Longer is Better, Except when it is Not, Really: Hemodialysis Edition

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 2017 Jun;28(6):1898-1911. doi: 10.1681/ASN.2015111225. Epub 2017 Feb 1.

A Trial of Extending Hemodialysis Hours and Quality of Life.

Jardine MJZuo LGray NAde Zoysa JRChan CTGallagher MPMonaghan HGrieve SMPuranik RLin HEris JMZhang LXu JHoward KLo SCass APerkovic VACTIVE Dialysis Steering Committee

PMID: 28151412 Free Full text (free through Sep 15, thanks to JASN!) link

Background

Whenever the topic of improving the dismal outcomes with hemodialysis comes up, longer dialysis is one of the options that comes up. Indeed, a global survey of 324 nephrologists suggested that our faith in longer dialysis was the strongest of all modality options. 

Figure 2 from Fluck et al, BMC Nephrology 2014

Figure 2 from Fluck et al, BMC Nephrology 2014

What explains this strong belief? Physiologically it does make sense that longer time on dialysis would remove more uremic toxins, not just phosphate and beta-2 microglobulin, but also more sodium and water. Indeed, data from Tassin (where 8 hour dialysis sessions have been always the norm) strongly suggests that the better cardiovascular outcomes stem from better volume control. But this is where the trial experience hit the Nephrology Negativity Wall™. The FHN Nocturnal trial results were disappointingly negative. However, we found many possible reasons: most notably that only 87/250 planned could be enrolled. Unfortunately, a longer follow up reported recently shows higher mortality in the intervention group, with some Bayesian modelling suggesting any mortality benefit being extremely unlikely. Other badness from longer dialysis: faster residual function loss, which is a robust predictor of mortality on dialysis patients. However, many centers still continue to have nocturnal dialysis programs (either in-center or home hemodialysis), and such programs are clearly more expensive from a societal perspective. Despite not having a mortality benefit, if longer dialysis could be shown to result in better quality of life, then the increased cost of providing this could still be justified. Against this backdrop, the ACTIVE (A Clinical Trial of IntensiVE Dialysis) trial was conceived and executed.

Methods

Intervention:

  • The Control group received conventional hemodialysis (at least 12 hours, and not more than 18 hours a week)
  • The Intervention group received longer dialysis (at least 24 hours a week) 

The frequency of dialysis was not fixed, though there had to be at least three treatments a week, but patients could receive dialysis more often.

Population:

  • Incident or prevalent dialysis patients
  • not currently receiving extended hours (>18 hours per week),
  • with a life expectancy of at least 6 months,
  • and no planned renal transplantation within 12 months

Outcomes:

The primary study outcome was the difference in quality of life at study end, adjusted for baseline, as measured by the EQ-5D.

Secondary end points included

  • cardiovascular effects (change in left ventricular mass index,
  • change in BP, cardiovascular events),
  • other quality of life measures (including SF-36–based PCS and MCS),
  • patient adherence,
  • laboratory outcomes (collected according to site routine practices, before dialysis and not at the first weekly session after a long break),
  • and medication usage (BP-lowering, phosphate-binding, and erythropoiesis-stimulating agents).

Safety outcomes included serious adverse events, dialysis vascular access events, and survival.

Sample Size

The trial assumptions assumed that 200 patients would provide >90% power to detect an absolute difference of 0.10 in baseline-adjusted health-related quality of life with a mean EQ-5D score of 0.70 in the standard dialysis group. The study also had 90% power with 100 participants completing cardiac MRI imaging to detect a difference between the groups in the change in left ventricular mass index from baseline to 12 months of 8.7 g/m^2. 

Funding: 

The trial was supported by a National Health and Medical Research Council (NHMRC) of Australia and Baxter as part of an investigator initiated research grant.

Results

Unlike the FHN trial group, the ACTIVE group successfully enrolled the planned 200 patients, from 40 centres in 4 countries. There was a nice separation of time, with median times of 12 and 24 hours in the standard and intervention groups. The frequency for most patients also remained at 3 times a week. 

As expected, the numbers were better with longer dialysis, with higher urea reduction ratio in the intervention arm. 

The difference in primary outcome? Zilch, nada, nothing, whichever way you slice it. Not even a hint of a difference.

figure 3 from Jardine et al, JASN 2017

figure 3 from Jardine et al, JASN 2017

figure 4 from Jardine et al, JASN 2017

figure 4 from Jardine et al, JASN 2017

Table 3 from the article shows all the secondary outcomes:

  • lower potassium in the extended hours arm
  • lower phosphate in the extended hours arm
  • higher hemoglobin in the extended hours arm
  • No difference in blood pressure
  • Reduced number of BP medications in the extended hours arm
  • No difference in left ventricular mass index 

Discussion

It is hard to argue with the results of this well conducted and eminently sensible trial. Our bias is that indeed longer dialysis *must* be better - if not in mortality, perhaps in some patient centered outcomes such as quality of life. Surely the better phosphate control, higher hemoglobins and lower pill burden mean something? 

On the other hand, decreasing time on dialysis (ie increasing dialysis free time) was one of the top research priorities identified by the SONG group from patient perspective. Longer dialysis definitely does not represent dialysis free time, especially when survival is not increased. The trade-off of longer dialysis could have been justified if there some tangible benefits from longer dialysis. Unfortunately, we have come up empty handed, suggesting the tribulations are not worth the trials. 

Summary for NephJC by Swapnil Hiremath, Ottawa