Cardiology

Drugs Used for Immunosuppression Post-transplant

General (including evidence of efficacy)

Immunosuppression following cardiac transplantation

Heart transplantation is a well-established therapeutic option for patients with end-stage heart disease.  The development of immunosuppressive agents has resulted in a dramatic improvement in the survival of heart transplant recipients, with 1- and 10-year survival rates approaching 90% and 50%, respectively.

Despite this, there is a 25-30% risk of acute rejection requiring treatment in the first year following transplantation.  The benefits of immunosuppression must be balanced against the risks of long-term therapy, including infection and malignancy; toxic side effects, such as nephrotoxicity, dyslipidemia, hypertension, and diabetes; and complications, such as cataracts, osteoporosis, and avascular necrosis. 

Most immunosuppressive regimens involve a combination of therapies that inhibit multiple pathways in the activation of T cells.  The major therapeutic classes include antibodies directed against T cells, corticosteroids, calcineurin inhibitors (CNI), cell-cycle inhibitors, and the proliferation signal inhibitors (PSI).  Ongoing research is directed at developing novel agents with less toxicity, leading to preservation of graft function with fewer side effects.

Induction therapy

Induction therapy refers to the use of intensified immunosuppression initially following heart transplantation, when the allograft is most vulnerable to acute rejection.  It allows the delayed introduction of nephrotoxic calcineurin inhibitors, which may be beneficial in patients with significant renal dysfunction.

There are two classes of induction agents: depleting antibodies (horse or rabbit antithymocyte globulin [ATG]) and non-depleting monoclonal antibodies (anti-CD25 agent basiliximab and anti-CD52 agent alemtuzumab).

Depleting antibodies

There are two ATG preparations available: thymoglobulin (rabbit ATG) and Atgam (horse ATG). These agents may decrease acute rejection after heart transplantation by depleting lymphocytes and modulating T-cell function.

Their use after thoracic organ transplantation is controversial because of the potential for increased risk of infections, such as cytomegalovirus, and post-transplant malignancy.  Greater than 75% of patients experience infusion-related reactions (fever, chills), and approximately 6% develop serum sickness due to complex formation between the drug and preformed antibodies.

Leukopenia and thrombocytopenia are common (20% to 50%).  Induction protocols vary from 3 to 7 days, with dose adjustment to target CD2 or CD3 counts between 25 to 50 cells/mm3or absolute total lymphocyte counts <100 to 200 cells/mm3.  Side effects may be limited by increasing the infusion time.

Thymoglobin dosing: 1 mg/kg daily to a maximum dose of 125 mg for 3 to 5 days.  Patients are premedicated with hydrocortisone 100 mg IV, Benadryl 25 to 50 mg IV, and acetaminophen 650 mg PO orally 30 to 60 minutes prior to administration of the rATG (rabbit antithymocyte globulin).

Non-depleting antibodies

There are two agents currently available. Basiliximab targets CD 25 (IL-2 receptor) thereby preventing lymphocyte activation. Alemtuzumab is a cytolytic antibody against CD 52; an antigen present on the surface of T and B cells resulting in profound lymphocyte depletion. There is little trial data on efficacy and safety of Alemtuzumab and therefore it is only used in about 1% of cases.

The clinical evidence for the utility of Basiliximab is conflicting.  When compared with ATG induction therapy, the rate of rejection was higher; however infection rates were lower with basiliximab. A recent registry analysis suggested long-term survival was superior with ATG (77% vs 82% p=0.005). This remains an area of research.

Basiliximab dosing: 20 mg IV within 2 hours of the transplant followed by a second dose of 20 mg IV on day 4.

The use of induction therapy after heart transplantation remains controversial with approximately half of North American centres and a third of European centres adopting this strategy.  There is limited evidence to suggest that it is superior to a strategy without induction.  It remains indicated in patients with acute graft failure due to either hyperacute rejection or humoral rejection, and in patients with severe renal dysfunction, allowing the delayed initiation of calcineurin inhibitors.

Maintenance

The mainstay of maintenance immunosuppression involves the use of multiple synergistic agents with complimentary targets of action against T-cell activation pathways.  This results in the use of lower, and therefore less toxic, doses of each drug.

Immunosuppression is most intense in the early phase post-transplant and is weaned to maintenance doses within the first 6 to 12 months.  The typical regimen consists of three drugs: corticosteroids, a calcineurin inhibitor, and an antimetabolite or antiproliferative agent. The TICTAC trial randomized patients to monotherapy with tacrolimus or combination therapy tacrolimus and mycophenolate. Corticosteroids were weaned by 9 weeks. Three year survival, rejection and development of CAV was not statistically different between the two groups. This suggests some patients may be managed on monotherapy. Further research in this area is required.

