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In-center hemodialysis six times per week versus three times per In-center hemodialysis six times per week versus three times per
week week
Brent Miller
et al
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n engl j med 363;24 nejm.org december 9, 2010
2287
The new england
journal
of medicine
established in 1812
december 9, 2010
vol. 363 no. 24
In-Center Hemodialysis Six Times per Week
versus Three Times per Week
The FHN Trial Group*
ABSTR ACT
The members of the writing committee
(Glenn M. Chertow, M.D., M.P.H., Nathan
W. Levin, M.D., Gerald J. Beck, Ph.D.,
Thomas A. Depner, M.D., Paul W. Eggers,
Ph.D., Jennifer J. Gassman, Ph.D., Irina
Gorodetskaya, Tom Greene, Ph.D., Sam
James, M.B., B.Ch., Brett Larive, M.S.,
Robert M. Lindsay, M.D., Ravindra L.
Mehta, M.D., Brent Miller, M.D., Daniel B.
Ornt, M.D., Sanjay Rajagopalan, M.D.,
Anjay Rastogi, M.D., Ph.D., Michael V.
Rocco, M.D., Brigitte Schiller, M.D., Olga
Sergeyeva, M.D., Gerald Schulman, M.D.,
George O. Ting, M.D., Mark L. Unruh,
M.D., Robert A. Star, M.D., and Alan S.
Kliger, M.D.) assume responsibility for the
content and integrity of this article.
*The members of the Frequent Hemodi-
alysis Network (FHN) Trial Group are
listed in the Supplementary Appendix,
available at NEJM.org. The affiliations
of the writing committee are listed in
the Appendix.
This article (10.1056/NEJMoa1001593) was
published on November 20, 2010, and
updated on January 5, 2011, at NEJM.org.
N Engl J Med 2010;363:2287-300.
Copyright © 2010 Massachusetts Medical Society.
Background
In this randomized clinical trial, we aimed to determine whether increasing the
frequency of in-center hemodialysis would result in beneficial changes in left ven-
tricular mass, self-reported physical health, and other intermediate outcomes among
patients undergoing maintenance hemodialysis.
Methods
Patients were randomly assigned to undergo hemodialysis six times per week (frequent
hemodialysis, 125 patients) or three times per week (conventional hemodialysis, 120
patients) for 12 months. The two coprimary composite outcomes were death or
change (from baseline to 12 months) in left ventricular mass, as assessed by cardiac
magnetic resonance imaging, and death or change in the physical-health composite
score of the RAND 36-item health survey. Secondary outcomes included cognitive
performance; self-reported depression; laboratory markers of nutrition, mineral me-
tabolism, and anemia; blood pressure; and rates of hospitalization and of interven-
tions related to vascular access.
Results
Patients in the frequent-hemodialysis group averaged 5.2 sessions per week; the week-
ly standard Kt/V
urea
(the product of the urea clearance and the duration of the dialysis
session normalized to the volume of distribution of urea) was significantly higher in the
frequent-hemodialysis group than in the conventional-hemodialysis group (3.54±0.56
vs. 2.49±0.27). Frequent hemodialysis was associated with significant benefits with
respect to both coprimary composite outcomes (hazard ratio for death or increase in
left ventricular mass, 0.61; 95% confidence interval [CI], 0.46 to 0.82; hazard ratio for
death or a decrease in the physical-health composite score, 0.70; 95% CI, 0.53 to 0.92).
Patients randomly assigned to frequent hemodialysis were more likely to undergo
interventions related to vascular access than were patients assigned to conventional
hemodialysis (hazard ratio, 1.71; 95% CI, 1.08 to 2.73). Frequent hemodialysis was
associated with improved control of hypertension and hyperphosphatemia. There were
no significant effects of frequent hemodialysis on cognitive performance, self-reported
depression, serum albumin concentration, or use of erythropoiesis-stimulating agents.
