Azienda Ospedale di Lecco, Ospedale A. Manzoni, Lecco, Italy
Sir,
We have read with interest the study by Lars G. Weiss et al. [1]. The authors concluded that Once weekly SC administration of epoetin ß is as safe and effective in maintaining haemoglobin levels in stable haemodialysis patients as two or three times weekly administration of the same total dose.
Despite the fact that rHu-Epo therapy is effective in the treatment of anaemia in haemodialysis patients, the most useful and reliable frequency of its administration has still to be unequivocally established. Although the study is of a high quality, due to its randomized and controlled design, there are unfortunately some drawbacks which, in our opinion, reduce the strength of the conclusions reached by the authors. Our concerns are mainly related to the methodological and statistical approach used in this study.
The main argument is that the power of the study was calculated as if it was dealing with a difference study, and not with an equivalence study, as was actually the case with this investigation. It is worth noting that in an equivalence study the investigators are interested in demonstrating that there are no statistical differences between experimental and control treatments, and thus the power of the study should be 95% or, at least, 90%. This means that only a 5% (or 10%) probability of not detecting any difference between treatments is accepted, when the difference is actually present. By planning a power of only 80%, the authors have accepted a priori a probability of 20% that a difference which was actually present would not be detected.
Another point that the authors did not discuss is the a posteriori power of the study, which is likely to be much lower than the expected 80%. This is because the sample size was calculated assuming that the proportion of patients requiring a dose adjustment in the control group would have been only 1%, while 27% of these patients actually increased epoetin ß dose during the follow-up. The shift from the tail to the centre of a frequency distribution is notoriously associated with a relevant decrease in the power of the study. Although they were dealing with stable patients, it is difficult to accept the authors' prediction of such a low proportion of patients requiring dose adjustments in the control group, especially given the long follow-up (24 weeks).
The final statistical comment concerns the inappropriate multiple use of the two-sample t-test to compare differences in the haemoglobin levels and in weekly epoetin ß doses. In fact, this study was composed of repeated measures during the follow-up, taken at regular intervals in two different study groups. It is worth noting that in such a situation it is more suitable to use the technique of repeated measure analysis of variance. This is relevant, because analysis of variance is not only the correct one but is a far more powerful statistical test, as compared with multiple t-testing.
In summary, the lack of study power, due to the reasons explained above, might have resulted in a false conclusion of equivalence between the treatments under investigation. Furthermore, there are some clinically relevant drawbacks which can be highlighted. Regarding the distribution of the causes of renal failure, there is some incomplete information. The 14 patients with polycystic kidney disease are given for the whole population, whereas it would have been more useful to provide a frequency distribution of these between the two study groups. Another limitation of this study is that there is a high proportion of patients (25%) that were withdrawn from the evaluation prior to week 16. It is interesting to note that this percentage is higher than the proportional difference (20%) that was used in the sample size calculation. Moreover, there were many protocol violators (13 patients out of 158, 8%), and no information on their distribution between groups was given. What is more, as seen from Table 2 in the article, the variability in the haemoglobin levels doubled during the study follow-up, as standard deviation increased from 0.6 to 1.2 g/dl in both groups. This should have been taken into account and commented on by the authors.
Finally it should be noted that, in order to increase the contrast between treatments, it would have been better to restrict the control group only to those patients with three times per week administration of epoetin ß, as the patients with twice weekly administration are in an intermediate condition. This should be kept in mind when conducting equivalence studies.
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Department of Nephrology, Centralsjukhuset, Karlstad, Sweden
Sir,
On behalf of the Swedish Study Group, I would like to thank Dr Andrulli and colleagues for their valuable comments. I would like to take this opportunity to reply to some of the comments made.
The comments concerning the equivalent efficacy and safety of the once-weekly regimen compared to twice- or thrice-weekly regimens are in principle valid, as our study was not statistically designed as an equivalence trial to provide the basis for such a conclusion but rather as an exploratory trial to demonstrate the differences, if any, between the regimens. Aside from any formal statistical considerations, the study provides overwhelming evidence that once-weekly administration can be used as an alternative to twice- or thrice-weekly administration in clinical practice. In fact, it should be noted that not only were there no statistically significant differences in the proportion of patients who maintained stable haemoglobin levels without an increase in epoetin dose (primary endpoint), but that there was no difference at all in the point estimate. Therefore, power considerations as outlined in Dr Andrulli's comments are of no concern in this study and would only have been of primary interest in the case of a clinically relevant but statistically non-significant difference in the primary endpoint. Furthermore, the result of the primary endpoint is supported by the results of the secondary efficacy variables, because no clinically relevant between-group differences were observed for changes in haematocrit levels and epoetin ß doses. Therefore, from a clinical perspective, the conclusion of equal efficacy and safety between the different epoetin ß dosing schedules remains valid.
With regard to the distribution of causes of renal failure, as Dr Andrulli highlights, 14 of 158 randomized patients had polycystic kidney disease. This represents only 8.9% of the patient population and it is unlikely that such a small proportion of patients would have affected the overall epoetin ß requirements. Additionally, these patients were already receiving epoetin treatment before initiation of the study, and had been in maintenance phase and on haemodialysis for a lengthy period of time. Therefore, any reduction in their epoetin requirements would have been apparent prior to study entry.
Finally, Dr Andrulli et al. query the inclusion of patients receiving epoetin ß twice-weekly. The percentage of patients receiving treatment two or three times weekly was similar in patients entering both treatment groups, and overall haemoglobin levels were virtually identical in both groups. Therefore, we feel that the inclusion of patients receiving the twice-weekly regimen did not obscure any differences between thrice- and once-weekly administration.
In summary, this trial fulfilled its primary aim of confirming the clinical findings of previous, uncontrolled studies [13] in a randomized, well-controlled and parallel setting. We note with interest that the results are consistent with those of an equivalence study reported at the recent ERA-EDTA Congress [4]. This study confirmed that once-weekly and three times weekly subcutaneous epoetin ß were therapeutically equivalent in maintaining anaemia correction in patients with chronic renal failure, providing a statistically rigorous probe for equivalence and reconfirming the findings of our study.
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