Heart transplantation in adults: Induction and maintenance of immunosuppressive therapy

INTRODUCTION — 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 antirejection. 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 allograft vasculopathy are discussed separately. (See "Heart transplantation in adults: Treatment of rejection" and "Heart Transplantation: Prevention and treatment of cardiac allograft vasculopathy".)

GENERAL PRINCIPLES — 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 nonoverlapping 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 "Malignancy after solid organ transplantation" and "Treatment and prevention of post-transplant lymphoproliferative disorders".)

INDUCTION THERAPY — 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 40 to 50 percent of heart transplant programs currently employ a strategy of augmented immunosuppression (induction therapy) during the early postoperative period [1]. Several antilymphocyte 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 maintenance regimens after transplantation [2-4].

However, the overall utility of induction is uncertain and data comparing induction protocols are limited. The decreased early rejection observed with induction therapy may be negated by an increase in late rejection after induction therapy is completed and by the potential for increased rates of infection and malignancy associated with such therapy [5-11]. However, patients at highest risk for fatal rejection, including younger patients, African American patients, patients with a high number of HLA mismatches, and patients supported with ventricular assist devices with high levels of preformed antibodies, may derive a benefit from induction therapy [12].

A Cochrane review included 22 randomized controlled trials investigating the use of T-cell antibody for induction [13]. Five trials, with a total of 606 participants, compared any type of induction versus no induction. The remaining trials compared various types of induction regimens against each other. No significant differences were found for any of the comparisons for outcomes of mortality, infection, posttransplant lymphoproliferative disorder, cancer, adverse events, or cardiac allograft vasculopathy.

In the Cochrane review, the only significant differences found were a reduction in the incidence of acute rejection among patients treated with interleukin-2 (IL-2) receptor antagonists compared with no induction and fewer rejection episodes among patients treated with polyclonal antibody induction compared with IL-2 receptor antagonist therapy, though the numbers of events were small so an effect of chance cannot be excluded. (See 'Interleukin-2 receptor antagonists' below and 'Polyclonal antithymocyte antibodies' below.)

Interleukin-2 receptor antagonists — Use of interleukin-2 (IL-2) receptor antagonists for induction therapy has increased, and these drugs are now used in 30 percent of patients undergoing heart transplantation [1]. The currently available agent, basiliximab (Simulect), is a monoclonal antibody that selectively binds to the IL-2 receptor of T lymphocytes, blocks binding of IL-2 to the receptor complex, and exhibits its immunosuppressive effects by inhibiting IL-2-mediated T-lymphocyte proliferation.

The Cochrane review cited above included four trials with a total of 576 patients comparing IL-2 receptor antagonist versus no induction and found no significant difference in outcomes except possibly acute rejection [13]. Acute rejection occurred significantly less frequently with IL-2 receptor antagonist versus no induction when a fixed-effect model was used but not when a random-effects model was applied.

Polyclonal antithymocyte antibodies — Polyclonal antibodies are derived by immunization of horses (ATGAM, also called lymphocyte immune globulin) or rabbits (Thymoglobulin) with human thymocytes. These agents combined are employed in up to 20 percent of heart transplant recipients based upon the international transplant registry data [1].

These preparations contain antibodies directed against a wide variety of human T-cell antigens and cause rapid depletion of T lymphocytes by inducing complement-mediated cytolysis and cell-mediated opsonization in the spleen and liver. There are no head-to-head comparison trials of ATGAM and Thymoglobulin in heart transplantation, but data from the kidney transplant literature suggest that Thymoglobulin may result in a lower incidence of both short- and long-term acute rejection compared with ATGAM, possibly because of more profound and durable lymphopenia after Thymoglobulin administration [14,15]. (See "Kidney transplantation in adults: Induction immunosuppressive therapy".)

The major acute side effects associated with this class of drugs include a serum sickness reaction characterized by fevers, chills, tachycardia, hypertension or hypotension, myalgias, and rash. The reaction is typically noticed during the first or second drug infusion and can be treated by temporarily stopping the drug infusion and restarting at a lower infusion rate. Premedication with intravenous glucocorticoids, antihistamines, antipyretics, and H2 blockers can prevent or reduce the severity of symptoms. Dose-dependent leukopenia (30 to 50 percent) and thrombocytopenia (30 to 40 percent) have also been observed and typically respond to dose reduction or drug discontinuation for severe cases (WBC <2,000 cells/mm³ or platelet count <50,000 cells/mm³). These agents do not induce a host antibody response to horse or rabbit sera and can be re-used for the treatment of allograft rejection. Long-term side effects include a predisposition to opportunistic infections, particularly with cytomegalovirus and a possible increase in the incidence and aggressiveness of posttransplant malignancies [11,16,17].

