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Published on 1 July 2007

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New therapies for cardiac transplantation

teaser

Julia Hernández Martín
PharmD

Clinical Pharmacist

Monica Montero Hernández
PharmD

Clinical Pharmacist

Isabel Font Noguera
PhD

Clinical Manager

José Luis Poveda Andrés
PhD

Head of Department

Pharmacy Department
La Fé University Hospital
Valencia
Spain

E: hernandez_julmar@gva.es

Despite advances in heart failure management, cardiac transplantation remains the most successful treatment option for appropriately selected patients with end-stage cardiac ­disease.(1) The survival of heart recipients indicates that the graft half-life is currently 9.9 years, with a half-life of 13 years for those surviving the first year.(2)

The number of heart transplant procedures reported to the International Heart and Lung Transplant Registry each year continues to decrease, with 2,945 reported in 2004 as compared with 4,428 (35% reduction) at peak reporting in 1994 (see Resource).(2)

In 2004 it was estimated – based on an analysis of a variety of worldwide transplant registries – that more than 2,000 cardiac transplants are performed annually at centres not reporting to the registry, which puts the estimated annual worldwide number of heart transplants at more than 4,000.(3)

Immunosuppressive therapy has evolved considerably since the introduction of azathioprine in 1961. Azathioprine with low-dosage corticosteroids represented the standard for immunosupression in organ transplantation until the introduction of ciclosporin in 1978. This marked the advent of triple therapy with a calcineurin inhibitor, azathioprine and low-dosage corticosteroids.

Other milestones included the introduction of the microemulsion formulation of ciclosporin and the development of further novel immunosuppressants such as tacrolimus, mycophenolate mofetil, sirolimus and everolimus.(4)

Currently, the most common ­immunosuppression protocol for cardiac transplantation includes ciclosporin, mycophenolate mofetil and cortico­steroids (triple therapy).(5) An alternative to standard triple therapy at the time of cardiac transplantation has been the use of augmented immunosuppression, commonly termed “induction immunotherapy”, with antilymphocyte antibodies. These cytolytic agents include the murine monoclonal antibody muromonab-CD3 and other antithymocyte or anti­lymphocyte agents.

Retrospective evaluations from a large multi-­institutional database have suggested that ­cytolytic therapy reduces the risk of early rejection but increases the risk of infection.(6)

Tacrolimus has been used in treating allograft rejection resistant to treatment with other immunosuppressive medicinal products in adult patients, although the FDA approved tacrolimus for prevention of cardiac rejection in 2006. Tacrolimus acts by a mechanism similar to that of ciclosporin and offers an alternative. However, there are actually two drugs that impact upon immunossupresive therapy for cardiac transplantation in our area: everolimus and daclizumab.(7)

Everolimus
Everolimus is an orally administered mammalian target of rapamycin (mTOR) inhibitor (proliferation signal inhibitor) derived from sirolimus (rapamycin). It ­inhibits growth factor-stimulated cell proliferation of haematopoietic and nonhaematopoietic cells through the formation of a complex with FK506 (tacrolimus)-binding protein 12 (FKBP12).

It is indicated for the prophylaxis of cardiac or ­kidney transplant rejection in adult patients at low to moderate immunological risk and should be given in combination with ciclosporin microemulsion and corticosteroids.(8,9) Patients undergoing cardiac transplantation should have their dosage of ciclosporin reduced as necessary during the maintenance phase to improve renal function.(8,10,11) In these patients, it is recommended that an initial oral dosage of 0.75 mg twice daily is started as soon as possible after transplantation.

