardiac transplant patients receiving OKT3 rejection prophylaxis. Transplantation 1990; 50:776.
  27. Bloom DD, Hu H, Fechner JH, Knechtle SJ. T-lymphocyte alloresponses of Campath-1H-treated kidney transplant patients. Transplantation 2006; 81:81.
  28. Morris PJ, Russell NK. Alemtuzumab (Campath-1H): a systematic review in organ transplantation. Transplantation 2006; 81:1361.
  29. Teuteberg JJ, Shullo MA, Zomak R, et al. Alemtuzumab induction prior to cardiac transplantation with lower intensity maintenance immunosuppression: one-year outcomes. Am J Transplant 2010; 10:382.
  30. Grimm M, Rinaldi M, Yonan NA, et al. Superior prevention of acute rejection by tacrolimus vs. cyclosporine in heart transplant recipients--a large European trial. Am J Transplant 2006; 6:1387.
  31. Groetzner J, Meiser BM, Schirmer J, et al. Tacrolimus or cyclosporine for immunosuppression after cardiac transplantation: which treatment reveals more side effects during long-term follow-up? Transplant Proc 2001; 33:1461.
  32. Meiser BM, Uberfuhr P, Fuchs A, et al. Single-center randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of acute myocardial rejection. J Heart Lung Transplant 1998; 17:782.
  33. Rinaldi M, Pellegrini C, Martinelli L, et al. FK506 effectiveness in reducing acute rejection after heart transplantation: a prospective randomized study. J Heart Lung Transplant 1997; 16:1001.
  34. Reichart B, Meiser B, Viganò M, et al. European Multicenter Tacrolimus (FK506) Heart Pilot Study: one-year results--European Tacrolimus Multicenter Heart Study Group. J Heart Lung Transplant 1998; 17:775.
  35. Taylor DO, Barr ML, Radovancevic B, et al. A randomized, multicenter comparison of tacrolimus and cyclosporine immunosuppressive regimens in cardiac transplantation: decreased hyperlipidemia and hypertension with tacrolimus. J Heart Lung Transplant 1999; 18:336.
  36. Kobashigawa JA, Miller LW, Russell SD, et al. Tacrolimus with mycophenolate mofetil (MMF) or sirolimus vs. cyclosporine with MMF in cardiac transplant patients: 1-year report. Am J Transplant 2006; 6:1377.
  37. Kobashigawa JA, Patel J, Furukawa H, et al. Five-year results of a randomized, single-center study of tacrolimus vs microemulsion cyclosporine in heart transplant patients. J Heart Lung Transplant 2006; 25:434.
  38. Eisen HJ, Hobbs RE, Davis SF, et al. Safety, tolerability, and efficacy of cyclosporine microemulsion in heart transplant recipients: a randomized, multicenter, double-blind comparison with the oil-based formulation of cyclosporine--results at 24 months after transplantation. Transplantation 2001; 71:70.
  39. Kobashigawa J, Miller L, Renlund D, et al. A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients. Mycophenolate Mofetil Investigators. Transplantation 1998; 66:507.
  40. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm072438.htm (Accessed on June 12, 2009).
  41. Kobashigawa JA, Renlund DG, Gerosa G, et al. Similar efficacy and safety of enteric-coated mycophenolate sodium (EC-MPS, myfortic) compared with mycophenolate mofetil (MMF) in de novo heart transplant recipients: results of a 12-month, single-blind, randomized, parallel-group, multicenter study. J Heart Lung Transplant 2006; 25:935.
  42. Lehmkuhl H, Hummel M, Kobashigawa J, et al. Enteric-coated mycophenolate-sodium in heart transplantation: efficacy, safety, and pharmacokinetic compared with mycophenolate mofetil. Transplant Proc 2008; 40:953.
  43. Kuppahally S, Al-Khaldi A, Weisshaar D, et al. Wound healing complications with de novo sirolimus versus mycophenolate mofetil-based regimen in cardiac transplant recipients. Am J Transplant 2006; 6:986.
  44. González-Vílchez F, de Prada JA, Exposito V, et al. Avoidance of calcineurin inhibitors with use of proliferation signal inhibitors in de novo heart transplantation with renal failure. J Heart Lung Transplant 2008; 27:1135.
  45. Keogh A, Richardson M, Ruygrok P, et al. Sirolimus in de novo heart transplant recipients reduces acute rejection and prevents coronary artery disease at 2 years: a randomized clinical trial. Circulation 2004; 110:2694.
  46. Zakliczynski M, Nozynski J, Kocher A, et al. Surgical wound-healing complications in heart transplant recipients treated with rapamycin. Wound Repair Regen 2007; 15:316.
  47. García-Luque A, Cordero E, Torelló J, et al. Sirolimus-associated pneumonitis in heart transplant recipients. Ann Pharmacother 2008; 42:1143.
  48. Khalife WI, Kogoj P, Kar B. Sirolimus-induced alveolar hemorrhage. J Heart Lung Transplant 2007; 26:652.
  49. Delgado JF, Torres J, José Ruiz-Cano M, et al. Sirolimus-associated interstitial pneumonitis in 3 heart transplant recipients. J Heart Lung Transplant 2006; 25:1171.
  50. Eisen HJ, Kobashigawa J, Starling RC, et al. Everolimus versus mycophenolate mofetil in heart transplantation: a randomized, multicenter trial. Am J Transplant 2013; 13:1203.
  51. Miller LW, Wolford T, McBride LR, et al. Successful withdrawal of corticosteroids in heart transplantation. J Heart Lung Transplant 1992; 11:431.
