The case of azathioprine versus mycophenolate. Do different drugs really cause different transplant outcomes?

D ifferent drugs, same outcomes. Different drugs, different outcomes. Which is it? At first glance these two studies published in this issue of Transplantation offer starkly conflicting findings that have important clinical and policy implications. Antimetabolites, either azathioprine or mycophenolate are used for almost all kidney transplant recipients worldwide. What is certain is the price differential. The yearly cost of azathioprine is approximately A$600, compared with A$6000 for mycophenolate, a 10-fold difference (1). The newer drug costs substantially more than the older drug is expected. Almost all newer drugs are more expensive than the older drugs which they are designed to replace, but policy makers typically accept such cost increments provided that there are concomitant health gains resulting in an acceptable cost-effectiveness ratio (2). It is a simple question which should have a simple answer. What are the relative benefits and harms of mycophenolate compared with azathioprine for death, graft loss, infection, and malignancy? What do these studies tell us? One is a study-level meta-analysis of randomized controlled trials of azathioprine versus mycophenolate in kidney transplant recipients. Overall, 19 randomized controlled trials (RCTs) involving 3143 recipients were included but this number varied with outcome (17 for acute rejection and 12 for graft loss). The authors found a reduction in acute rejection (relative risk [RR] 0.62) and graft loss (RR 0.76) with mycophenolate but no difference in death, creatinine, infection, or malignancy. Diarrhea was increased with mycophenolate use (RR 1.57). A particular strength of this study was the informative sub-group analyses. For example, the authors showed that the reduction in acute rejection with mycophenolate use varied with immunosuppression co-interventions and was less with cyclosporine-microemulsion than cyclosporinesandimmune. As the authors point out, potential sources of bias were publication bias and outcomes reporting bias. Publication bias, the tendency for studies with positive results to be reported preferentially over studies with negative result (3), can be minimized by searching for studies only published in conference proceedings and other “gray literature,” including trial registration sites. It is unclear how much the authors have searched and included studies that have not been published in Medline indexed journals. They have generated and reported a series of funnel plots, but a funnel plot is an unreliable test for publication bias (4). A symmetrical plot does not exclude publication bias and an asymmetrical plot may arise from other reasons such as poor study designs leading to over-estimation of the magnitude of the true treatment effect. Outcomes reporting bias has been recognized more recently (5). This is the bias introduced when only selected outcomes are reported in any given trial, often the outcomes that favor the investigational intervention, or when the outcomes are changed during the study. Changing denominators is often a clue to the presence of possible outcomes reporting bias. Although data from 19 RCT and 3143 recipients are included overall, for the most important outcome, death, only 10 trials and 2647 contributed data. For adverse event data like infection and malignancy, the uncertainty of the validity of the conclusions is even greater because few trials contributed data. Other concerns about this study are the pooling of all studies irrespective of duration of followup, use of the unvalidated Jadad system for scoring trial quality (6) and by calculating and pooling hazard ratios from incompletely reported survival data. How does the other study differ? It is a report of the Collaborative Transplant Study and is a retrospective cohort study of 51,303 deceased donor renal transplant recipients from 1998 to 2007. The authors compared the outcomes of recipients who received cyclosporine versus tacrolimus and azathioprine versus mycophenolate. They noted a substantial shift in the prescribing patterns of transplant physicians away from azathioprine and cyclosporine during the study period, but no difference in graft loss for either of the two main comparisons. Treatment of acute rejection was less frequent in mycophenolate-treated recipients (RR 0.78), but hospitalization due to acute infection was more common (RR 1.35). 1 School of Public Health, University of Sydney, Sydney, Australia. 2 Department of Nephrology, Children’s Hospital at Westmead, Sydney, Australia. 3 Nephrology and Transplantation Services, The Queen Elizabeth Hospital, Adelaide, Australia. 4 Disciplines of Medicine and Public Health, University of Adelaide, Adelaide, Australia. 5 ANZDATA Registry, Adelaide, Australia. 6 Address correspondence to: Jonathan C. Craig, Ph.D., Department of Nephrology, Children’s Hospital at Westmead, Sydney, Australia. E-mail: jonc@health.usyd. edu.au Received 23 January 2009. Accepted 27 January 2009. Copyright © 2009 by Lippincott Williams & Wilkins ISSN 0041-1337/09/8706-803 DOI: 10.1097/TP.0b013e31819e86cd