Multiple drug interactions exist that may either increase or decrease the therapeutic levels of the immunosuppressive drugs.  Common medications that may increase the levels of the calcineurin inhibitors or the antiproliferative agents are: antifungals, antiretrovirals, amiodarone, diltiazem, verapamil, levofloxacin, glipizide, glyburide, and some macrolides. 

Levels may be decreased by antiepileptics, antiretrovirals, and antacids.  This is not a comprehensive list, and consultation with a transplant pharmacist is advisable when prescribing new medications.

Corticosteroids

Corticosteroids remain an integral component of immunosuppressive therapy.  They act by binding to glucocorticoid receptors leading to inhibition of IL-1, IL-2, and IL-6 production resulting in impaired lymphocyte function.  Intraoperatively, a bolus of methylprednisolone is usually administered and oral prednisone initiated thereafter at approximately 0.5 mg/kg daily. 

Most centers target discontinuation of prednisone by 6 to 12 months in the absence of significant rejection.  This is advisable given the multiple adverse side effects from prolonged usage, including acne, obesity, dyslipidemia, hypertension, hyperglycemia, Cushing's syndrome (truncal obesity, "buffalo hump," abdominal striae), hirsutism, cataract formation, osteoporosis, and avascular necrosis of long bones.

Example prednisone taper:  

  • Weeks 0-2: 40 mg PO daily  

  • Weeks 2-3: 30 mg PO daily

  • Weeks 4-8: 20 mg PO daily

  • Month 3: 10 mg PO daily

  • Month 4: 8 mg PO daily

  • Month 6: 4 mg PO daily

  • Month 7: 2 mg PO daily

  • Month 8: discontinue  

Taper schedule may be accelerated in patients with infectious or metabolic complications.

Similarly, the taper may be halted or slowed in patients with frequent or severe rejection episodes.  All patients should be placed on vitamin D and calcium supplementation, and antiresorptive therapy (bisphosphonate) during the first post-transplant year to prevent osteoporosis.

Calcineurin inhibitors: Cyclosporine and Tacrolimus

  • The development of calcineurin inhibitors (CNI) has led to significant improvements in recipient survival.  Cyclosporine A (CsA) and tacrolimus (Tac) bind to their respective receptors, resulting in inhibition of calcineurin; a calcium dependent phosphatase.

  • The downstream effect is inhibition of IL-2 production by the T cell.  Both drugs are metabolized by the hepatic cytochrome P450 system.

  • Drug interactions may result in significant alterations to drug levels.  Both drugs are monitored by 12-hour trough levels.

  • When used in conjunction with mycophenolic acid (MPA), the current guidelines suggest the following CsA target 12-hour trough values post-transplant:

  • First 6 weeks (250-350 ng/ml) 

  • 6-12 weeks (200-350 ng/ml)

  • 3-6 months (150-300 ng/ml)

  • >6 months (150-250 ng/ml)

The TAC therapeutic trough levels when used in conjunction with MPA are:

  • <2 months (10-15 ng/ml)

  • 3-6 months (8-12 ng/ml)

  • >6 months (5-10 ng/ml)

The target therapeutic levels of the CNI when used in conjunction with sirolimus or everolimus are not established in the current  International Society for Heart and Lung Transplantation (ISHLT) guidelines; however, it is the authors' opinion that lower levels are appropriate given drug synergy and the need to reduce nephrotoxicity.

Multiple toxicities exist including neurotoxicity, nephrotoxicity, hypertension, hyperglycemia, and dyslipidemia. CsA has higher rates of hirsutism and gingival hyperplasia.  Tacrolimus has a lower incidence of hypertension, gingival hypertension, and dyslipidemia; however, diabetes risk is increased.

An extended release formulation of tacrolimus is available allowing for once-daily administration. Studies from the renal literature suggest it is equally efficacious and safe compared to the short-acting drug.

Cell cycle inhibitors: Azathioprine and Mycophenolic Acid

Azathioprine is a pro-drug that is metabolized into a molecule that incorporates into nucleic acids, leading to inhibition of DNA and RNA synthesis.  Mycophenolic acid is the active metabolite of mycophenolate mofetil (MMF) and mycophenolate sodium preparations.