  52. Olivari MT, Jessen ME, Baldwin BJ, et al. Triple-drug immunosuppression with steroid discontinuation by six months after heart transplantation. J Heart Lung Transplant 1995; 14:127.
  53. Kobashigawa JA, Stevenson LW, Brownfield ED, et al. Initial success of steroid weaning late after heart transplantation. J Heart Lung Transplant 1992; 11:428.
  54. Teuteberg JJ, Shullo M, Zomak R, et al. Aggressive steroid weaning after cardiac transplantation is possible without the additional risk of significant rejection. Clin Transplant 2008; 22:730.
  55. Taylor DO, Bristow MR, O'Connell JB, et al. Improved long-term survival after heart transplantation predicted by successful early withdrawal from maintenance corticosteroid therapy. J Heart Lung Transplant 1996; 15:1039.
  56. Renlund DG, O'Connell JB, Gilbert EM, et al. Feasibility of discontinuation of corticosteroid maintenance therapy in heart transplantation. J Heart Transplant 1987; 6:71.
  57. Gustafsson F, Ross HJ, Delgado MS, et al. Sirolimus-based immunosuppression after cardiac transplantation: predictors of recovery from calcineurin inhibitor-induced renal dysfunction. J Heart Lung Transplant 2007; 26:998.
  58. Raichlin E, Khalpey Z, Kremers W, et al. Replacement of calcineurin-inhibitors with sirolimus as primary immunosuppression in stable cardiac transplant recipients. Transplantation 2007; 84:467.
  59. Rothenburger M, Teerling E, Bruch C, et al. Calcineurin inhibitor-free immunosuppression using everolimus (Certican) in maintenance heart transplant recipients: 6 months' follow-up. J Heart Lung Transplant 2007; 26:250.
  60. Bestetti R, Theodoropoulos TA, Burdmann EA, et al. Switch from calcineurin inhibitors to sirolimus-induced renal recovery in heart transplant recipients in the midterm follow-up. Transplantation 2006; 81:692.
  61. Fernandez-Valls M, Gonzalez-Vilchez F, de Prada JA, et al. Sirolimus as an alternative to anticalcineurin therapy in heart transplantation: experience of a single center. Transplant Proc 2005; 37:4021.
  62. Kushwaha SS, Khalpey Z, Frantz RP, et al. Sirolimus in cardiac transplantation: use as a primary immunosuppressant in calcineurin inhibitor-induced nephrotoxicity. J Heart Lung Transplant 2005; 24:2129.
  63. Hunt J, Lerman M, Magee MJ, et al. Improvement of renal dysfunction by conversion from calcineurin inhibitors to sirolimus after heart transplantation. J Heart Lung Transplant 2005; 24:1863.
  64. Groetzner J, Kaczmarek I, Landwehr P, et al. Renal recovery after conversion to a calcineurin inhibitor-free immunosuppression in late cardiac transplant recipients. Eur J Cardiothorac Surg 2004; 25:333.
  65. Gleissner CA, Doesch A, Ehlermann P, et al. Cyclosporine withdrawal improves renal function in heart transplant patients on reduced-dose cyclosporine therapy. Am J Transplant 2006; 6:2750.
  66. Potter BJ, Giannetti N, Edwardes MD, et al. Calcineurin inhibitor substitution with sirolimus vs. reduced-dose calcineurin inhibitor plus sirolimus is associated with improved renal dysfunction in heart transplant patients. Clin Transplant 2007; 21:305.
  67. Roche Laboratories Inc. Higher than expected incidence of acute rejection in cardiac transplant patients switched from calcineurin inhibitors in combination with CellCept (mycophenolate mofetil) to Rapamune (sirolimus) in combination with CellCept at 12 weeks post heart transplantation. 2007.
  68. Andreassen AK, Andersson B, Gustafsson F, et al. Everolimus initiation and early calcineurin inhibitor withdrawal in heart transplant recipients: a randomized trial. Am J Transplant 2014; 14:1828.
  69. Eisen HJ, Tuzcu EM, Dorent R, et al. Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med 2003; 349:847.
  70. Mancini D, Pinney S, Burkhoff D, et al. Use of rapamycin slows progression of cardiac transplantation vasculopathy. Circulation 2003; 108:48.
  71. Raichlin E, Bae JH, Khalpey Z, et al. Conversion to sirolimus as primary immunosuppression attenuates the progression of allograft vasculopathy after cardiac transplantation. Circulation 2007; 116:2726.
  72. Mathew T, Kreis H, Friend P. Two-year incidence of malignancy in sirolimus-treated renal transplant recipients: results from five multicenter studies. Clin Transplant 2004; 18:446.
  73. Campistol JM, Eris J, Oberbauer R, et al. Sirolimus therapy after early cyclosporine withdrawal reduces the risk for cancer in adult renal transplantation. J Am Soc Nephrol 2006; 17:581.
  74. Kauffman HM, Cherikh WS, Cheng Y, et al. Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies. Transplantation 2005; 80:883.
  75. Stallone G, Schena A, Infante B, et al. Sirolimus for Kaposi's sarcoma in renal-transplant recipients. N Engl J Med 2005; 352:1317.
  76. Euvrard S, Morelon E, Rostaing L, et al. Sirolimus and secondary skin-cancer prevention in kidney transplantation. N Engl J Med 2012; 367:329.
  77. Guba M, von Breitenbuch P, Steinbauer M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 2002; 8:128.
  78. Page RL 2nd, Miller GG, Lindenfeld J. Drug therapy in the heart transplant recipient: part IV: drug-drug interactions. Circulation 2005; 111:230.
  79. Wynn GH, Oesterheld JR, Cozza KL, Armstrong SC. Clinical manual of drug interaction principles for medical practice, American psychiatric publishing, Washington DC 2009.