Alemtuzumab — Alemtuzumab (Campath-1H) is a humanized rat monoclonal antibody that targets the CD52 antigen expressed on both T and B cells. It is used in fewer than 2 percent of heart transplant recipients [1]. This powerful cytolytic agent produces a profound lymphopenia that lasts for approximately six months and that may persist for up to three years in some individuals [18]. The agent was originally developed to treat chronic lymphocytic leukemia but has also been used as induction therapy in solid organ transplantation, mostly in kidney transplant recipients, where it has permitted use of lower intensity maintenance immunosuppression [19]. Early experience suggests that Campath may decrease the incidence of early (<12 months) acute cellular rejection while allowing the use of lower intensity maintenance immunosuppression [20].

MAINTENANCE IMMUNOSUPPRESSIVE REGIMENS — The strategies and drugs used for immune suppression have advanced considerably since the first heart transplant was performed in 1967. Beginning with the introduction of cyclosporine in 1983, significant advances have been made in moving from drugs that provide broad and nonspecific immunosuppression to newer agents that provide more targeted immunosuppression through selective inhibition of lymphocyte activation and proliferation. This selectivity has resulted in a marked increase in patient survival due to a decrease in the incidence of both life-threatening opportunistic infections and rejection episodes. Most maintenance immunosuppressive protocols employ a three-drug regimen consisting of a calcineurin inhibitor (CNI; cyclosporine or tacrolimus), an antimetabolite agent (mycophenolate mofetil or less commonly azathioprine), and tapering doses of glucocorticoids over the first year posttransplantation. The commonly used drugs in heart transplantation and their toxicities are outlined (table 1).

Calcineurin inhibitors — Since the introduction of cyclosporine in the early 1980s, CNIs have remained the cornerstone of maintenance immunosuppressive therapy in heart and other solid organ transplantation. These drugs exert their immunosuppressive effects by inhibiting calcineurin, which is normally responsible for the transcription of IL-2 and several other cytokines, including TNF alpha, granulocyte-macrophage colony-stimulating factor, and interferon-gamma. The end result is blunting of T-lymphocyte activation and proliferation in response to alloantigens. The two available CNIs, cyclosporine and tacrolimus, form complexes with different intracellular binding proteins, and these drug-protein complexes subsequently bind to and inhibit calcineurin. The drugs differ with respect to both efficacy and side effect profile. (See "Pharmacology of cyclosporine and tacrolimus".)

Tacrolimus — Tacrolimus (Prograf), previously known as FK-506, is a macrolide compound derived from the fungus Streptomyces tsukubaensis. It binds to a cytoplasmic protein called FK binding protein and inhibits calcineurin via a similar pathway to that of cyclosporine. The US Food and Drug Administration (FDA) originally approved the drug in 1995 for use in liver transplantation and later approved it for use in kidney (1997) and heart (2006) transplantation. Tacrolimus is the most widely used CNI.

Multiple single-center and multi-center randomized comparisons between de novo use of tacrolimus and cyclosporine after heart transplantation have been reported [21-27]. As a whole, these trials have shown similar patient survival and a more favorable side effect profile with tacrolimus. For example, CNI-associated metabolic derangements appear to be significantly attenuated with tacrolimus use. Patients on tacrolimus, compared with cyclosporine, consistently had lower incidences of hypertension and hyperlipidemia. Two studies showed modest benefits with respect to renal function in the tacrolimus group [27,28], while one study demonstrated a higher incidence of posttransplant diabetes with tacrolimus [21]. With respect to efficacy, a few studies showed a decreased incidence of biopsy-proven acute rejection or drug-treated acute rejection in the tacrolimus treated patients [21,28].

In the largest head-to-head comparison of tacrolimus and cyclosporine, 314 de novo heart transplant recipients were randomized to either tacrolimus or microemulsion-based cyclosporine in combination with azathioprine and glucocorticoids [21]. All patients underwent induction therapy with either thymoglobulin or OKT3. Over 18 months of follow-up, patient survival was similar in both groups. However, patients in the tacrolimus group had a lower incidence of biopsy-proven moderate or severe acute cellular rejection at six months compared with the cyclosporine group (28 versus 42 percent, p = 0.013). Significant differences were also detected between the tacrolimus and cyclosporine group with respect to new onset diabetes mellitus (20 percent versus 11 percent), hypertension (66 versus 78 percent), and dyslipidemia (29 versus 40 percent). The incidence and patterns of infection, as well as renal function, were similar in the two groups.

