During recent years, new immunosuppressive agents have been developed with the aim of reducing immunologic and nonimmunologic renal transplant injury, which ultimately decreases long-term graft survival (1). These new agents include the interleukin 2 receptor antagonists (IL-2Ra), commercially available as basiliximab and daclizumab. Use has increased globally over time, with 38% of new renal transplant recipients in the United States and 23% in Australasia receiving IL-2Ra in 2002 (2,3).
IL-2Ra are humanized or chimeric IgG monoclonal antibodies to the alpha subunit of the IL-2 receptor present only on activated T lymphocytes. IL-2–mediated activation of lymphocytes is a critical pathway in the cellular immune response of allograft rejection. The binding of IL-2 to its receptor induces second messenger signals to stimulate T cells to enter the cell cycle and proliferate, resulting in clonal expansion and differentiation. IL-2Ra competitively antagonize this IL-2–mediated activation (4). The rationale has been to use IL-2Ra as induction agents, in combination with standard agents, to minimize early graft injury by preventing acute rejection (5).
There is concern that the additional immunosuppression afforded by newer drugs or combinations, although apparently improving early graft outcome, may in fact increase the risk of malignant, infectious, or cardiovascular disease in the longer term, thereby curtailing patient survival (i.e., deaths with functioning allograft would increase) (6,7). The objective of this study was to systematically identify and summarize the effects of IL-2Ra as induction agents, as an addition to standard therapy, or as an alternative to other antibody therapies in common use (antithymocyte globulins, antilymphocyte globulins, monomurab-CD3).
All randomized controlled trials (RCT) in which an IL-2Ra was compared with either placebo or no treatment, or an alternative antibody preparation, or a different IL-2Ra were included.
Trials in any language, and in which the IL-2Ra was used in any dosage, were eligible. All combinations of additional immunosuppressive agents in either the intervention or control arms of the trials were included. Participants in the trials were patients of any age, were followed for any duration, and were recipients of a first or subsequent cadaveric or living donor renal transplant. Studies in which participants received another solid organ in addition to a renal transplant (e.g., kidney with pancreas) were excluded.
The MEDLINE database (1966 to November 2002) was searched using the optimally sensitive strategy developed for the Cochrane Collaboration (8). We added MESH terms (“kidney transplantation” and “monoclonal antibody”) and text words (“IL2,” “interleukin 2 receptor,” “basiliximab,” “daclizumab,” “cd25,” “bt563,” “simulect,” and “zenapax.” A similar strategy was used in the EMBASE database (1980 to November 2002). The Cochrane Controlled Trials Register in the Cochrane Library (issue 3, 2002) and the Specialist Register of the Cochrane Renal Group were also searched. Reference lists and abstracts of conference proceedings and scientific meetings were hand searched (including, but not limited to, the American Society of Nephrology, the International Transplant Society, the American Society of Transplant Physicians, and the European Dialysis and Transplantation Society) from 1998 to 2002. The reference lists of all identified trials were examined for other relevant articles. To locate unpublished trials, we contacted trial groups, authors of included reports, and drug manufacturers.
When duplicate reporting of the same trial or patient group was suspected, authors were contacted for clarification. If duplication was confirmed, the first complete publication was selected (the “index” publication) and was the primary data source. However, any subsequent publications that included additional outcome data (such as longer term follow-up data) also contributed to the meta-analysis.
Index publications only are referenced here, but a full list of all reports identified for and used in this review are available, grouped by trial, in the expanded version found in the Cochrane library, issue 1, 2004.
Primary outcomes analyzed were graft loss (censored for death), acute rejection, and steroid-resistant rejection. Other outcome measures sought were all-cause mortality, graft loss including death with a functioning allograft, malignancy, infectious complications and specifically cytomegalovirus (CMV) infection, adverse reactions (as a direct consequence of drug treatment), chronic allograft nephropathy, and incidence of delayed graft function. Outcome events were assessed at 3 and 6 months and at 1 and 3 years after transplantation. When median or mean follow-up duration was quoted, and clarification from the report authors was not forthcoming, data contributed to the analysis at the nearest time point below the point estimate given.
