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Name required. See also article by Vincenti et al in this issue on page The wide spectrum of morbidity associated with steroids has generated great enthusiasm in considering how they might be eliminated from immunosuppression regimens. Historically attempts to slowly wean steroids have yielded high rates of acute rejection 1 , 2 , raising concerns for a potential increased risk of graft loss.
Subsequent studies have focused on early steroid withdrawal or steroid avoidance. While many of the reports have been single center and nonrandomized, these studies have often been of large size and suggest that steroid minimization may be safe in the short term and in the correct setting 3 - 6.
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While these reports are encouraging, the issue of early steroid avoidance has not been tested with the same rigor the FDA would evaluate a new agent or new immunosuppressive regimen. The study is relatively unique in that it allows evaluation of both steroid avoidance and early steroid withdrawal across a common protocol.
Other strengths of the trial include a thorough evaluation of comorbidities associated with steroid therapy. Both experimental arms of steroid avoidance and early withdrawal failed to meet the primary noninferiority endpoint for renal function compared to steroid maintenance. In strictest terms according to its own design, the trial did not prove efficacy and safety of either investigational arm for the primary study endpoint.
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Stated another way, the trial did not prove that steroid avoidance or steroid withdrawal were not inferior to maintenance steroid therapy. An advantage of utilizing a noninferiority design is that it often allows for a smaller sample size in terms of the primary endpoint 8. In addition population subanalyses can introduce significant selection biases by altering the makeup of the original study population by typically looking at lower risk patients.
Renal function as a primary endpoint has a potential bias already built in as it can be measured only in patients with a functioning graft. Unless graft losses are counted as a low GFR value in the analysis, differential graft loss between the analysis groups can introduce a significant bias. When the investigators evaluated subgroups, including only recipients without delayed graft function or major protocol deviations, many of the differences became less apparent.
In fact, the study was probably not powered to detect differences in the smaller sample size associated with these analyses. These offprotocol patients also affect the interpretation of other endpoints, specifically those related to the benefits of freedom from steroids. Because the current trial was open label, it is possible that investigators were more likely to biopsy the recipients not receiving maintenance steroids, potentially leading to a higher rate of detection of rejection.
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A double blind study design would help address this bias. The only double blind randomized trial of early steroid withdrawal to date is the trial being conducted by the Astellas Steroid Withdrawal Group. Woodle et al. It is important to note that comparability between these two trials and others is limited by the differences in induction and maintenance immunosuppression employed.
To date most studies of early steroid withdrawal have been designed based on the currently most widely used immunosuppressive maintenance regimen of tacrolimus combined with mycophenolate mofetil and variable induction therapy. The results of the current trial by Vincenti et al. The study by Vincenti et al. It helps highlight that in addition to the widely advertised benefits of steroid avoidance strategies, there are potential risks of more acute rejection and worse renal function. Volume 8 , Issue 2. If you do not receive an email within 10 minutes, your email address may not be registered, and you may need to create a new Wiley Online Library account.
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