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NDT Advance Access originally published online on September 22, 2007
Nephrology Dialysis Transplantation 2007 22(10):2746-2748; doi:10.1093/ndt/gfm173
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org


Randomized controlled trials in PD

Peter G. Blake

Division of Nephrology, University of Western Ontario and London Health Sciences Center, London, Canada

Correspondence and offprint requests to: Dr Peter G. Blake, Chair, Division of Nephrology, London Health Sciences Centre, Victoria Hospital, 800 Commissioners Road, East London, Ontario N6A 4G5, UK. Email: peter.blake{at}lhsc.on.ca

Keywords: peritoneal dialysis; randomized controlled trials; Automated peritoneal dialysis; peritoneal dialysis solutions

The publication of a systematic review comparing continuous ambulatory peritoneal dialysis (CAPD) and automated peritoneal dialysis (APD) in this issue of NDT is very timely [1]. The growth in APD relative to CAPD has been striking over the past decade. Lifestyle factors, in particular, have resulted in more than half of new PD patients in North America using a cycler [2]. Similar trends have been seen in Europe and Japan. This move to APD was initially accompanied by the notion that the therapy was probably superior in terms of its ability to provide higher doses of dialysis and more effective fluid removal [3]. There was also the suggestion, from a randomized trial, that peritonitis might be decreased with APD [4]. Thus medical and lifestyle factors combined to drive the trend.

Recently however, the efficacy of APD has been questioned. In particular, a number of studies have challenged the ability of APD to remove salt and water as effectively as CAPD, and so teasing out the relative merits of these two PD modalities is both topical and important [5,6]. However, the systematic review, although well carried out, is somewhat disappointing in that there are so few comparative studies of high quality for the authors to synthesize. In particular, there are only three randomized controlled trials. One of these was largely abortive and a second was small in size and short in duration, leaving only one of sufficient size and quality to draw convincing conclusions [1,4].

All these might lead readers to lament again the lack of randomized controlled trials in PD and indeed in the area of dialysis generally. The truth, however, is that the last decade has seen the publication of a substantial number of high-quality randomized controlled trials in PD and the consequent answering of many important clinical questions. This achievement has perhaps not received appropriate recognition. It is timely, therefore, to review this record and look at the problems associated with randomized trials in this area. Before doing this, it is appropriate to consider the concepts of valid endpoints and of statistical power in such trials. The most important and valid endpoint of all is, of course, mortality. It can be said, however, that even with the high death rates typically seen in dialysis populations, a randomized trial is unlikely to have sufficient power to detect even a large mortality difference between two treatments if it does not enroll ~1000 patients and follow them for ~2 years [7]. Yet, only one randomized controlled trial of this size has ever been completed in PD [7]. This raises the question of using other endpoints, so that smaller patient numbers can provide sufficient statistical power. An example of this is trials of interventions that may influence peritonitis or exit site infection rates. Typically, trials with these endpoints can be successful with only a few hundred patients [4,8–11]. Other legitimate and important endpoints to look at in PD are hospitalization and technique failure rates, although these are often influenced by local factors and may be difficult to compare across countries [7]. An alternative approach, now widely used, is to have a composite outcome such as mortality plus cardiac events as a primary endpoint [12]. Quality of life scores can also be an endpoint and clearly this is an important consideration for patients. Much smaller patient numbers are required in such trials. There are, however, concerns about how ‘hard’ an endpoint these quality of life scores really are and about how initial differences may lessen with time. The use of laboratory measurements such as serum or effluent levels of various cytokines or biomarkers as an endpoint is much less satisfactory and is an example of what are called ‘intermediate’ outcomes. Even if these ‘intermediate’ outcomes have been shown to be associated with more significant ‘hard’ endpoints, this relationship is not necessarily ‘cause and effect’ and convincing conclusions cannot be drawn from randomized controlled trials based on such measures. An intermediate outcome that is popular in PD is residual renal function [13–15]. There is a widespread belief that this is very important and it has regularly been shown to be associated with better patient survival [7]. This does not necessarily mean, however, that an intervention which preserves residual renal function will also improve survival of itself.

Let us now look at the recent record of randomized controlled trials in PD. The most controversial area of PD in the 1990s was the question of solute clearance targets. The controversies that once raged in this area have now subsided and this is due to the publication of two large controlled trials. ADEMEX, the largest and best ever randomized controlled trial done in PD, with almost 1000 patients, was reasonably well-powered to show a mortality difference and found no survival benefit for augmented as compared with standard clearance targets [7]. An analogous but smaller randomized controlled trial from Hong Kong, while less definitive in its findings, essentially supported the ADEMEX results [16]. These two trials have conclusively answered a very important question and have moved PD researchers into more fruitful areas.