Contributions of Reviewers
There were five reviewers (A.W., E.G.P., G.H., J.R.C., and J.C.C.). The literature search strategy described above was developed and performed to identify eligible studies (G.H. and A.W.). The search results were combined, and all titles, abstracts, or when necessary the full text, were independently screened by two reviewers (A.W. and E.G.P.). Disagreement was resolved by discussion (A.W. with J.R.C. and J.C.). Data extraction was performed independently by two reviewers (A.W. and E.G.P.), using a standardized form. Any discrepancies were resolved by discussion (A.W. with J.R.C. and J.C.). Data were entered twice into the Cochrane meta-analytical software (REVMAN 4.1) (A.W.).
Quality of studies was assessed independently by two reviewers (A.W. and E.G.P.) without blinding to journal or authorship. The quality items assessed were allocation concealment, blinding, intention-to-treat analysis (ITT), and completeness of follow-up. These were assessed separately, rather than combined in a scoring system, using the checklist developed for the Cochrane Renal Group (9). Patients who were randomly assigned but did not undergo transplantation were regarded as legitimate exclusions from the ITT population.
Data were extracted first from individual trials and then pooled for a summary estimate using the random effects model. Dichotomous outcomes results were expressed as relative risk (RR) with 95% confidence intervals (CI), where values of less than 1 favored IL-2Ra treatment. Heterogeneity was analyzed using the Cochran Q test (χ2 distribution with n −1 degrees of freedom), with P less than 0.05 used to denote statistical significance. Additionally I2 was calculated to measure the proportion of total variation in the estimates of treatment effect that was caused by heterogeneity between trials. Possible sources of heterogeneity considered, in the effects of IL-2Ra across trials, were trial quality, combination of additional baseline immunosuppressive agents used, and baseline risk of participants.
A total of 117 reports (publications and abstracts) of 38 trials (10–47) qualified for inclusion in the review (Fig. 1). The 38 combined trials represented a total of 4,893 randomly assigned participants. Seventeen of these trials (11–14,16, 19,23,24,29,33,36,37,39,40,43,45,47) were available in abstract form only (2,037 participants), whereas the remaining 21 (2,901 participants) (10,15,17,18,20–22,25–28,30–32,34, 35,38) were published in 10 different journals. All trials identified were in English.
Table 1 shows the characteristics of trials included in the review. Sixteen trials (2,682 participants) (10,11,13,15,18, 20,21,26,31,32,34,35,37,38,44,46) compared an IL-2Ra with placebo or no treatment; 14 trials (1,108 participants) (12,14,17,22,25,27,29,33,36,39–43) compared IL-2Ra to another mono- or polyclonal antibody (either monomurab-CD3, antithymocyte globulin, or antilymphocyte globulin). One trial with three arms (156 participants) compared an IL-2Ra both with no treatment and with a polyclonal antibody (24). Two trials (19,30) (82 participants) compared basiliximab with daclizumab, and the remaining five trials (16,23,28,45,47) involved IL-2Ra in a unique comparison (different dosing of the same IL-2Ra, IL-2Ra within a calcineurin inhibitor-free regimen, and IL-2Ra within a steroid reduced or steroid-free regimen). Basiliximab was used in 59% of trials, daclizumab was used in 30%, and other IL-2Ra were used in 22% (either Anti-tac, BT563, 33B3.1, or Lo-tac-1).
Information on the study population demographics was not available for all trials. The majority of trials were restricted to unsensitized participants with low baseline risk for transplantation. However, 11 trials included participants with panel-reactive antibodies of greater than 50% (12,17,20,21, 25,32,36,42–44,46), although the proportion of these high-risk participants within these trials varied from 4% to 100%. Eight trials (25,26,29,33–35,41,43) included a proportion of participants with a previously failed renal transplant.
Baseline immunosuppression varied both within trials (when three arms were investigated) and among trials. Cyclosporine was used in 32 trials (11–15,17–32,34–42,44,46). In 16 trials (12,13,18,24,26–29,31,34,35,37–41), cyclosporine was stated to be the microemulsion (Neoral) formulation, in 13 trials (11,14,15,17,22,23,25,30,32,36,42,44,46) the formulation was not stated, and the remainder (20,21) used the earlier formation (Sandimmune). Tacrolimus was used in seven trials (10,16,19,33,43,45,47).