Routine therapeutic drug level monitoring is ­recommended to maintain individual through concentrations of everolimus in whole blood at
≥ 3 ng/ml. Preliminary data suggest that calcineurin-inhibitor-free immunosuppression using everolimus is safe, with excellent efficacy in maintenance ­cardiac transplant recipients and significant improvement in arterial hypertension and renal function.(12)

Daclizumab
Daclizumab is a humanised anti-IL-2R (CD5) monoclonal antibody that has murine antigen-­binding sequences molecularly grafted onto a human ­antibody.(13) It functions as an immunosuppressant by antagonising interleukin-2-mediated proliferation of T-cells.(6)

Daclizumab’s only FDA-labelled indication is renal transplant rejection, with the regimen including ciclosporin and corticosteroids, and in prophylaxis. The recommended dose is 1 mg/kg diluted in 0.9% sodium chloride solution over 15 minutes every
14 days for a total of five doses; the first dose should be given no more than 24 hours before transplantation.(14) Another possible dosage is daclizumab 2 mg/kg per dose given every 14 days for only two total doses; this appears to be as safe and effective as the approved five-dose regimen.(15)

In randomised trials, the prophylactic use of ­daclizumab in kidney transplant patients was observed to reduce the frequency of acute rejection episodes after transplantation.(16) Other therapeutic uses in transplanted organs, not FDA-approved, are kidney-pancreas transplant rejection, liver transplant rejection, gastrointestinal tract transplantation and cardiac transplantation.

In cardiac transplant patients, daclizumab ­versus placebo and versus OKT3 has been shown to be effective as induction therapy to reduce the incidence of acute rejection episodes without ­increasing patient mortality and would reduce the number of endomyocardial biopsies.(17–20)

In our hospital daclizumab is used as part of the cardiac transplantation protocol, for compassionate use. All patients receive daclizumab (1 mg/kg) within eight hours of cardiac transplantation and a second dose (1 mg/kg) two weeks thereafter. Concomitant immunosuppression therapy compromised mycophenolate mofetil, ciclosporin and corticosteroids.

One study has demonstrated that the number of cardiac acute rejection episodes of grade 2 or higher during the first year was significantly lower among patients treated with two bolus doses of daclizumab than patients treated with five doses. There were no significant differences in terms of the number of infections and patient mortality.(16)

Another clinical trial was designed to evaluate the efficacy of daclizumab versus placebo in patients undergoing cardiac transplantation who were given triple-drug immunosuppressive therapy (ciclosporin, mycophenolate mofetil and corticosteroids). Here, five doses of daclizumab were administered, the first in the immediate post-transplantation period, with four additional doses given up until week 7. The results indicated a decreased overall incidence of rejection in the daclizumab group, with no increased incidence of any serious opportunistic infections.(6)

This finding was previously reported in studies of daclizumab after renal transplantation.(21,22) Although more patients in the daclizumab group than in the placebo group died during the first 12 months after transplantation (6.5% versus 3.2% respectively), review of these patients’ clinical history showed that they had also received cytolytic therapy; this drug combination may have contributed to the increased numbers of patients who died from infection.(6)

Conclusion
Immunosuppression as a field is changing rapidly, due to the increasing number of drugs and ­biological agents. It is necessary to know whether new agents provide more specific or simply more potent immunosuppression, which combination of drugs can achieve maximal efficacy with minimal adverse effects and whether the new agents will prevent chronic rejection and improve long-term survival after cardiac transplant.

One of the most recent agents to be used in cardiac transplantation is daclizumab, a monoclonal antibody that has been shown to be efficacious as prophylaxis against acute cellular rejection.

Induction therapy in cardiac transplantation with two doses of daclizumab is at least as effective as the five-dose regimen to prevent rejection, with no negative effects on patient survival or infection rate. The main advantages of the two-dose regimen are the lower costs and the avoidance of repeated intravenous administrations.