Dosing and therapeutic drug monitoring — Tacrolimus is available as oral capsules, liquid oral formulation, and as an injectable solution. The drug is typically given orally. When intravenous administration is required, approximately one-third of the daily oral dose should be given as a continuous infusion over 24 hours. Drug dosing is titrated to achieve therapeutic 12-hour trough levels for oral dosing and steady-state levels (approximately 1.4 times higher than trough levels) for intravenous dosing. In general, target trough levels are typically highest in the first two months (10 to 15 ng/mL), with reduced target levels later after transplantation (8 to 12 ng/mL during months 3 to 6, and 5 to 10 ng/mL after six months) [29].

Major toxicities — Compared with cyclosporine, use of tacrolimus is associated with less hypertension and dyslipidemia. However, an increased frequency of new-onset diabetes mellitus has been observed in patients on tacrolimus compared with cyclosporine. (See "Pharmacology of cyclosporine and tacrolimus".)

Cyclosporine — Cyclosporine is a peptide derived from the fungus Tolypocladium inflatum that has powerful immunosuppressive properties. It binds to the cytoplasmic protein cyclophilin to inhibit calcineurin. The drug is available in several formulations. The older oil-based formulation called Sandimmune was characterized by variable and incomplete absorption. The newer modified formulations, including Gengraf and Neoral, are microemulsion formulations that result in improved and more reproducible drug absorption. In a randomized, multi-center, double-blind comparison of the oil-based (Sandimmune) versus the microemulsion (Neoral) cyclosporine formulations in de novo heart transplant recipients, the use of Neoral was associated with fewer rejection episodes requiring antilymphocyte antibody therapy compared with Sandimmune at 24 months (7 versus 18 percent, p = 0.002). Graft and patient survival were identical in both groups [30].

Due to their improved pharmacokinetic profile, the microemulsion preparations are generally preferred over the oil-based formulation. The two formulations are not considered bioequivalent, and patients should not be routinely switched from one to the other without close monitoring of drug levels.

Dosing and therapeutic drug monitoring — Cyclosporine is available as oil-based or microemulsion capsules, as an oral microemulsion solution, and as a concentrate for injection. When given intravenously, approximately one-third of the daily oral dose should be given as a continuous infusion over 24 hours. The drug is typically titrated to achieve therapeutic 12-hour trough levels for oral dosing and steady-state levels (approximately 2.6 times higher than trough levels) for intravenous dosing. In general, cyclosporine levels are kept highest in the first six months posttransplantation (275 to 375 ng/mL during the first six postoperative weeks, 200 to 350 ng/mL for weeks 6 to 12, and 150 to 300 ng/mL for months 3 to 6) and lowered in subsequent periods (150 to 250 ng/mL from month 6 onward) [29]. However, target drug levels should be individualized to balance a patient's risk of rejection with drug toxicities, particularly renal dysfunction, and long-term complications of immunosuppression (infections and malignancy).

Major toxicities — The major toxicities of cyclosporine include kidney function impairment, hypertension, dyslipidemia, hypokalemia and hypomagnesemia, and neurotoxicity (table 1). Gingival hyperplasia and hirsutism are two additional side effects that are unique to cyclosporine and can be especially bothersome in young patients. (See "Pharmacology of cyclosporine and tacrolimus".)

ANTIMETABOLITES — The antimetabolites, or antiproliferative agents, interfere with the synthesis of nucleic acids and exert their immunosuppressive effects by inhibiting the proliferation of both T and B lymphocytes.

Azathioprine — Azathioprine (Imuran) is a prodrug that is first rapidly hydrolyzed in the blood to its active form, 6-mercaptopurine, and subsequently converted to a purine analogue, thio-inosine-monophosphate. This antimetabolite is incorporated into DNA and inhibits further nucleotide synthesis, thereby preventing mitosis and proliferation of rapidly dividing cells such as activated T and B lymphocytes. This drug is typically used as an adjunctive immunosuppressive agent with either glucocorticoids or, more commonly, in conjunction with a calcineurin inhibitor. A typical dose is 1 to 3 mg/kg/day, and the maximum dose is 200 mg/day. The dose of azathioprine is adjusted to keep the white blood cell count at or slightly above 3000/mm³. The major side effects include dose-dependent myelosuppression, particularly leukopenia. Azathioprine should be temporarily withheld if the white cell count falls below 3000/mm³ or drops by 50 percent compared with the previous value. Other potentially serious side effects include hepatotoxicity and pancreatitis.