The reporting of outcome measures was variable. Only two trials reported incidences of chronic allograft nephropathy. Reporting of harmful effects was limited and inconsistent. Participants with any infection were reported in 52% of trials; however, a further 21% of trials also assessed infection but expressed their results as “infectious episodes,” and therefore this data could not be combined. Reporting of adverse reactions directly relating to drug administration was found only in trials in which an IL-2Ra was compared with another antibody preparation.
Quality of Included Studies
Reporting of details of trial methodology was incomplete for the majority of trials (Table 2). Five trials (20,21,31,35,42) (14%) reported adequate allocation concealment. Of the remaining 33 trials, 32 (84%) were randomized but gave no information on the method used and 1 trial (29) (3%) used inadequate methods. Nine trials (13,18,26,31,32,35,37,44,46) (24%) reported blinding of both participants and investigators. There were no trials that reported the blinding status of either outcome assessors or data analysts. ITT analysis was confirmed in 10 trials (10,17,18,28,31,32,35,37,38,46) (26%), unclear in a further 25 trials (68%), and not undertaken in the remaining 3 trials (41,42,47) (8%). Completeness of follow-up was clear in 14 trials (10,15,18,20,21,24,27,28,31,32, 35,41,46,47) (38%), with values that ranged from 89% to 100%, but was neither reported nor deducible in the remaining 24 trials (62%).
IL-2Ra compared with placebo/no treatment.
Results were homogeneous across all outcomes, with no differences demonstrated between the different IL-2Ra used and the differing combinations of additional immunosuppressants (Table 3). Graft loss (Fig. 2) favored the use of IL-2Ra, but was not significantly different (at 1 year, 14 trials: RR 0.84; CI 0.64–1.10). Incidence of clinically diagnosed acute rejection within 6 months of transplantation (Fig. 3) was reduced by 34% for those treated with an IL-2Ra (12 trials: RR 0.66; CI 0.59–0.74). This advantage was increased for biopsy-proven rejection, showing a 36% reduction. Treatment with an IL-2Ra showed a substantial effect in preventing steroid-resistant rejection, reducing incidence at 6 months by 49% (7 trials: RR 0.51; CI 0.38–0.67). CMV infection was reduced in IL-2Ra–treated patients (Fig. 4), but the difference was not statistically significant (1 year, 7 trials: RR 0.82; CI 0.65–1.03). All other outcomes favored the use of IL-2Ra, but none reached statistical significance (Table 3, Fig. 5).
IL-2Ra compared with other mono- or polyclonal antibody preparations.
IL-2Ra were equally as effective as other mono- and polyclonal antibodies in preventing acute rejection (Fig. 6). No statistically significant differences in treatment effects were demonstrated for graft loss, mortality, CMV infection, or malignancy (Table 3). Adverse reactions to the study drug were not widely reported, but statistically significant differences were shown for fever, leucopenia, thrombocytopenia, and overall adverse reactions, in favor of IL-2Ra compared with other antibody therapies.
Significant heterogeneity among trials was demonstrated for the incidence of CMV [6 months only, 4 trials: χ2(3) 12.65; P =0.005] and total adverse reactions (4 trials: χ2(3) 14.14; P =0.003). I2 was 76.3% for CMV and 78.8% for adverse reactions. The largest trial (Brennan) contributing to both analyses was identified as the main cause of the heterogeneous results. Sensitivity analysis, by removal of this trial from each analysis, left three trials with homogeneous results strongly favoring IL-2Ra (CMV: RR 0.37, CI 0.22–0.62; χ2(2) 0.25; P =0.88; I2 0%; and adverse reactions: RR 0.29, CI 0.18–0.47; χ2(2) 1.77; P =0.41; I2 0%). This was not explicable by either baseline immunosuppression, CMV prophylaxis protocol, or by trial quality.
The comparative efficacy of different IL-2Ra preparations.
