Evidence in Transplantation

Introduction

As each day goes by, the medical literature expands almost exponentially, and the literature in organ transplantation is no different. Some 27 million medical articles have been listed on PubMed and there are well over 220,000 articles on organ transplantation alone. Seeking evidence in informing our practice in organ transplantation, be it the value of a particular immunosuppressive drug or a surgical intervention, such as the prophylactic use of a stent in the ureter in kidney transplantation, is therefore challenging for an inexperienced literature searcher. Thus competence in searching the medical literature is essential for members of the transplant community (or indeed any clinician).

Levels of Evidence

Evidence is ranked according to levels, which prioritize study designs on the basis of internal validity ( Table 42.1 ; Fig. 42.1 ). Systematic reviews and meta-analyses of randomized controlled trials (RCTs) provide level I evidence, with individual RCTs providing level II evidence. Level I and II studies provide the most valuable evidence to allow us to arrive at a management decision of our patient population during and after organ transplantation or indeed of the individual patient.

RCTs are the most desirable form of evidence to answer a question about an intervention, with many advantages due to the ability to minimize risk of bias ( Table 42.2 ). However, there are a number of disadvantages that mean that a randomized trial is not always the best study design to answer every clinical question. Inclusion and exclusion criteria are often restrictive in clinical trials, and this can limit the generalizability of the results to external populations. Cost constraints and recruitment issues often mean a small sample size, limiting the statistical power to detect differences in infrequent outcomes. In addition, cost often limits the length of follow-up, which does not allow the study of the long-term efficacy and safety outcomes.

Even RCTs vary in methodologic quality. In a previous analysis of the methodology of reporting of trials in organ transplantation by our group, just over one-third of trials were considered to be of good quality, showing a significant risk of bias in many studies that limit their value in informing practice.

Other levels of evidence, although perhaps not as robust, do have advantages in certain circumstances. One such source of evidence is transplant registry data. In our specialty there are a number of national, regional, and international registries for organ transplantation, for example, United Network for Organ Sharing (UNOS) in the US ( www.unos.org ), the international Collaborative Transplant Study ( www.ctstransplant.org/ ), the ANZDATA registry for Australia and New Zealand ( www.anzdata.org.au/ ), and the Eurotransplant registry ( www.eurotransplant.org ). National registries also exist, such as that maintained by National Health Service Blood and Transplantation (NHSBT) for the United Kingdom ( www.odt.nhs.uk ).

Transplant registry data have the advantages of large numbers and diverse real-world populations, which mean that findings may be more generalizable than those from clinical trials with restrictive inclusion criteria ( Table 42.3 ). They not only identify current practice but the large numbers will allow detection of rare events that smaller clinical trials may not be powered to investigate. The major disadvantages of registry data are that data are often recorded retrospectively with lack of validation, data may be incomplete, and one cannot exclude a selection bias in analysis. To minimize the disadvantages of registry data, an effort should be made to require the return of all data to registries; national registries should be able to achieve that.

The debate over the role of RCTs versus registry data should not be regarded as a contest. Both sources supply useful data, and they should be regarded as complementary. Used together they can provide more robust evidence for interventions in transplantation. For example, registry data can be used to generate hypotheses that need to be tested in properly designed RCTs or identify patients that are expected to benefit from an intervention. Well-run registries provide the facility for long-term follow-up of participants in trials. For example, in the large 3C study in the UK of alemtuzumab versus basiliximab induction with subsequent randomization to sirolimus or tacrolimus at 6 months, all recipients have been registered with the national registry at NHSBT to enable long-term follow up, and there are other examples too.

Searching the Literature

Searching for evidence can be a challenging task. There is an abundance of resources available and a rapidly increasing number of citations. This section provides a brief introduction of how to search for evidence in commonly used resources.