Conclusions
Frequent hemodialysis, as compared with conventional hemodialysis, was associ-
ated with favorable results with respect to the composite outcomes of death or
change in left ventricular mass and death or change in a physical-health composite
score but prompted more frequent interventions related to vascular access. (Funded
by the National Institute of Diabetes and Digestive and Kidney Diseases and others;
ClinicalTrials.gov number, NCT00264758.)
The New England Journal of Medicine
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The
new engla nd jour na l
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n engl j med 363;24 nejm.org december 9, 2010
2288
W
hen 90% or more of usual kidney
function is lost, either kidney transplan-
tation or dialysis is required to sustain
life. Nearly 400,000 persons in the United States
and 2 million worldwide are dependent on dialy-
sis; of these, approximately 90% in the United
States and 70% in Canada undergo hemodialysis,
which is typically delivered three times a week.
1
The rationale for thrice-weekly hemodialysis was
derived from a combination of physiological ex-
periments, assessments of patient acceptance,
feasibility, logistics, and costs.
2-4
Mortality re-
mains high (approximately 18 to 20% per year)
despite improvements in the technology for dialy-
sis, the development of new pharmaceutical
agents, and experience over the course of more
than 40 years since maintenance dialysis became
available. Moreover, although dialysis can sustain
life, it rarely restores health; patients undergoing
dialysis have considerable complications (includ-
ing frequent and extended hospitalizations)
1
and
relatively poor functional status and health-related
quality of life.
5-7
The optimal “dose” of hemodialysis remains
uncertain. Anchored to a thrice-weekly regimen
and typically expressed as a metric of small-
solute (urea) clearance, dialysis dosing has been
informed by numerous observational studies
8-10
and a few carefully conducted, randomized clini-
cal trials.
11,12
Despite ample observational data
suggesting that the dose of hemodialysis (ex-
pressed as the per-session Kt/V
urea
, which is the
product of the urea clearance and the duration of
the dialysis session normalized to the volume
of distribution of urea) correlates directly with
survival, the Hemodialysis (HEMO) Study showed
that there was no benefit from more intensive
hemodialysis (higher per-session Kt/V
urea
) when
patients underwent hemodialysis three times a
week.
12
However, solute removal can be dramati-
cally augmented by increasing the frequency of
hemodialysis sessions.
13
Several uncontrolled
studies showed that there were significant im-
provements in patient-reported outcomes and re-
sults of laboratory tests when patients were treated
with more frequent in-center or at-home hemo-
dialysis.
14,15
Because of ongoing uncertainty re-
garding the optimal dose of hemodialysis, we
tested the hypothesis that frequent (six times per
week) in-center hemodialysis, as compared with
conventional thrice-weekly hemodialysis, would
improve an array of objective and patient-reported
outcomes.
Methods
Study Protocol
The Frequent Hemodialysis Network (FHN) Daily
Trial was a multicenter, prospective, randomized,
parallel-group trial of frequent (six times per
week), as compared with conventional (three times
per week) in-center hemodialysis. The study was
conducted between January 2006 and March
2010 at 11 university-based and 54 community-
based hemodialysis facilities in North America
(for a list of participating sites, see the Supple-
mentary Appendix, available with the full text of
this article at NEJM.org). The design of the FHN
Daily Trial has been described previously.
16
The FHN Daily Trial and a companion Noctur-
nal Trial (ClinicalTrials.gov number, NCT00271999)
were sponsored by the National Institute of Dia-
betes and Digestive and Kidney Diseases and the
Centers for Medicare and Medicaid Services, with
additional support from DaVita, Dialysis Clinics,
Fresenius Medical Care, Renal Advantage, Renal
Research Institute, and Satellite Healthcare. The
dialysis companies donated several weekly dialy-
sis sessions; they had no role in the design of the
study or in the analysis of the data. Recruitment
and data collection were performed by site inves-
tigators and study coordinators. An independent
data and safety monitoring board reviewed the
safety data and interim results. The study was
approved by the institutional review board at each
participating study site. The protocol for the study,
including the statistical analysis plan, is available
at NEJM.org. The authors attest to the fidelity of
this report to the trial protocol.
