The Practical Utility of an Economic Analysis of Calcineurin Withdrawal following Renal Transplantation
Authors: Bruce Kaplan, Jesse D. Schold
Journal: Journal of the American Society of Nephrology (2008)

Economic models can be powerful tools for understanding cost-utility, effectiveness, and informing decision-making processes in health care. Limited health care resources necessitate objective evaluations and the identification of potential efficiencies of medical interventions. At base, economic analyses are often about evaluating choices, and the identification of cost-savings associated with certain therapies can potentially be reallocated to other efficacious treatment strategies. In these respects, economic analyses in the field of transplantation are important contributions to enhancing the ultimate goal of maximizing patient care. Both a strength and a limitation of economic analyses are that they often provide a net result, a bottom line that can be easily interpreted in a given health care context; however, as with any model, it is also important to recognize that the conclusions drawn from economic evaluations are also often critically dependent on the inputs of the analysis and the assumptions that are made. The study by Earnshaw et al.1 in this issue of JASN examines the cost-utility of calcineurin inhibitor (CNI) withdrawal in de novo renal transplant recipients. The study attempts to estimate the relative cost-savings associated with CNI withdrawal using a lifetime Markov model, aggregating data from both clinical trial and population-based studies. The model incorporates health states and medication costs and concludes that “CNI withdrawal not only shows potential for long-term clinical benefits but also is expected to be cost-saving over a patient's life.” Clearly, these results may be provocative to the transplantation community; therefore, it is essential to examine critically the analysis to gauge the plausibility of the end results and the likelihood of a robust finding. Two primary assumptions incorporated in this study have less than certain information and may significantly alter the external validity of these findings. The first of these relates to the estimated efficacy of the therapeutic strategies. The second relates to the long-term outcomes extrapolated from these results over the lifetime of the patient. One of the core inputs of this analysis is the impact of transplant recipients’ renal function on costs and health status associated with the respective therapeutic strategies. Importantly, the estimated renal function between CNI withdrawal and cyclosporine-based therapy is derived from the Rapamune Maintenance Regimen (RMR) study.2 The clear limitation of the selection of this trial as a basis to estimate the effect of the respective treatment arms is that the control arm is particularly nephrotoxic and likely represents only the most extreme benefit of CNI withdrawal, and the control arm does not represent a standard of care, is infrequently used in current practice, and as such provides little basis by which to generalize evidence. Given this, the presumption that similar effects will be attributable to other forms of maintenance CNI therapies is problematic. In fact, in the era after the RMR trial, additional studies have now accumulated data about CNI withdrawal. The Cyclosporine Avoidance Eliminates Serious Adverse Renal-toxicity (CAESAR) study found no differences in renal function at 1 yr between CNI-based therapies and a significantly increased acute rejection rate in the withdrawal arm.3 In addition, Larsen et al.4 conducted a trial of CNI withdrawal using a tacrolimus-based treatment arm and found no differences in renal function, survival, or acute rejection at 1 yr; therefore, it is important to recognize that the estimated effects described in this study may exaggerate the immunologic and metabolic risks associated with the therapeutic regimens, and using data from one of the more recent (and applicable) studies may dramatically alter these findings. In fact, examining some of the results of the study critically (see Table 1) indicates that the tacrolimus–mycophenolate mofetil arm was estimated to have the lowest life-years and quality-adjusted life-years among recipients despite other studies’ indicating superior efficacy in this arm. This type of input data seems to lack some degree of face validity on the basis of empirical evidence, and, as such, it is difficult to discern whether the selected studies for the analysis alter the estimates, whether the inputs can reliably be aggregated from different studies, and whether the cumulative uncertainty associated with the assumptions for the analysis even lend themselves to conducting any type of rigorous study examining this important topic at this stage. Better renal function leads to better graft survival among transplant recipients. This general association has been shown in population-based analyses and is of course not a surprising result; however, the appropriate application of these data in this circumstance (and others) is certainly worthy of discussion. At base, the issue is whether this general association can be appropriately applied to novel circumstances, specifically whether elevated renal function necessarily translates into improved survival. For instance, given the same logic stream, treating patients with angiotensin blockers or inhibitors would independently improve graft survival as a function of their impact on renal function. Similarly, simple fluid changes can substantially affect estimated renal function, but this artificial event clearly does not translate to differences in long-term survival. The analysis by Hariharan et al.,5 which was the basis for the estimation in this analysis, demonstrated an association that would be reasonable given that all further injuries to the allograft are evenly and randomly distributed across the population. In the case of CNI withdrawal, we certainly cannot assume that further allograft damage (e.g., late antibody-mediated injury) would be randomly distributed when such a large intervention is imposed. Using this type of associative data to make assumptions when conditions are nonrandomly changed is problematic and potentially misleading. To date, there is no compelling evidence for improved graft survival associated with CNI withdrawal, and, as such, extrapolation of selected renal function changes to long-term efficacy and cost-effectiveness may be premature. Furthermore, even accepting the assumptions of the analysis and the long-term extrapolation to results, the estimated cost savings of the CNI withdrawal arm was less than $12,000 over a patient's lifetime, and the estimated benefit in life years was 0.06 yr. If we then consider the mathematical variability in the estimates in conjunction with the accuracy and precision of the assumptions, then the question that arises is what can be reasonably concluded from these net results? At the end of the day, left unanswered for any practical purposes, unfortunately, is the essential question asked by this study. We hope that these data are interpreted only with consideration of the strong caveats and that readers along with media approach these data with similar restraint. For the time being, one cannot assume a cost saving or a health benefit of CNI withdrawal, and patience for additional data accumulation will likely be the most important prospective strategy. This important issue requires—and our patients deserve—studies specifically designed to answer this question. DISCLOSURES None.