A second key area in PD has been the selection of the most effective ‘giving set’ or delivery system for CAPD. Randomized controlled trials from the 1980s, using peritonitis as the endpoint, demonstrated the superiority of ‘flush before fill’ Y-sets over standard systems [8,9]. The past decade saw similar randomized controlled trials confirm the superiority of integrated double-bag systems over the original Y-set models [10,17]. The issue is now resolved and the integrated systems appropriately dominate the CAPD market. The related topic of exit site infection has also been well-studied in randomized trials. The European Mupirocin Group's findings from the early 1990s made intranasal mupirocin application a standard of care [11]. Recently, the field has been moved forward again with Bernardini et al.'s [18] randomized trial, suggesting that a local exit site application of gentamicin leads to less exit site infection and peritonitis than locally applied mupirocin. Further trials are ongoing on this topic.

A third focus for randomized trials, prominent in the past 5–10 years is new PD solutions. The early randomized trials looking at icodextrin and its beneficial effects on ultrafiltration has been succeeded by more recent ones, showing that icodextrin not only raises ultrafiltration, but also significantly improves volume status and echocardiographic indices [19–21]. Amino acid solutions have been less rigorously evaluated, but there is a recent randomized trial looking at their use over 3 years in 60 patients and showing that some nutrition markers are better maintained over time in patients receiving these solutions [22]. Biocompatible solutions, all with normal pH and low levels of glucose degradation products, and some with bicarbonate buffer, have also been tested in multiple randomized trials [23–25]. Advantages for these novel solutions have been identified, using as endpoints serum and effluent levels of inflammatory markers such as C-reactive protein and interleukins, as well as markers of peritoneal membrane integrity such as effluent levels of CA125. Findings have been less consistent with regard to endpoints such as ultrafiltration capacity and residual renal function preservation. Newer strategies based on combinations of solutions and hybrid prescriptions are now being tested in randomized trials. It should be noted that in all these solution trials, the endpoints used are classic intermediate outcomes. It is not always clear to the clinician whether lower effluent levels of interleukins or of CA125, or even whether better anthropometric indices are clinically relevant to patient outcome. It is not even clear that improved volume status translates into better outcome, but there is perhaps more confidence regarding this association. The lack of very large trials in this area is regrettable.

Another area where randomized trials have been conducted in PD is that of interventions to preserve residual renal function. Loop diuretics, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have all been shown in small, randomized trials to have significant beneficial effects in maintaining renal clearance and/or urinary volume [13–15]. Again, these are intermediate outcomes, though there is perhaps greater confidence that there may be translation into really important patient outcomes. Other important areas addressed in recent PD-related randomized trials include correction of acidosis, administration of recombinant hormones, both of which have appeared to improve nutritional endpoints, treatment of peritonitis and catheter placement techniques [26–29].

There have been, therefore, contrary to the common perception, a significant number of important randomized trials in PD. Good efforts have been made to answer most of the clinically relevant questions and have been quite successful in doing so in many areas. The key deficiency is not that the trials have not been performed, but rather that in some areas they have been relatively small and powered only to examine intermediate endpoints of unclear significance. Studies that could compare APD with CAPD or new solutions to standard ones in a clinically conclusive way will need in excess of 1000 patients. To achieve this, there needs to be large-scale, multicentre, international cooperation, and of course, large-scale funding. With utilization of PD rising less rapidly than a decade ago, industry may be less inclined to take on this role. If this issue is not addressed, clinical research in PD may continue to progress with modest-sized randomized trials often using intermediate outcomes and answering some questions, but the really major issues of which interventions improve survival will not conclusively be resolved.

Conflict of interest statement. None declared.

(See related article by K. S. Rabindranath et al. Automated vs continuous ambulatory peritonealdialysis: a systematic review of randomized controlled trials. Nephrol Dial Transplant 2007; 22: 2991–2998.)



   References
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Received for publication: 5. 2.07
Accepted in revised form: 6. 3.07


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Related articles in NDT:

Automated vs continuous ambulatory peritoneal dialysis: a systematic review of randomized controlled trials
Kannaiyan S. Rabindranath, James Adams, Tariq Z. Ali, Conal Daly, Luke Vale, and Alison M. MacLeod
NDT 2007 22: 2991-2998. [Abstract] [FREE Full Text]  

In this issue ...

NDT 2007 22: i. [Extract] [FREE Full Text]  




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