References
1. Lake K, Aaronson K. Cardiac transplantation. In: DiPiro JT, Talbert RL, Yee GC (eds). Pharmacotherapy. Columbus OH: McGraw-Hill; 2002: 321-36.
2. Taylor DO, Edwards LB, Boucek MM, et al.
The Registry of the International Society for Heart and Lung Transplantation: twenty-third official adult heart transplantation report, 2006.
J Heart Lung Transplant 2006;25:880-92.
3. Taylor DO, Edwards LB, Boucek MM, et al.
The Registry of the International Society for Heart and Lung Transplantation: twenty-second official adult heart transplantation report, 2005.
J Heart Lung Transplant 2005;24:945-55.
4. Perico N, Remuzzi G. Prevention of transplant rejection. Drugs 1997;54:533-70.
5. Sepúlveda L, Zamorano J, Cotera A, et al. First case of simultaneous heart plus kidney transplantation in Chile: case report. Transplant Proc 2007;39:625-6.
6. Hershberger RE, Starling RC, Eisen HJ, et al. Daclizumab to prevent rejection after cardiac transplantation. N Engl J Med 2005;352:2705-13.
7. Baran DA, Galin ID, Gass AL. Current practices: immunosuppression induction, maintenance, and rejection regimens in contemporary post-heart transplant patient treatment. Curr Opin Cardiol 2002;17:165-70.
8. Dunn C, Croom KF. Everolimus: a review of its use in renal and cardiac transplantation. Drugs 2006;66:547-70.
9. Rothenburger M, Zuckermann A, Bara C, et al. Certican Consensus Study Group. Recommendations for the use of everolimus (Certican) in heart transplantation.
J Heart Lung Transplant 2007;26:305-11.
10. Lehmkuhl H, Ross H, Eisen H, et al. Everolimus (certican) in heart transplantation: optimizing renal function through minimizing cyclosporine exposure. Transplant Proc 2005;37:4145-9.
11. Schweiger M, Wasler A, Prenner G, et al.
Everolimus and reduced cyclosporine trough levels in maintenance heart transplant recipients.
Transpl Immunol 2006;16:46-51.
12. Rothenburger M, Teerling E, Bruch C, et al.
Calcineurin inhibitor-free immunosuppression using everolimus (Certican) in maintenance heart transplant recipients. J Heart Lung Transplant 2007;26:250-7.
13. Lindenfeld J, Miller GG, Shakar SF, et al.
Drug therapy in the heart transplant recipient. Part I. Circulation 2004;110:3734-40.
14. Daclizumab drug evaluation monograph. In: Hutchison TA, Shahan DR (eds). Drugdex® System. Micromedex 132. Greenwood Village CO: Micromedex; 2006.
15. Stratta RJ, Alloway RR, Hodge E, et al. A multicenter, open-label, comparative trial of two daclizumab dosing strategies versus no antibody simultaneous kidney-pancreas transplantation: 6 month interim analysis. Transplant Proc 2002;34:1903-5.
16. Ortiz V, Almenar L, Martínez-Dolz L, et al. Induction therapy with daclizumab in heart transplantation: how many doses? Transplant Proc 2006;38:2541-3.
17. 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;342:613-9.
18. Kobashigawa J, David K, Morris J, et al.
Daclizumab is associated with decreased rejection and no increased mortality in cardiac transplant patients receiving MMF, cyclosporin, and corticosteroids.
Transplant Proc 2005;37:1333-9.
19. Cuppoletti A, Perez-Villa F, Vallejos I, et al.
Experience with single-dose daclizumab in the prevention of acute rejection in heart transplantation. Transplant Proc 2005;37:4036-8.
20. Lage E, Ballesteros S, Mogollon MV, et al.
Is it possible to reduce the number of endomyocardial biopsies with new immunosuppressive drugs? Transplant Proc 2006;38:2544-6.
21. Vincenti F, Kirkman R, Light S, et al.
Interleukin-2-receptor blockade with daclizumab to prevent acute rejection in renal transplantation.
N Engl J Med 1998;338:161-5.
22. Nashan B, Light S, Hardie IR, et al. Reduction of acute renal allograft rejection by daclizumab.
Transplantation 1999;67:110-5.

Resource
International Society for Heart and Lung Transplantation: Registries
W: www.ishlt.org/registries



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