Mycophenolate mofetil — Mycophenolate mofetil (MMF; Cellcept) has replaced azathioprine as the preferred antimetabolite agent. It is also a prodrug that is rapidly hydrolyzed to its active form, mycophenolic acid (MPA). MPA is a reversible inhibitor of inosine monophosphate dehydrogenase, a critical enzyme for the de-novo synthesis of guanine nucleotides. Lymphocytes lack a key enzyme in the guanine salvage pathway and are dependent upon the de novo pathway for the production of purines necessary for RNA and DNA synthesis. Therefore, both T- and B-lymphocytes proliferation is selectively inhibited.

In a multicenter, active-controlled, randomized trial, MMF was compared with azathioprine when used in conjunction with cyclosporine and glucocorticoids in 650 de novo heart transplant recipients. Because an intravenous form of the study drug (MMF) was not available at the time of the trial, 11 percent of the patients withdrew before receiving the drug. Survival and rejection were similar in both groups when analyzed in an intention-to-treatment manner. However, among treated patients, MMF was associated with a significant reduction in both mortality (6 versus 11 percent, p = 0.031) and in the incidence of treatable rejection (66 versus 74 percent, p = 0.026) at one year [31].

Dosing and therapeutic drug monitoring — MMF is available as a tablet or capsule, oral suspension (liquid), and as a powder for injection. The intravenous solution is given at the same oral dose as a two-hour infusion every 12 hours. The drug is typically administered at a starting dose of 1000 to 1500 mg twice daily and subsequently decreased as needed in response to leukopenia and gastrointestinal intolerance.

Routine monitoring of mycophenolate levels is not recommended [29,32]. Monitoring of mycophenolic acid (MPA) levels may be helpful in patients with high risk for rejection or adverse effects [33-35]; levels can also be useful to assess compliance when that is a concern. Some centers target MPA trough levels between 2 to 5 mcg/mL. However, MPA trough levels are poorly correlated with AUC [36]. In patients receiving mycophenolate mofetil at steady-state, limited sampling strategies to estimate the area under the concentration-time curve (AUC_0-12h) were found to correlate with a full AUC measurement [37-39].

Major toxicities — MMF is not nephrotoxic and causes less bone marrow suppression compared with azathioprine. The main side effects include dose-related leukopenia and gastrointestinal toxicities such as nausea, gastritis, and diarrhea. A possible association between MMF and Progressive Multifocal Leukoencephalopathy (PML) has been reported [40]. The drug is contraindicated during pregnancy due to the risk of miscarriage and teratogenicity, and women of childbearing potential should not take MMF without appropriate birth control measures. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Mycophenolate mofetil'.)

Mycophenolate sodium — Mycophenolate sodium (EC-MPS) is an enteric coated, delayed release salt of mycophenolic acid developed to improve the upper gastrointestinal tolerability of mycophenolate. Mycophenolic sodium is available in 180 mg and 360 mg enteric coated tablets. Because of this coating, the tablet should NOT be crushed. The following conversions between MMF and mycophenolate sodium should provide equimolar amounts of MPA:

●1000 mg MMF = 720 mg mycophenolate sodium

●1500 mg MMF = 1080 mg mycophenolate sodium

Thus, a typical starting dose is 720 to 1080 twice daily. Single- and multi-center studies in de novo heart transplant recipients have shown that EC-MPS is therapeutically similar to MMF with respect to prevention of treatment failure (defined as biopsy-proven and treated acute rejection episodes, graft loss, or death). However, significantly fewer patients in the EC-MPS group required dose reductions during treatment [41,42].

Limited sampling strategies to estimate the area under the concentration-time curve for mycophenolate mofetil are not directly applicable to patients receiving mycophenolate sodium [43]. Limited sampling strategies to estimate full AUC have been proposed for patients treated with enteric-coated mycophenolate sodium [44,45]; however, consensus is lacking on the utility of these methods.

PROLIFERATION SIGNAL INHIBITORS — A new class of drugs known as proliferation signal inhibitors, or mammalian target of rapamycin (mTOR) inhibitors, has been used in selected patients with kidney function impairment, cardiac allograft vasculopathy, or malignancies in an attempt to reverse or slow progression of these conditions. However, the high incidence of drug-related adverse effects, including delayed sternal wound healing after transplantation, may limit the widespread use of these agents as de novo therapy following transplantation [46-48].

