Immunosuppressive T-cell antibody induction for heart transplant recipients

Heart transplantation has become a valuable and well-accepted treatment option for end-stage heart failure. Rejection of the transplanted heart by the recipient's body is a risk to the success of the procedure, and life-long immunosuppression is necessary to avoid this. Clear evidence is required to identify the best, safest and most effective immunosuppressive treatment strategy for heart transplant recipients. To date, there is no consensus on the use of immunosuppressive antibodies against T-cells for induction after heart transplantation.

To review the benefits, harms, feasibility and tolerability of immunosuppressive T-cell antibody induction versus placebo, or no antibody induction, or another kind of antibody induction for heart transplant recipients.

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 11, 2012), MEDLINE (Ovid) (1946 to November Week 1 2012), EMBASE (Ovid) (1946 to 2012 Week 45), ISI Web of Science (14 November 2012); we also searched two clinical trial registers and checked reference lists in November 2012.

We included all randomised clinical trials (RCTs) assessing immunosuppressive T-cell antibody induction for heart transplant recipients. Within individual trials, we required all participants to receive the same maintenance immunosuppressive therapy.

Two authors extracted data independently. RevMan analysis was used for statistical analysis of dichotomous data with risk ratio (RR), and of continuous data with mean difference (MD), both with 95% confidence intervals (CI). Methodological components were used to assess risks of systematic errors (bias). Trial sequential analysis was used to assess the risks of random errors (play of chance). We assessed mortality, acute rejection, infection, Cytomegalovirus (CMV) infection, post-transplantation lymphoproliferative disorder, cancer, adverse events, chronic allograft vasculopathy, renal function, hypertension, diabetes mellitus, and hyperlipidaemia.

In this review, we included 22 RCTs that investigated the use of T-cell antibody induction, with a total of 1427 heart-transplant recipients. All trials were judged to be at a high risk of bias. Five trials, with a total of 606 participants, compared any kind of T-cell antibody induction versus no antibody induction; four trials, with a total of 576 participants, compared interleukin-2 receptor antagonist (IL-2 RA) versus no induction; one trial, with 30 participants, compared monoclonal antibody (other than IL-2 RA) versus no antibody induction; two trials, with a total of 159 participants, compared IL-2 RA versus monoclonal antibody (other than IL-2 RA) induction; four trials, with a total of 185 participants, compared IL-2 RA versus polyclonal antibody induction; seven trials, with a total of 315 participants, compared monoclonal antibody (other than IL-2 RA) versus polyclonal antibody induction; and four trials, with a total of 162 participants, compared polyclonal antibody induction versus another kind, or dose of polyclonal antibodies.No significant differences were found for any of the comparisons for the outcomes of mortality, infection, CMV infection, post-transplantation lymphoproliferative disorder, cancer, adverse events, chronic allograft vasculopathy, renal function, hypertension, diabetes mellitus, or hyperlipidaemia. Acute rejection occurred significantly less frequently when IL-2 RA induction was compared with no induction (93/284 (33%) versus 132/292 (45%); RR 0.73; 95% CI 0.59 to 0.90; I(2) 57%) applying the fixed-effect model. No significant difference was found when the random-effects model was applied (RR 0.73; 95% CI 0.46 to 1.17; I(2) 57%). In addition, acute rejection occurred more often statistically when IL-2 RA induction was compared with polyclonal antibody induction (24/90 (27%) versus 10/95 (11%); RR 2.43; 95% CI 1.01 to 5.86; I(2) 28%). For all of these differences in acute rejection, trial sequential alpha-spending boundaries were not crossed and the required information sizes were not reached when trial sequential analysis was performed, indicating that we cannot exclude random errors.We observed some occasional significant differences in adverse events in some of the comparisons, however definitions of adverse events varied between trials, and numbers of participants and events in these outcomes were too small to allow definitive conclusions to be drawn.

This review shows that acute rejection might be reduced by IL-2 RA compared with no induction, and by polyclonal antibody induction compared with IL-2 RA, though trial sequential analyses cannot exclude random errors, and the significance of our observations depended on the statistical model used. Furthermore, this review does not show other clear benefits or harms associated with the use of any kind of T-cell antibody induction compared with no induction, or when one type of T-cell antibody is compared with another type of antibody. The number of trials investigating the use of antibodies against T-cells for induction after heart transplantation is small, and the number of participants and outcomes in these RCTs is limited. Furthermore, the included trials are at a high risk of bias. Hence, more RCTs are needed to assess the benefits and harms of T-cell antibody induction for heart-transplant recipients. Such trials ought to be conducted with low risks of systematic and random error.