The two trials (19,30) comparing basiliximab and daclizumab head to head were small (n=82 total). Outcomes were not reported at the same time point, and zero events occurred for the majority of outcomes; therefore data could not be combined in a meaningful way. Indirect comparison, by subgrouping trials by their intervention (daclizumab or basiliximab), showed no clear difference for any outcomes. Adding basiliximab to a double-drug or triple-drug therapy regimen had the same benefit as adding daclizumab in preventing acute rejection (at 6 months: basiliximab RR 0.67; CI 0.59–0.77 versus daclizumab RR 0.66; CI 0.53–0.82).
IL-2Ra in other trial comparisons.
The other five trials (16,19,23,28,47) examined unique comparisons. Thus no summary beyond their individual results was possible.
The use of an IL-2Ra in addition to standard double-drug or triple-drug therapy significantly reduces acute rejection within the first year after transplantation. This is a class effect, because there is no evidence that the effects of basiliximab and daclizumab are different. Although use of an IL-2Ra in addition to standard therapy favors graft survival, the effect was not significant. There is no demonstrable difference in acute rejection rates or graft loss among IL-2Ra and other mono- or polyclonal antibody preparations used in this context. Adverse drug reactions affect significantly more patients receiving antibody preparations other than IL-2Ra. CMV infection is relatively reduced when IL-2Ra are used, whatever the comparative arm, but the difference did not reach statistical significance. The short follow-up duration of all trials was insufficient to clarify differences in the incidence of new malignancies.
Strengths and Limitations
This meta-analysis was undertaken with deliberately broad inclusion criteria, to better explore the totality of evidence available. The results demonstrated a remarkable consistency of effect for IL-2Ra. Despite this, there was still insufficient power to show definite reduction in some important transplant-centered outcomes. Graft loss, including death with a functioning allograft, suggested a 17% reduction at 1 year for those treated with an IL-2Ra in addition to standard regimens. However, lack of power resulted in wide CIs around this estimate (0.66 to 1.04), with the result that, although tantalizingly close, the reduction was not statistically significant. Summary estimates of complications of immunosuppression, such as CMV infection and malignancy, were also underpowered to show a difference in treatment effect, although the RR of all trials favored IL-2Ra, compared with placebo and compared with other antibodies. To clarify these uncertainties, the importance of publishing further follow-up data from the RCTs contributing to this review is paramount.
Harmful effects were reported in insufficient detail or were measured or grouped differently among trials, making it impossible to adequately determine the relative frequency of adverse events or to summarize the drawbacks of therapy in an informative way. However, this is not peculiar to this review but is common to many RCTs and systematic reviews (48).
The applicability of the meta-analysis results to other populations and settings may be limited by the circumstances of the constituent trials. The recipient population was not stated for 6 trials, and limited information was available for 12 trials. Seven trials (21,28,31,32,40,42,46) were conducted in recipients of a first cadaveric graft; for trials that included living donor grafts (9 trials:10,13,18,26,29,30,35,41,44), these were a minority. Only two small trials (25,36) were conducted exclusively in “high risk” recipients, and the RCTs containing mixed-risk participants did not report stratified results. However, the high level of homogeneity of results between RCTs for the majority of outcomes, particularly the primary outcomes of graft loss and acute rejection, suggests that the results are likely to be generalizable to populations of greater and lesser risk.
In an attempt to minimize publication bias, this meta-analysis included both unpublished data and data from conference abstracts. We also made strenuous efforts to include non-English language sources. Fourteen (38%) trials included were not present on the electronic databases, and 16 (11,13,14,16,19,23,24,29,33,36,37,39,40,43,45,47) (46%) had not yet been reported in journal format. Confining a meta-analysis to published data or English language alone has been previously demonstrated to overestimate the positive treatment effects (49). This approach led to the inclusion of preliminary results from current ongoing RCTs; whether this may lead to bias in results has not been previously investigated, to our knowledge.
The internal validity of the design, conduct, and analysis of the included RCTs was difficult to assess because of the omission of important methodologic details in the trial reports. Only 2 trials adequately reported all four methodologic quality items assessed, even though 14 RCTs has been published in journals since the advent of the CONSORT statement (50). The internal validity of RCTs reported so far in only abstract form was even more difficult to ascertain. Thus it is impossible to exclude the possibility that elements of internal biases may be present in the results of the meta-analysis.