The two drugs in this class, sirolimus and everolimus, have similar mechanisms of action. They are structurally similar to tacrolimus and also bind to the FK binding protein. However, they exert their immunosuppressive effects via a calcineurin-independent mechanism. The drug-immunophilin complex inhibits a protein kinase in the cytoplasm called mammalian target of rapamycin (mTOR). mTOR is involved in the transduction signals from the IL-2 receptor to the nucleus, causing cell cycle arrest at the G1 to S phase. The consequence of mTOR inhibition is inhibition of both T- and B-cell proliferation in response to cytokine signals.

Sirolimus — Sirolimus (Rapamune) is a macrolide antibiotic derived from the fungus Streptomyces hygroscopicus. The efficacy of sirolimus as an alternative to azathioprine was evaluated in a prospective, open-label, randomized trial of 136 de novo heart transplant recipients. Patients were randomized 2:1 to receive one of two sirolimus doses (3 or 5 mg) or to azathioprine. Sirolimus doses were subsequently adjusted in both groups to achieve similar target blood levels. All patients received concurrent immunosuppression with cyclosporine and glucocorticoids. Compared with azathioprine, the proportion of patients with a biopsy-proven moderate to severe acute cellular rejection episode at six months was lower in both the 3 mg/day (32 versus 57 percent, p = 0.027) and 5 mg/day sirolimus groups (33 versus 57 percent, p = 0.013). Additionally, the progression of cardiac allograft vasculopathy, as defined by intravascular ultrasound, was significantly reduced in the sirolimus group at both six months and two years. Patient survival at 12 months was comparable among groups [48].

Dosing and therapeutic drug monitoring — Sirolimus is available in a liquid or tablet formulation. When used in conjunction with cyclosporine-modified capsules (Gengraf or Neoral), sirolimus should be given four hours after cyclosporine administration to minimize the pharmacokinetic interaction between the two drugs. Dosing is typically adjusted to achieve serum trough levels of 4 to 12 ng/mL when used with a concurrent calcineurin inhibitor (CNI) and 8 to 14 ng/mL when used as part of a CNI-free regimen [29,49]. Target ranges may vary depending upon the assay (immunoassay versus chromatographic) used, so clinicians should be familiar with the reference range for the assay used at their institutions.

Major toxicities — The most common drug-related toxicities include hyperlipidemia, oral ulcerations, lower extremity edema, and bone marrow suppression with leukopenia, thrombocytopenia, and anemia [48]. Postsurgical wound healing complications, as well as an increase in the incidence of pleural and pericardial effusions requiring drainage, have also been reported [46,50]. Finally, rare but serious cases of sirolimus-related pulmonary toxicity have been described [51-53].

Sirolimus has no inherent nephrotoxic effects but can potentiate the nephrotoxic effects of CNIs. Therefore, when these agents are used together, the dose of the CNI should be reduced by approximately 25 percent. Additionally, moderate or higher proteinuria (≥300 mg/day) has been observed in 26 percent of patients after the first year following conversion from a CNI, particularly in patients with preexisting proteinuria prior to conversion. The development of proteinuria after conversion has been associated with worsening renal function, cardiac allograft vasculopathy progression, and increased all-cause mortality [54]. In our practice, we order a random morning urine collection and calculate a spot protein to creatinine ratio (UPCR) as an estimate of 24-hour protein excretion because collection of 24-hour urine samples is cumbersome and prone to collection errors. We check the UPCR prior to sirolimus conversion and at 4, 8, and 12 months and yearly thereafter. We place patients who have preexisting proteinuria, or who develop proteinuria after conversion, on angiotensin converting enzyme inhibitors, and discontinue sirolimus if the protein excretion is >1000 mg/day.

Everolimus — Everolimus (Zortress) is an analog of sirolimus that was approved for clinical use in the United States for prevention of rejection in kidney and liver transplantation. The main difference between sirolimus and everolimus is that the half-life of everolimus (30 hours) is approximately half that of sirolimus (60 hours).

