Dialysis Unplugged: FREEDOM, Green Eggs and Ham

Lately, I have been listening to my wife read to our two-and-a-half year old daughter the acclaimed book by Dr. Seuss: Green Eggs and Ham. One interpretation of the book can be found on Wikipedia. But the question that you're thinking of is what in the world has this got to do with a nephrology article? Basically, as I see it, the story is about not being distracted by something that looks awful on the surface.  

Sam the main character goes through several maneuvers to try and persuade the other character in the story (who is unnamed) to taste the green eggs and ham dish. The unnamed character is naturally resistant - green eggs - ughh! The conclusion of the tale occurs when the unnamed character finally gives in and tries the green eggs and ham. He realizes that he does in fact like green eggs and ham and would eat them in all the places and with all the dining partners suggested throughout the book.

Well, the Dr. Seuss story is a metaphor for the short-comings of the FREEDOM study. This shortcomings and subsequent criticisms of this study shouldn't dissuade you from the benefits of short daily dialysis. 

FREEDOM is the acronym for "Following Rehabilitation, Economics and Everyday-Dialysis Outcome Measurements” Study. It is an ongoing prospective cohort study with matched control group (details of the study design were published in AJKD in 2009) and compares the benefits of home short daily hemodialysis (SDHD) (6 times/week) with a historical control group. New data from the study was presented at the ASN a few weeks back.

The study is enrolling adult patients with end-stage renal disease who are considered suitable candidates by the treating physician for SDHD with the NxStage System One device, and who have Medicare as their primary insurance payer. The control group are matched thrice-weekly in-center HD cohort patients derived from the US Renal Data System database using a 10:1 ratio, totaling 5,000 patients.

The research question is:  Is daily HD economically attractive compared with thrice weekly HD, while improving health-related quality of life and other dialysis adequacy measures?

In an earlier article in this blog Dr. Bertrand Jaber discussed the results of FREEDOM, published in CJASN, as they pertain to the Restless Leg Syndrome.

At the ASN, FREEDOM reported interim quality-of-life data from 235 subjects that were enrolled of which 127 completed the 12-month follow-up. The data is shown in Fig. 1.

Fig.1

• Patients reported a better overall quality of life (as reported on a 10-point Likert scale with 0 = worst, 10 = best). The baseline score improved from 6.4 to 7.0. (Index: P<0.0001)

• Patients reported more satisfaction with physical intimacy (as reported on a 10-point Likert scale with 0 = least satisfied, 10 = most satisfied). The baseline score improved from 4.9 to 5.7. (Index: P=0.0005)
• Patients reported they are less likely to return to their prior dialysis regimen (as reported on a 10-point Likert scale with 0 = most likely to return, 10 = least likely to return). The baseline score improved from 8.1 to 9.1. (Index: P=0.002). 

In an earlier report the effect of short frequent dialysis on depression was presented. The data is shown in Fig.2. There was a significant decrease in mean BDI score over 12 months (11.2 [95% CI, 9.6-12.9] vs 7.8 [95% CI, 6.5-9.1]; P<0.001). The percentage of patients with depressive symptoms (BDI score>10) significantly decreased during 12 months (41% vs 27%; P=0.03).Also, the percentage of patients experiencing prolonged postdialysis recovery time (>or=60 minutes) also significantly decreased (81% vs 35%; P=0.001).

Fig.2

What are limitations? The most important is that this is not a randomized controlled study. There is a tremendously high likelihood of bias because physicians will choose patients who are "good candidates" for SDHD and match these with patients selected from USRDS, an administrative data-base. 

One of the exclusions in the study is "likelihood of not surviving the training period". Selecting healthier patients and trying to match these with similar USRDS patients may be the intent of the investigators, but it's unlikely they would have achieved this. Furthermore, one is comparing contemporary patients recruited for SDHD with historical patients who are part of USRDS. 

Second, the study is not blinded -- admittedly this is impossible, but it makes the patient-reported outcomes (PRO) all the more open to bias. The longitudinal assessments of PROs in an unblinded study, particularly where the investigators themselves may be champions of the therapy (for example, of NxStage), needs to be interpreted cautiously. 

The other important issue is discussed extensively in the literature and has been prominent in FDA documents -- namely the issue of  "Minimal Important Difference" (MID), where MID represents the smallest change perceived by the patient as an advantage, or that could lead to a change of treatment. The MID needs to be determined, but is frequently 3 to 5 points. The data may be statistically significant, but may fall within the MID and so is unlikely to be of clinical significance. In FREEDOM, making a lot out of "significant improvements in measures of QOL" could be viewed as misleading.

The bottom-line: I believe that the evidence will ultimately show the short daily dialysis is better than thrice-weekly dialysis. Other studies, better designed, have already made major in-roads in making the case (discussed here). FREEDOM has lots of limitations. But like the Dr. Seuss story, the FREEDOM study shouldn't detract from the underlying message: more dialysis is better and short daily dialysis is one option to get there.