Mycophenolic acid inhibits lymphocyte purine synthesis by reversibly inhibiting inosine monophosphate dehydrogenase, the rate limiting enzyme in de novo purine synthesis.  Clinical trials have demonstrated its superiority compared to azathioprine, with lower rates of graft loss and mortality.

MMF has become the antiproliferative drug of choice in modern immunosuppressive regimens.  MMF is usually administered as a standard dose (1,000 mg bid) and the utility of MPA levels has not been established; however, a trough MPA level of <1.5 mg/L is considered subtherapeutic. 

The most common side effects are gastrointestinal intolerance (diarrhea) and myelosuppression (leukopenia, thrombocytopenia).  Patients with intolerable gastrointestinal side effects from MMF may tolerate the sodium preparation.  Neither preparation is nephrotoxic and therefore both remain useful in patients with renal insufficiency.

Proliferation signal inhibitors: Sirolimus and Everolimus

There are two proliferation signal inhibitors (PSIs) approved for use in heart transplant patients: sirolimus and everolimus.  These agents bind to circulating FK506-binding protein 12, thereby forming a complex that blocks the mammalian target of rapamycin. This results in cell cycle arrest and inhibition of lymphocyte proliferation.  Both drugs have been associated with lower incidences of acute rejection when used in combination with a calcineurin inhibitor compared to other cell cycle inhibitors (MMF or azathioprine). However, the combination with a calcineurin inhibitor has also been associated with diminished renal function. Given the synergistic effect when used with CNI, it is recommended that the target therapeutic level of the CNI be reduced when used in combination with the PSI to preserve renal function.

The ISHLT guidelines suggest trough levels of 4 to 12 ng/ml and 3 to 8 ng/ml for sirolimus and everolimus, respectively, when used in conjunction with cyclosporine.  The optimal trough level with tacrolimus has not been established.

CMV reactivation is lower with PSI regimens.  Common side effects include peripheral edema, pleural/pericardial effusion, oral ulcers, acne, diarrhea, hyperlipidemia, and leukopenia.

Lung toxicity, pneumonitis leading to bronchiolitis obliterans, is a potentially lethal side effect of PSIs and may occur with an incidence as high as 24% with sirolimus.  Resolution is likely following discontinuation of the drug.

Currently these drugs are used as alternative agents for patients with recurrent rejection, in calcineurin inhibitor sparing protocols in patients with renal dysfunction, and in patients with cardiac allograft vasculopathy and malignancies (see section on chronic rejection). There is evidence suggesting transitioning from a CNI to everolimus in patients at low risk of rejection results in improved renal function and a lower incidence of vasculopathy. It should be noted that wound healing is markedly impaired with these drugs and they should not be used in the immediate postoperative period as this is associated with sternal wound dehiscence.

Management of rejection

Rejection following heart transplantation may be hyperacute, acute cellular (ACR), antibody mediated (AMR), or chronic in the form of cardiac allograft vasculopathy (CAV). 

Hyperacute rejection occurs almost immediately following graft reperfusion due to the presence of pre-formed recipient antibodies directed against antigens expressed on the graft endothelium.  This stimulates an inflammatory response throughout the vasculature leading to thrombosis, ischemia, and ultimately loss of the graft. Therapy with high dose intravenous corticosteroids, rATG, plasmapheresis, and intravenous immunoglobulin may be attempted.  Eculizumab is a monoclonal antibody that binds to C5 thereby inhibiting complement activation and formation of the membrane attack complex. It may have a role in hyperacute rejection and severe antibody mediated rejection. More research is required in this area. Mechanical circulatory support and/or emergent re-transplantation may be required in addition to medical therapies.

Acute cellular rejection

Acute cellular rejection (ACR) occurs in up to 25-30% of heart transplant recipients patients within the first year, and most frequently within the first 6 months.  It is predominately a T-cell mediated process. 

Patients may present with nonspecific findings (fever, fatigue, nausea), symptomatic graft dysfunction (hypotension, dyspnea, orthopnea), or arrhythmias (relative bradycardia, AV block, atrial fibrillation/flutter).  Alternatively, rejection may be identified by endomyocardial biopsy in an otherwise asymptomatic patient. 

The general treatment strategy involves a high-dose corticosteroid pulse (1 g methylprednisolone IV daily for 3 days) with or without a slow prednisone taper for patients with rejection graded as >=2R.   ATG may also be administered to patients with hemodynamic compromise, high-grade cellular rejection (3R), or those with no signs of clinical improvement after 24 hours of steroid therapy. The IL-2 receptor antagonists should not be used to treat acute cellular rejection.  A repeat endomyocardial biopsy should be performed in 1 to 2 weeks to ensure resolution. 