When added to standard double-drug or triple-drug therapy, IL-2Ra reduced the risk of clinically diagnosed acute rejection by 34% and the risk of steroid-resistant rejection by 49%, compared with standard therapy alone. The combined risk of acute rejection in the placebo arm was 40% and the combined risk of steroid-resistant rejection was 16%. Based upon these RRs, for every 100 patients treated with IL-2Ra, 14 fewer patients could be expected to experience acute rejection and 8 fewer to experience steroid-resistant rejection. Seven patients would need to be treated to prevent 1 patient from experiencing acute rejection (NNT acute rejection = 7), and 13 patients would need to be treated to prevent 1 patient from experiencing steroid-resistant rejection (NNT steroid resistant rejection = 13). These results concur with a previous, more limited systematic review and meta-analysis of fewer RCTs that examined the addition of IL-2Ra to cyclosporine-based therapy (51). Basiliximab and daclizumab are equally effective. When IL-2Ra are compared with other antibody preparations, they are of equal benefit but incur fewer associated adverse effects.
There was insufficient information in the reported data of the RCTs in this review to undertake a formal economic evaluation of the efficacy of IL-2Ra. Any excess costs arising from the addition of an IL-2Ra to standard regimens or the substitution of an IL-2Ra for a different antibody preparation could not be calculated. This would be possible only if more specific data were available, allowing the drug costs to be offset against the costs of treating rejection and infection.
Many of the uncertainties of the meta-analysis might be clarified if meta-analysis of individual patient data were possible. This would increase the statistical power of the analysis and thus might clarify the estimates of effect that approach, but do not reach, statistical significance. Individual data analysis would also allow time-to-event data to be incorporated and allow more flexible analysis of patient subgroups and outcomes. However, if complete data were not available from all RCTs, then analysis of only selected data would obviously risk the introduction of bias to the estimates (52).
IL-2Ra show significant benefit in reducing acute allograft rejection, but not graft loss, in renal transplant recipients when added to standard therapy. IL-2Ra are as efficacious as other mono- or polyclonal antibody preparations but have significantly fewer side effects.
A.W. and E.G.P. acknowledge the help and support of Narelle Willis, the Cochrane renal review group coordinator. The authors thank all report authors who responded to our inquiries about their work, and especially Drs. N. Ahsan, D. Brennan, H. Ekberg, I. Folkmane, J. Kovarik, G. Mourad, B. Nashan, S. Sandrini, H. Sheashaa, H. Shidban, and R. Stratta, who were particularly helpful in providing additional information.
1 This work has been presented at the 38th Annual Scientific Meeting of the Australian and New Zealand Society of Nephrology, Sydney 2002; the 21st Annual Scientific Meeting of the Transplantation Society of Australia and New Zealand, Canberra 2003; and the World Congress of Nephrology, Berlin 2003. The systematic review will appear in its entirety in the Cochrane Library, issue 1, 2004.
Potential conflicts of interest are as follows for the Cochrane renal group (A.C.W., G.H., J.C.C.). The Cochrane renal group receives financial support from several sources including government and industry. These funds go into a general fund managed by the Children’s Hospital at Westmead. These funds are used to support key activities including handsearching, the development of a trials registry, training and support for reviewers conducting reviews, and consumer participation in the group. Those contributing funds have no rights of authorship or publication. The authors of the review retain the right to interpretation of the results and the right to publish. Funding sources are as follows: Amgen Australia, Amgen Inc., Aventis Pharma (past), Janssen-Cilag, Novartis Pharmaceuticals, Servier (past), Wyeth Australia, Australian Department of Health and Ageing, Australian Kidney Foundation, Australian and New Zealand Society of Nephrology, and National Health and Medical Research Council of Australia.
A.C.W. receives indirect support for infrastructure costs associated with unrelated research with ANZDATA, the dialysis and transplant registry of Australia and New Zealand, in the form of an unrestricted educational grant from Novartis Pharmaceuticals Australia. J.R.C. has advisory board and clinical trial involvement with Novartis, Roche, Janssen-Cilag, Fujisawa, and Wyeth and has also been an invited speaker at national and international meetings sponsored by these companies. E.G.H. declares no conflicts of interest.
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