Susan L. Smith, MN, PhD

Disclosures

March 31, 2003

Clinical Trials in Transplantation

In his editorial comments in a recent AST Newsletter,[8]James Young, MD, expressed concern about the paucity of presentations at the American Transplant Congress Transplant 2002 on large-scale, randomized clinical trials in heart transplantation. He acknowledged the complexity, costs, and difficulties of these types of studies and noted that not all questions can be answered by the clinical trial.

The clinical trial has long been the gold standard for measurement of outcomes. The focus of clinical trials in transplantation for the last 2 decades has been on the safety and efficacy of new immunosuppressive agents. The major dependent variables (primary efficacy end points) have been patient and graft survival, incidence of acute rejection, time to first acute rejection episode, drug side effects and adverse reactions, complications of immunosuppression, and, to some extent, cost. The current thrust of clinical trials in transplantation is to find more effective and less toxic immunosuppressive agents and regimens.

The scope of clinical trials is limited as efficacy reflects outcomes of treatment delivered only under experimental conditions that are designed to isolate the effects of those treatments. As a result, we may learn very little about what happens in the naturalistic setting. Furthermore, clinical trials are expensive and the research designs are not practical or feasible for investigating many important research questions.

Surrogate End Points

Optimizing long-term kidney function is a central focus of clinical research and practice in kidney transplantation. Dramatic improvements in short-term outcomes have shifted the goal to sustaining graft function over time, forcing investigators to take a closer look at interactions occurring early on that contribute to graft loss over time and to identify protective mechanisms that prevent graft loss.

Renal function is now accepted as an "additional" end point for outcomes in kidney transplantation because the serum creatinine within the first 6-12 months (reaching both a threshold level and change in level over time) after transplantation is associated with the likelihood of graft loss.[9] However, serum creatinine cannot be the only end point in clinical practice because of the low predictive value of serum creatinine for graft loss. This is easily illustrated by an example: Although the use of angiotensin-converting enzyme inhibitors (ACEIs) is believed to potentially prolong graft survival and protect against fatal cardiovascular events, ACEIs are also associated with an increase in the serum creatinine. Therefore, it is conceivable that a drug that might actually increase the serum creatinine could have a beneficial effect on long-term graft survival. Thus, renal function is an additional and probably very meaningful end point for outcomes research in kidney transplantation.

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