The maintenance immunosuppression should be adjusted.  This may require increasing the dose of current therapies, or addition of another agent such as a PSI or conversion to a different regimen (for example conversion from CSA to tacrolimus or MMF to a PSI).

Antibody mediated rejection

Antibody mediated rejection (AMR) is characterized by antibody and complement deposition in the vasculature of the transplanted heart.  It is associated with an increased risk of cardiac allograft vasculopathy (CAV) and decreased survival.

AMR should be suspected when there is unexplained graft dysfunction, the presence of circulating donor-specific alloantibodies, and the presence of capillary injury and intravascular macrophages on endomyocardial biopsy.  Biopsy samples should be sent for immunohistochemical staining to test for the presence of immunoglobulin (IgG, IgM, or IgA), complement (C3D, C4D , C1q), or macrophages (CD68).

AMR and ACR may coexist in up to 25% of acute rejection events.  Hemodynamically significant AMR is treated with high-dose intravenous steroids (methylprednisolone 1,000 mg IV daily for 3 days). Cytolytic therapy with ATG may be considered. Decreasing the levels of circulating antibodies may be achieved by plasmapheresis and intravenous immunoglobulin (IV Ig).

Rituximab (monoclonal antibody that depletes CD-20 expressing B cells) may be used as an off-label therapy.  Rituximab IV dosing of 1 g on days 7 and 22:  (IV infusion at an initial rate of 50 mg/hr.  The rate may be increased to a maximum of 400 mg/hr). Premedication with Benadryl 25 to 50 mg IV, acetaminophen 650 mg PO, and hydrocortisone 100 mg IV should occur.   Hypotension is common with infusion, and nonessential antihypertensives should be avoided.

Bortezomib, a proteosome inhibitor, has been used to treat AMR and ACR in renal transplant patients. It has also been used in desensitization protocols prior to heart transplant in observational studies. Further studies are required to determine its role in the cardiac transplant population.

Follow-up with a repeat biopsy should be performed 2 to 4 weeks after therapy is initiated.  Adjustment to the maintenance immunosuppression should be performed similar to those strategies employed for ACR.

Chronic rejection/Cardiac Allograft Vasculopathy (CAV)

CAV is a transplant-specific coronary arteriopathy that presents by coronary angiography in at least 30% of patients at 5 years post-transplant, and in 50% of patients at 1-year post-transplant when evaluated by coronary artery intravascular ultrasound (IVUS).  The etiology of CAV is multifactorial with factors such as prior acute rejection, hypertension, hyperlipidemia, and infectious agents (i.e., cytomegalovirus) contributing.

Statins have been shown in clinic trials to reduce CAV progression and improve mortality in heart transplant recipients.  In addition to their lipid-lowering properties, statins exert pleiotropic effects. In vitro studies suggest they inhibit natural killer cells, decrease the release of pro-inflammatory cytokines, reduce macrophage activation and block T-cell costimulatory molecules.

PSIs have been shown to reduce and/or prevent the development of CAV. Data exists supporting the use of either sirolimus or everolimus.

Current research goals

Clinical research is directed at developing novel therapies for diagnosing, treating and preventing rejection in transplant patients.  The goals of this research are multiple:

  1. To effectively deliver individualized immunosuppression resulting in improved long-term survival without long-term toxicity (cytopenia, nephrotoxicity, diabetes, malignancy etc.)

  2. To develop validated biomarkers used to diagnose rejection and guide immunosuppressive therapies

  3. To develop drugs with longer half-lives and reliable pharmacokinetics thereby obviating the need for drug level monitoring

  4. To further understand the role of T cells and B cells in the allograft immune response and develop novel therapies targeting cellular and antibody mediated graft injury

  5. To deliver evidence-based care by conducting randomized clinical trials with current and novel drug combinations

Summary

Heart transplantation has the potential to prolong life in many patients with end-stage heart disease.  Patient survival is dependent upon balancing adequate immunosuppression with minimizing the long-term side effects of therapy, such as nephrotoxicity, infections, and malignancy.

Modern era immunosuppressive regimens generally combine two classes of medications (selected from either cell cycle inhibitors, proliferation signal inhibitors, or calcineurin inhibitors) to minimize toxicity and take advantage of synergistic drug effects. Corticosteroids are administered early in the post-transplant course and are usually weaned off within the first year post-transplant in the absence of rejection. Emerging data suggests there are some patients who may be maintained on monotherapy with tacrolimus.