Everolimus was studied in a 24-month, multi-center, randomized, open-label, noninferiority study involving 721 de novo heart transplant recipients [55]. Patients were randomized to one of two everolimus drug exposures (1.5 mg/day or 3.0 mg/day in divided doses) with reduced-dose cyclosporine, or to mycophenolate mofetil (MMF) with standard-dose cyclosporine. Patients received glucocorticoids with or without induction therapy according to individual transplant center protocols. Enrollment into the higher dose (3.0 mg/day) everolimus arm was stopped prematurely due to a higher incidence of early mortality, mostly due to infections, in this group. Everolimus was found to be noninferior to MMF with respect to the primary efficacy end point of biopsy-proven acute cellular rejection, acute rejection with hemodynamic compromise, graft loss or retransplantation, death, or loss to follow-up. Patients on everolimus had reduced progression of coronary artery intimal wall thickening on intravascular ultrasound at 12 months posttransplantation. More nonfatal serious adverse events, particularly pericardial effusions, and a higher rate of drug discontinuations due to adverse events were reported in the everolimus group compared with the MMF group. Finally, everolimus was noted to be inferior to MMF with respect to renal function, but a post hoc analysis indicated that this finding was largely driven by a subset of study centers that were not successful in reducing the cyclosporine exposure in the everolimus group.

Use within the first three months posttransplantation — The United States Food and Drug Administration issued a black box warning for everolimus because of the increased risk of mortality observed within the first three months posttransplantation among patients started on the higher dose (3.0 mg/day) of everolimus as de novo immunosuppression. Therefore, the use of everolimus early after heart transplantation is not recommended.

Dosing and therapeutic drug monitoring — Everolimus is available in a tablet formulation. The starting dose is 0.75 mg twice daily, adjusted according to trough blood levels. Target blood levels are 3 to 8 ng/mL when used in combination with a CNI and 6 to 10 ng/mL when used as part of a CNI-free regimen [29,56].

Major toxicities — Everolimus has a similar toxicity profile compared with sirolimus. Although no head to head comparison between the two drugs exists, clinical observations suggest that patients on everolimus may experience less severe side effects compared with those taking sirolimus.

GLUCOCORTICOIDS — Glucocorticoids are nonspecific antiinflammatory agents that interrupt multiple steps in immune activation, including antigen presentation, cytokine production, and proliferation of lymphocytes. Although glucocorticoids are highly effective for the prevention and treatment of acute rejection, their long-term use is associated with a number of adverse effects, including new onset or worsening diabetes mellitus, hyperlipidemia, hypertension, fluid retention, myopathy, osteoporosis, and a predisposition toward opportunistic infections. (See "Major adverse effects of systemic glucocorticoids".)

Glucocorticoids are begun upon separation from cardiopulmonary bypass after the transplant surgery. Methylprednisolone is typically given at an initial dose of 500 mg, followed by 125 mg every eight hours during the first 24 hours after transplantation. Subsequently, oral prednisone is started at a dose of up to 1 mg/kg/day in two divided doses, and subsequently tapered to 0 to 0.05 mg/kg/day by 6 to 12 months. (See "Glucocorticoid effects on the immune system".)

Thus, while most programs employ glucocorticoids as one of the three maintenance immunosuppressive agents, they are used in relatively high doses in the early postoperative period but then tapered to low doses or discontinued altogether after the first 6 to 12 months [57-60]. Certain low-risk patients may tolerate earlier (within one to two months posttransplantation) steroid withdrawal without long-term adverse consequences [61,62].

TRENDS IN DRUG USE — International trends in the use of maintenance immunosuppressive agents at one year posttransplantation include a steady increase in tacrolimus use over cyclosporine since 2005 [1]. At one year post-heart transplant, tacrolimus is currently the most widely prescribed calcineurin inhibitor (CNI; 95 percent of patients) in heart transplantation. Mycophenolate mofetil (MMF) and mycophenolate sodium remain the predominant antimetabolite agents (91 percent of patients). The use of the antiproliferative agents sirolimus and everolimus has remained low (9 percent of patients). Finally, 83 percent of patients remained on some amount of glucocorticoid at one year posttransplantation. With respect to drug combinations, use of tacrolimus and MMF with or without steroids was most common (78 percent of patients) during the first year posttransplantation. For additional information, see the slides Adult Heart Transplantation Statistics.

SPECIAL CONSIDERATIONS — Most programs employ a standard de novo immunosuppressive regimen immediately after transplantation. Once stabilized on a particular regimen, immunosuppressive agents are not routinely altered except in response to significant drug toxicities or posttransplant complications. The most common changes in drug regimens and their rationale are described below.

Refractory or recurrent rejection — Following one or more episodes of acute rejection, many centers will attempt to optimize a patient's baseline immunosuppression. Some programs that routinely utilize cyclosporine as the de-novo calcineurin inhibitor (CNI) of choice will switch patients to tacrolimus. Patients previously on azathioprine may be converted to the newer and more effective antimetabolite agent, mycophenolate mofetil (MMF). Finally, patients on either azathioprine or MMF may be converted to the proliferation signal inhibitor sirolimus or everolimus. (See "Heart transplantation in adults: Treatment of rejection".)

