DreamRCT: FHN Do-over
Jason Prosek
The legacy of the HEMO Trial
Outcomes for ESRD patients in the United States have been stagnant for decades. The HEMO trial, which was a study ten-fold larger than its predecessor (NCDS), probed the potential benefit of high flux filters and increased dialysis dose as measured by eKt/Vurea. As we all know, it was a famously negative trial for the primary endpoints of patient survival. The HEMO study continues to serve the nephrology community as it’s data is mined for secondary and retrospective analyses. But regardless of the smoke and mirrors applied the fact remains, HEMO definitively showed that improving small molecule clearance by 30% was not able to provide better outcomes so our meager targets for urea clearance were verified.
Perhaps the most important lesson of HEMO is that further tweaking of the current hemodialysis paradigm is unlikely provide significant benefits to our patients and what we need is a radical rethinking of the hemodialysis prescription.
Look to France
This radical rethinking has already ben done in the Tassin dialysis center of France. While the rest of the world shortened treatment times and improved dialysis filters by focusing on small molecule clearance, Tassin focused on patient survival and ended up in a very different place. This single-center cohort dialyzes patients 24 hours every week. They showed that BP control was a more effective predictor of cardiovascular death than spKT/Vurea. In there view treatment time should be whatever it takes to reliably achieve euvolemia and blood pressure control. Amazingly only 1.6% of their cohort required antihypertensive medications. Overall, the survival half-life of this cohort was an unheard of 17 years.
The Tassin experience has all of the pitfalls of any single center, uncontrolled case series.
- The patients have superior nutrition, PCR 1.6 g/kg/d, mean albumin 4.19.
- Low prevalence of diabetic patients (10%)
But the hypothesis that blood pressure and volume control need to take precedence over small molecule clearance is too tantalizing not to explore further.
This was in part the impetus for the RCTs by the Frequent Hemodialysis Network (FHN) who published their findings in 2010 (NEJM) and 2011 (Kidney International). The Six-Treatment per Week version of FHN (NEJM) did demonstrate benefit with regard to their primary outcome (death or increase in LV mass), albeit a soft outcome, while the Nocturnal version of FHN (KI) did not reach signifigance for the same endpoint. This may have been driven by a problem with enrollment for the latter study, but regardless, both studies demonstrated superior phosphorous control, BP control, and LV mass regression. The signal of improved dialysis by these alternative schedules is there, but was not demonstrated in a profound enough proportion to cause a sweeping change in behavior, culture, and infrastructure that widespread acceptance of frequent dialysis schedules would require.
As a result, alternative dialysis schedules are reserved for the morbidly obese, patients unable to control their blood pressure/volume or clear adequate phosphorous. And with that, the potential benefits of the Tassin experience are trapped in this small suburb of Lyon, France.
The Trial
Only the ultimate RCT with hard endpoints should be accepted as adequate to settle this debate. Five thousand patients would be required to achieve a 90% power to detect a 30% difference in mortality at one year. I acknowledge that enrollment in FHN was limited, many of which could be interpreted as lack of patient interest, but others were artificial constraints based on the protocol (necessity of MRI for LV mass measurements, for example). But I believe some of these could be alleviated. I propose an “FHN redo” with the following changes to the protocol:
- 24 hours of weekly dialysis is the treatment goal
- Make treatments flexible for the patient — they choose their treatment, as long as they hit 24 hours.
- Eliminate the requirement for in-center daily treatments. Fourteen percent failed screening because they refused to come in-center six times a week.
- Eliminate residual renal function as an exclusion criteria. Twenty percent were excluded on this basis.
- Use echocardiograms for LV mass measurement. MRI contraindications excluded 13% of screened patients!
Hemodialysis outcomes have become far too stagnant for far too long. In addition, we have spent billions of dollars on in-center dialysis infrastructure and have been stuck in this rut of thrice weekly dialysis, both of which have created enormous organizational inertia resistant to change. It will be a huge undertaking, but it will take no less than this to destroy the complacency that has settled in and has contributed to providing inadequate dialysis to our ever burgeoning dialysis population.
Jason Prosek, MD
