The impact of the tacrolimus concentration/dose ratio on kidney function in heart transplant recipients
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Background. Tacrolimus is the backbone of immunosuppression after heart transplantation (HTx). Although being highly effective, nephrotoxicity is a frequent complication. Tacrolimus-induced nephrotoxicity is considered to be an important cause of kidney disease after HTx. The tacrolimus concentration/dose ratio (C0/D-ratio) is a reflection of the metabolic rate of a patient for tacrolimus. Recent studies demonstrated a relationship between the tacrolimus C0/D-ratio and adverse clinical outcomes, including nephrotoxicity in solid organ transplantation, mainly kidney transplants. We investigated the impact of the tacrolimus C0/D-ratio on kidney function, assessed with the estimated glomerular filtration rate (eGFR), in HTx-recipients. Methods. This was a retrospective study in HTx-recipients who were treated with tacrolimus as initial immunosuppression for at least six months after transplantation. Data on C0/D-ratio and eGFR were collected at three and six months, and at one, three and five years post-HTx. Patients were categorized into four tacrolimus metabolism groups based on the median C0/D-ratio of the population. A linear mixed model was performed to assess the correlation between time-varying C0/D-ratio and time-varying eGFR. Additionally, multivariate analyses were carried out to assess the relationship between the C0/D-ratio and eGFR at the different time points. Furthermore, a survival analysis between the four groups was carried out. Results. Two-hundred and nine HTx-recipients were included. No relationship between time-varying logarithmically-transformed (Log) C0/D-ratio and time-varying eGFR was found in the linear mixed model (p = 0.71). However, the Log tacrolimus C0/D-ratio was positively associated with eGFR at three months, six months and one year after HTx in multivariate analyses (p = 0.02, p<0.001, and p = 0.009, respectively). Finally, no noticeable difference in survival rate was found between the four groups (p = 0.25). Conclusions. The Log tacrolimus C0/D-ratio was positively associated with kidney function up to one year after HTx in multivariate analyses, but no association was found between time-varying Log C0/D-ratio and eGFR in a linear mixed model. So, the question remains whether a real association is present.
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Background: A non-inferiority (NI) design aims to demonstrate that the experimental arm is not worse than a comparator within a pre-specified margin. A margin of a risk difference of 10% or a Geometric Mean Titer (GMT) ratio from 1.5 to 2.0 is implicitly recommended for vaccine trials. This study explores which NI margins were used in vaccine studies and how they were determined. Methods: A systematic literature search was performed on February 21st, 2013. This resulted in 260 eligible articles, 148 articles were selected randomly; data was collected by the use of a data extraction form. This thesis had an explorative character and therefore descriptive statistics were used to show the determination of the NI margins and which NI margins were used. Results: From the selected articles, 48 were excluded because they did not met the predefined criteria. In 81/100 articles a NI margin on difference was determined. In 71% of reviewed articles a margin of 10% was used, 19% of the articles stated margins lower than 10% (range 3-7.5%), whereas in 10% of the articles margins larger than 10%(range 11.5-50%) were stated as the NI margin. In 55/100 articles a NI margin on the GMT ratio was stated. In 60% of the articles a margin of 0.67/1.5 was used, in 33% the stated margins were 0.5/2.0. A large amount (85%) of the examined articles did not discuss how the NI margin was determined. Only five articles referred to the FDA or EMA guidelines, eight articles referred to methodological articles and two articles referred to previous articles specific for the vaccine. In 82/100 articles the conclusion corresponded to the results, in fourteen the conclusion could not be checked because the effect estimates were not shown, in four articles the conclusion of the authors was not in line with the results. Conclusion: The majority of reviewed articles showed no determination of the NI margin. Not all articles showed all their estimates on NI. Reporting on design and results of NI vaccine trials could therefore be improved. Current guidelines on NI trials contain no explicit margin for vaccine trials. The choice of the NI margin is essential for the outcome of the NI trials, although determination is a great challenge. Regulatory offices might help with presenting guidelines which contain an explicit margin (for a specific vaccine/disease). Donken, R. (2013)Background: A non-inferiority (NI) design aims to demonstrate that the experimental arm is not worse than a comparator within a pre-specified margin. A margin of a risk difference of 10% or a Geometric Mean Titer (GMT) ...
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