Kidney function impairment — Several renal sparing protocols are employed to slow or reverse the progression of CNI-mediated kidney function impairment. Strategies include use of the proliferation signal inhibitors in lieu of the antimetabolite agents to allow minimization of the CNI dose or complete withdrawal of CNIs in favor of using the combination of a proliferation signal inhibitor and MMF (CNI-free regimens). Both strategies have resulted in significant improvements in renal function [63-70]. However, the use of CNI-free regimens may provide additional improvements in renal function compared with low-dose CNI strategies in carefully selected patients who are at low risk of rejection and do not have significant proteinuria (≥1000 mg/day) at baseline [71-73]. Of note, use of a CNI-free regimen within the first six-month postoperative period or in patients at higher risk for rejection should be done with caution due to the observed increased incidence of biopsy-proven rejection in these settings [47,56,73].

Cardiac allograft vasculopathy — Because mammalian target of rapamycin (mTOR) also signals smooth muscle cell and endothelial cell proliferation in response to growth factors, the proliferation signal inhibitors have been used to slow allograft vascular disease progression and to reduce the incidence of clinically significant cardiac events when used in a de novo setting after heart transplantation or in patients with established disease on the basis of intravascular ultrasound or coronary angiography [48,74-76]. (See "Heart Transplantation: Prevention and treatment of cardiac allograft vasculopathy".)

Malignancies — Observational data, mostly from the kidney transplant literature, suggest that the proliferation signal inhibitors sirolimus and everolimus may reduce the incidence of posttransplant skin and solid organ malignancies [77-79]. Limited data also suggest that sirolimus monotherapy may cause regression of certain skin tumors, such as Kaposi sarcoma, in kidney transplant recipients [80]. In a randomized clinical trial of kidney transplant recipients with a prior history of cutaneous squamous-cell carcinoma, patients who were switched from a CNI to sirolimus had a lower risk of subsequent skin cancers [81]. Postulated mechanisms responsible for this antitumor effect include direct antiproliferative actions of these drugs on tumor growth and angiogenesis, as well as facilitation of CNI dose reduction or withdrawal [82].

COVID-19 — Maintenance immunosuppression in cardiac transplant recipients with COVID-19 is discussed separately. (See "COVID-19: Evaluation and management of cardiac disease in adults", section on 'Cardiac transplantation'.)

Side effects — Certain side effects, such as hirsutism or gingival hyperplasia, are unique to cyclosporine. Therefore, individuals who develop severe forms of these complications on cyclosporine may be converted to tacrolimus. Patients with persistent upper gastrointestinal symptoms on MMF despite an initial dose reduction may better tolerate enteric-coated mycophenolate sodium. Severe cases of sirolimus-related lower extremity edema and rare but potentially life-threatening episodes of sirolimus-related interstitial pneumonitis will prompt most centers to discontinue the drug.

DRUG INTERACTIONS — Clinicians involved in the care of heart transplant recipients should be aware of the potential for drug interactions when other agents are added to or deleted from a patient's medical regimen [83]. A common juncture for such changes is when a transplant recipient requires antiinfective therapy.

A list of the most common and clinically important drug interactions is presented in the table (table 2). Specific interactions of antirejection agents with other medications may be determined using the drug interactions program included in UpToDate. This program can be accessed from the UpToDate online search page or through the individual drug information topics in the section on Drug interactions.

Drug interactions involving immunosuppressive agents are numerous and medication regimens for transplant recipients are complex. While most drug interactions are not clinically significant and few combinations are absolutely contraindicated, many can create serious consequences in the absence of appropriate monitoring and dose adjustments. Preventable consequences can include organ rejection or acute kidney injury from supratherapeutic levels of calcineurin inhibitors (CNIs). An evaluation by a clinical pharmacist with transplant expertise may be valuable in some instances.

One combination involving azathioprine and allopurinol should be avoided. Allopurinol inhibits the activity of xanthine oxidase, which is involved in the metabolism of azathioprine, resulting in high levels of the active metabolite 6-mercaptopurine and possible severe bone marrow suppression if the two drugs are used together. Mycophenolate is an alternative to azathioprine in patients who require allopurinol therapy.

Pharmacokinetic drug interactions — Pharmacokinetic drug interactions occur when a drug changes the immunosuppressive drug blood concentration profile, by interfering with the absorption, distribution, metabolism, or elimination of the immunosuppressive agent. Most clinically important pharmacokinetic drug interactions occur due to altered drug metabolism. CNIs and proliferation signal inhibitors are extensively metabolized by the cytochrome P-450 3A4 enzyme pathway in the liver so their blood levels are affected by drugs that induce or inhibit this pathway.