Induction therapy immediately post-transplant remains controversial and may be achieved with ATG or IL-2 receptor antibodies.  Acute rejection remains common in the first year and pulse steroids and intensification of the baseline immunosuppressive strategy remain the mainstays of therapy.

Cardiac allograft vasculopathy is associated with chronic rejection and remains an ongoing plague of long-term outcomes.  The PSIs have been shown to be effective in preventing CAV development and limiting its progression.

Current research is aimed at developing novel therapeutic agents with favorable side effect profiles and reliable pharmacodynamics in an effort to prevent both antibody mediated and cellular rejection events and ultimately improve clinical outcomes.  Given the advancing age of transplant recipients with associated comorbidities, novel therapeutic options with less toxicity are required. 

Clinical research in this arena remains challenging given the limited number of heart transplants performed at individual centers.  Advancement of this field will ultimately require a cooperative strategy engaging multiple centres, industry and drug regulatory agencies.

REFERENCES

Taylor, D, Meiser, B, Webber, S. "The International Society of Heart and Lung Transplantation guideline for the care of heart transplant recipients task force 2: immunosuppression and rejection.". J Heart Lung Transplant. vol. 29. 2010. pp. 914-56.

(First guideline statement addressing immunosuppressive therapy post-transplant.)

Lund, LH, Edwards, LB, Kucheryavaya, AY. "Registry of the International Society for Heart and Lung Transplantation: Thirty-second official adult heart transplant report—2008.". J Heart Lung Transplant. vol. 34. 2015. pp. 1244-54.

(Comprehensive presentation of recent heart transplant statistics, including immunosuppressive strategies.)

Hunt, SA, Haddad, F.. "The changing face of heart transplantation.". J Am Coll Cardiol. vol. 52. 2008;. pp. 587-98.

(Comprehensive review of recent developments in heart transplantation.)

Halloran, PF. "Immunosuppressive drugs for kidney transplantation.". N Engl J Med. vol. 351. 2004.

(Discussion of T-cell activation and costimulatory pathways.)

Segovia, J, Rodriguez-Lambert, JL, Crespo-Leiro, MG. "A randomized multicenter comparison of basiliximab and muromonab (OKT3) in heart transplantation: SIMCOR study.". Transplantation.. vol. 81. 2006. pp. 1542-8.

(Multicenter, randomized trial comparing induction therapy with basiliximab and OKT3.)

Keogh, A, Richardson, M, Ruygrok, P. "Sirolimus de novo heart transplant recipients reduces acute rejection and prevents coronary artery disease at 2 years: a randomized clinical trial.". Circulation. vol. 110917. 2004. pp. 2694-700.

(Clinical trial assessing efficacy of sirolimus therapy for prevention of acute rejection and coronary allograft vasculopathy.)

Eisen, HJ, Tuzcu, EM, Dorent, R. "Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients.". N Engl J Med. vol. 349. 2003. pp. 847-58.

(Clinical trial assessing efficacy of everolimus for prevention of acute rejection and coronary allograft vasculopathy.)

Andreassen, AK, Andersson, B, Gustafsson. "Everolimus Initiation and Early Calcineurin Inhibitor Withdrawal in Heart Transplant Recipients: A Randomized Trial.". Am J Transplantation. vol. 14. 2014. pp. 1828-1838.

(Clinical trial assessing early initiation of everolimus and discontinuation of calcineurin post-transplant demonstrating improved renal function, less CMV infection and lower incidence of CAV in the everolimus treatment arm.)

Kobashigawa, J, Miller, L, Renlund, D. "A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients. Mycophenolate mofetil investigators.". Transplantation. vol. 66. 1998. pp. 507-15.

(Clinical trial investigation efficacy of mycophenolate mofetil [MMF] for prevention of heart transplant rejection.)

Baran,, DA,, Zucker, MZ, Arroyo, LH. "A Prospective, Randomized Trial of Single-Drug Versus Dual-Drug Immunosuppression in Heart Transplantation (TICTAC Trial).". Circ Heart Fail.. vol. 4. 2001. pp. 129-137.

(Clinical trial assessing efficacy and safety of monotherapy immunosuppression with tacrolimus.)

Stegall, MD, Morris, RE, Alloway, RR. "Developing New Immunosuppression for the Next Generation of Transplant Recipients: The Path Forward.". Am J Transplantation. vol. 16. 2016. pp. 1094-1101.

(Editorial addressing the challenges in developing novel immunosuppression.)
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