This review compared polyclonal and monoclonal antithymoglobulins as induction immunosuppression agents after heart transplantation. The authors concluded that there were no statistically significant differences in rejection, infection or survival rates between treatments, but there was a higher rate of side-effects in the monoclonal group. Given the limitations of the included studies, the authors' conclusions should be interpreted with caution.

To assess the relative benefits and side-effects of polyclonal and monoclonal antithymoglobulins when used as induction immunosuppression agents after heart transplantation.

MEDLINE (1966 to March 2004), EMBASE (1980 to March 2004) and the Cochrane CENTRAL Register (2004) were searched; the search terms were stated. The references of identified papers were checked for further relevant studies. There were no restrictions based on language or country of publication. No attempts were made to identify unpublished or non peer-reviewed articles.

Study designs of evaluations included in the review

Randomised controlled trials (RCTs) were eligible for inclusion. The length of follow-up ranged from 6 to 24 months after heart transplantation.

Specific interventions included in the review

Studies comparing polyclonal and monoclonal antithymoglobulins as induction immunosuppression agents after heart transplantation were eligible for inclusion. The included studies compared polyclonal antithymoglobulin (ATG) with the monoclonal antibody orthoclone (OKT3). Dosages were similar across studies, but were not reported. The majority of studies used ATG for 7 days and OKT3 for 14 days. One study used ATG and OKT3 for equal lengths of time. All patients received steroids and cyclosporine following induction of immunosuppression, while some patients also received azathyprine.

Participants included in the review

Adults who had undergone heart transplantation were eligible for inclusion. The mean age of the participants ranged from 27.3 to 51.8 years across studies, and the majority of the participants were male.

Outcomes assessed in the review

The primary outcomes included in the review were the number of patients who developed acute rejection episodes in the first 6 months post-transplantation (defined as episodes requiring treatment, rejection grade 2 out of 4 using the International Society of Heart and Lung Transplantation Scale), the incidence of post-operative infections (episodes requiring treatment), survival and drug-related side-effects.

How were decisions on the relevance of primary studies made?

Two reviewers screened all studies for inclusion.

The validity of the included studies was assessed using the Jadad scale, which assesses randomisation, blinding, and withdrawals or drop-outs. Studies scoring 3 or more out of a maximum of 5 were considered to be of a high quality. The authors did not state how the validity assessment was performed.

The authors did not state how the data were extracted for the review, or how many reviewers performed the data extraction. Where information was missing, an attempt was made to obtain it from the primary authors.

Estimates of rejection and infection rates were calculated at 6 months after transplantation. Survival rates were calculated for up to 1 year post-transplantation. Mean differences were calculated for continuous outcomes (time to first rejection), whilst relative risks (RRs) were calculated for dichotomous outcomes (e.g. graft rejections, number of infections)

How were the studies combined?

The studies were grouped according to outcome and combined, using a random-effects model, to produce a weighted mean difference (WMD) and pooled RRs with 95% confidence intervals (CIs). Medication-related side-effects were summarised in a table.

How were differences between studies investigated?

Statistical heterogeneity between the studies was assessed using the chi-squared method and a sensitivity analysis of high- and low-quality studies was planned.

Five RCTs (n=215; 105 treated with ATG and 110 with OKT3) were included in the review.

Only one trial was rated as high quality (3 out of 5); other trials scored 2 out of 5 as they did not use blinding.

There was no statistically significant difference between ATG and OKT3 for the mean time to first rejection episode (5 studies; WMD 6.73, 95% CI: -8.75, 22.21). Heterogeneity was statistically significant (P<0.00001). There was no statistically significant difference between treatment groups for the number of patients with rejection at 6 months (3 studies). One study showed a higher incidence of rejection in the ATG group relative to the OKT3 group, whereas another study showed no difference between the groups at 6 months.

There was no statistically significant difference between treatment groups in the number of patients who developed infection in the first 6 months (4 studies) or in the number of infection episodes per patient (1 study).

There was no statistically significant difference between groups in survival up to 1 year after transplantation (4 studies).

Most studies reported higher rates of drug -elated complications in the OKT3 group relative to the ATG group. These side-effects included fever, headache, acute respiratory distress and hypotension.

All included studies had equivalent quality scores so a sensitivity analysis on study quality was not carried out.

A 5-day course of ATG cost approximately CAN $7500 (5 vials/day), compared with CAN $3,200 for OKT3 (5 mg/day).

There were no statistically significant differences in rejection, infection or survival rates between patients receiving monoclonal and polyclonal antithymoglobulins as induction immunosuppression agents after cardiac transplantation. The increased rate of side-effects with monoclonal antibodies might suggest that polyclonal antibodies are superior to monoclonal antibodies.

The authors set out a clear question and inclusion criteria were defined in terms of the participants, intervention, outcomes and study design. Appropriate sources were searched without language restrictions, which helps to reduce the risk of language bias. However, no attempt was made to obtain unpublished data and publication bias was not assessed. The study selection was carried out in duplicate, which helps to reduce the risk of error and bias. However, it was unclear whether similar methods were used in the quality assessment and data extraction processes. Study quality was assessed using appropriate criteria and individual study details were provided.

Although statistical heterogeneity was assessed, it was not reported for all analyses. Where significant heterogeneity was detected, it was not investigated. Also, time-to-event data (e.g. time to rejection) would have been more appropriately analysed using survival analysis. The included studies were small and few studies were included in each analysis; this suggests that for some analyses there might have been insufficient power to detect a difference between the treatment groups. Given the possibility of bias, limited quality of the included studies, and the small number of participants included in the review, the authors' conclusions should be interpreted with caution.

Practice: The authors stated that patients receiving OKT3 should undergo close monitoring for side-effects. Platelet and white cell counts should be monitored in patients receiving ATG because of a slight risk of thrombocytopaenia and leukopenia.

Research: The authors stated that a large, multicentred RCT is required.