Drugs that induce the P-450 3A4 pathway result in enhanced metabolism of CNIs and proliferation signal inhibitors, thus lowering their blood levels and clinical effectiveness. Strong inducers of the cytochrome P-450 3A4 pathway include certain antiseizure medications (carbamazepine, phenobarbital, phenytoin), the antitubercular agent rifampin, certain antiretroviral agents (efavirenz, nevirapine), and the herbal agent St. John's wort.

Conversely, drugs that inhibit the cytochrome P-450 3A4 enzyme pathway result in decreased metabolism of CNIs and proliferation signal inhibitors, thereby increasing their blood levels and potentiating their toxicities. Many drugs inhibit cytochrome P-450 3A4 [84]. Common inhibitors include the macrolide antibiotics, azole antifungal agents, nondihydropyridine calcium channel blockers, amiodarone, and several antiretroviral drugs.

Pharmacodynamic drug interactions — Pharmacodynamic drug interactions occur when a drug modulates an immunosuppressive agent's effect at a given blood concentration, either increasing or diminishing the immunosuppressive drug's therapeutic and/or toxic effects. For example, concurrent use of ganciclovir, valganciclovir, or trimethoprim-sulfamethoxazole can potentiate the myelosuppressive effects of the antimetabolite agents and proliferation signal inhibitors. Another example of additive nephrotoxicity is observed when amphotericin B, aminoglycosides, foscarnet, or nonsteroidal antiinflammatory agents are used with CNIs.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topic (see "Patient education: Heart transplantation (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS — Induction and maintenance immunosuppressive regimens after heart transplantation vary according to transplant center experience and recipient characteristics (renal function, baseline risk of rejection, and individual drug tolerability). However, most regimens adhere to the following approach:

●The use of routine induction therapy remains controversial. (See 'Induction therapy' above.)

•Induction therapy may be of benefit in the subset of patients with the highest risk of acute rejection (presensitized patients, young patients, female patients, and African American patients) and in patients with impaired renal function to allow delayed initiation of calcineurin inhibitors (CNIs) posttransplantation.

•Commonly used induction agents include the interleukin-2 receptor antagonist basiliximab and polyclonal antithymocyte antibodies (thymoglobulin).

●Most modern immunosuppressive regimens consist of a two- or three-drug regimen, including a CNI (typically tacrolimus), an antimetabolite agent (typically mycophenolate mofetil), and tapering doses of glucocorticoids over the first year.

●Although tacrolimus and cyclosporine are both highly effective agents, evidence from clinical trials suggests that tacrolimus-based immunosuppression may offer an advantage over cyclosporine-based regimens with respect to decreased rates of acute rejection and an overall more favorable metabolic derangement profile (decreased incidence of hypertension and hyperlipidemia but higher incidence of posttransplant diabetes).

●The proliferation signal inhibitors sirolimus and everolimus are typically used in patients with cardiac allograft vasculopathy or kidney function impairment. Due to their inhibitory effects on smooth muscle proliferation and absence of intrinsic nephrotoxicity, they have been useful for slowing disease progression in these settings.

•The use of everolimus within the first three months after heart transplantation is not recommended due to a higher incidence of mortality due to infections.

•When used in conjunction with a CNI (cyclosporine or tacrolimus), the dose of the CNI should be reduced by 25 percent to reduce the risk of nephrotoxicity.

•Proliferation signal inhibitors should not be started in patients with significant proteinuria (≥1000 mg/day) and should be discontinued if significant proteinuria develops.

•The high incidence of drug-related adverse effects, including lower extremity edema, oral ulcerations, and poor wound healing, may limit generalized use of these agents.

●CNIs and proliferation signal inhibitors are heavily metabolized by the cytochrome P450 3A4 pathway and therefore are susceptible to numerous drug interactions.

●Clinicians managing heart transplant patients should become familiar with the common agents that can increase immunosuppressive drug levels (eg, erythromycin, diltiazem, amiodarone), decrease drug levels (eg, phenytoin, rifampin, St. John's wort), or potentiate the toxic properties of immunosuppressive agents (eg, nephrotoxicity associated with nonsteroidal antiinflammatory agents and aminoglycoside antibiotics). When these drugs are added to or deleted from a patient's baseline regimen, immunosuppressive drug levels and renal function should be carefully monitored.