Clinical heart transplantation
To induce or not to induce: Do patients at greatest risk for fatal rejection benefit from cytolytic induction therapy?

https://doi.org/10.1016/j.healun.2004.01.002Get rights and content

Abstract

Background

Induction immunosuppression utilizing lymphocytolytic agents in the early peri-operative period has a number of theoretical and practical advantages and disadvantages. However, the efficacy of cytolytic agents as induction therapy remains unproven.

Methods

To assess the current impact of induction therapy in heart transplantation, we queried a multi-institutional database regarding the frequency of use, type of agent, duration of therapy and outcomes of 6,553 patients transplanted from 1990 to 2001. A study group of 5,897 patients were identified who survived the first 48 hours post-transplant and received either no induction therapy (n = 4,161) or induction with OKT3 or anti-thymocyte preparations (n = 1,736).

Results

By multivariate analysis, risk factors for rejection death were identified and then applied to a model of overall mortality. Among patients with a 1-year risk of rejection death at >5%, induction therapy provided a survival advantage, but survival with induction was decreased when the risk of rejection death was <2%. Specific patient sub-sets that received a survival benefit in the current era with induction included younger patients of black race with ≥4 HLA mismatches and long-term (>6 months) support on a ventricular assist device (VAD).

Conclusions

Use and application of induction therapy continues to be controversial in heart transplantation. At present, this approach appears to be beneficial in selected patients who are at high risk for rejection death, but likely detrimental in patients who are at low risk for rejection death. Those with a combination of longer term VAD support, of black ethnicity, and having extensive HLA mismatching are most likely to benefit from cytolytic induction therapy.

Section snippets

Definition of induction

Induction therapy was defined as prophylactic lymphocytolytic therapy initiated within 48 hours of transplantation. The following preparations were considered lymphocytolytic therapy: OKT3, anti-thymocyte globulin (ATG), anti-lymphocyte globulin (ALG), anti-thymocyte serum (ATS) and thymoglobulin. Interleukin-2 receptor blockers were not considered induction therapy for this analysis.

Patient population

The CTRD is a multi-institutional event-driven analysis that includes 33 North American heart transplant

Differences between OKT3 and anti-thymocyte preparations

Separate analyses of the OKT3 group and the group receiving polyclonal anti-thymocyte/anti-lymphocyte preparations yielded the same effect of induction and non-induction on rejection death and overall mortality. Therefore, we have reported only the analysis that combines OKT3 and ATG patients together as the induction group.

Trends in use of induction therapy

Over the last 12 years of the CTRD, 67% of the patients undergoing primary cardiac transplantation received no induction therapy, whereas nearly 30% received induction with

Discussion

Acute rejection continues to be an important cause of early and mid-term mortality after cardiac transplantation.10, 11, 12 Multiple modalities have been employed to reduce the fatal consequences of rejection.13, 14 However, the potential for mortality results not only from the rejection phenomena, but also from infections and malignancies that can complicate aggressive immunosuppression.15 There has been controversy about the potential advantages and deleterious effects of induction therapy

References (34)

  • C. Chin et al.

    Pediatric Heart Transplant Study Group. Risk factors for recurrent rejection in pediatric heart transplantationA multicenter experience

    J Heart Lung Transplant

    (2004)
  • T.O. Felkel et al.

    Survival and incidence of acute rejection in heart transplant recipients undergoing successful withdrawal from steroid therapy

    J Heart Lung Transplant

    (2002)
  • R. John et al.

    Older recipient age is associated with reduced alloreactiavity and graft rejection after cardiac transplantation

    J Heart Lung, Transplant

    (2001)
  • B.E. Jaski et al.

    Cardiac transplant outcome of patients supported on left ventricular assist device vs intravenous inotropic therapy

    J Heart Lung Transplant

    (2001)
  • T.B. Spanier et al.

    Activation of coagulation and fibrinolytic pathways in patients with left ventricular assist devices

    J Thorac Cardiovasc Surg

    (1996)
  • R.E. Shaddy et al.

    Murine monoclonal CD3 antibody (OKT3) based early rejection prophylaxis in pediatric heart transplantation

    J Heart Lung Transplant

    (1993)
  • J.S. Ladowski et al.

    Prophylaxis of heart transplant rejection with either antithymocyte globulin–Minnesota antilymphocyte globulin-, or an OKT2-based protocol

    J Thorac Cardiovasc Surg

    (1993)
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