Study Population
Specific inclusion and exclusion criteria are listed
in
Table 1
in the Supplementary Appendix. Written
informed consent was obtained from all patients
18 years of age or older; patient assent and writ-
ten parental consent were obtained from partici-
pants younger than 18 years of age.
Study Design
Randomization
Randomization was stratified according to clini-
cal center and diabetes status, with the use of
randomly permuted blocks. Although treatment
assignments could not be concealed, between-
group comparisons of the outcomes were con-
cealed from the investigators throughout the
course of the trial.
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Frequency of Hemodialysis
n engl j med 363;24 nejm.org december 9, 2010
2289
Intervention
After randomization, prescriptions for dialysis
were determined centrally and were transmitted
to each clinical center. Patients who were assigned
to thrice-weekly hemodialysis (120 patients) con-
tinued their usual dialysis prescriptions, which in-
cluded a minimum target equilibrated Kt/V
urea
of
1.1 and a session length of 2.5 to 4.0 hours. The
equilibrated Kt/V
urea
is the ratio of the equilibrated
urea clearance during each dialysis session (Kt) to
the patient’s volume of urea distribution (V).
17
The
target equilibrated Kt/Vn, where Vn = 3.271 × V
2/3
,
in the group that underwent hemodialysis six
times per week (125 patients) was 0.9 provided
that the length of the session was between 1.5
and 2.75 hours. These prescriptions were factored
by V
2/3
rather than V (similar to scaling surface
area from body mass) to reduce the dependence
of dialysis prescriptions on body mass and to
avoid unfeasibly long dialysis treatments for pa-
tients with large body mass. Simulation studies
indicated that these interventions would provide
substantial differences in targeted weekly stan-
dard Kt/V
urea
between the treatment groups.
Other Measurements
We obtained data on demographic characteristics
at baseline, with clinical data and laboratory-test
results obtained at baseline and serially over the
course of the study. We calculated adherence as
the ratio of outpatient dialysis sessions attended
to outpatient dialysis sessions prescribed, by
month. We obtained standardized assessments
of coexisting conditions with the use of a modi-
fied version of the Charlson Comorbidity Index
18
supplemented with additional items from the In-
dex of Coexistent Diseases.
19
Questionnaires were
administered by telephone in either English or
Spanish through a centralized call center; per-
sonnel administering the questionnaire were un-
aware of the participants’ intervention assign-
ment. Cardiac magnetic resonance imaging (MRI)
was performed with the use of a standardized
protocol; images were analyzed in a blinded
fashion at a central core laboratory. A committee
overseeing standards of care periodically reviewed
and reported to the clinical centers the results of
prespecified measures (serum phosphate and bi-
carbonate and blood hemoglobin concentrations;
normalized protein nitrogen appearance; and
blood pressure relative to the achieved target
weight after dialysis) that were outside the ranges
recommended in published guidelines.
Outcomes
It was not feasible to recruit a sample large enough
to provide adequate statistical power to assess
individual end points of death, cause-specific
death, hospitalization, or other events. Therefore,
we selected two composite coprimary outcomes:
death or 12-month change in left ventricular
mass, as assessed by cardiac MRI, and death or
12-month change in the physical-health compos-
ite score from the RAND 36-item health survey
(RAND-36).
20
We determined that favorable ef-
fects on both coprimary outcomes would be re-
quired to provide evidence of overall benefit. We
selected nine domains for secondary analysis;
within eight of those domains, we selected a main
secondary outcome: for the domain of cardiovas-
cular structure and function, the outcome was
left ventricular mass; for the domain of physical
health, the outcome was the physical-health com-
posite score of the RAND-36; for the domain of
mental health, the outcome was the score on the
Beck Depression Inventory; for the domain of
cognitive function, the outcome was the score
on the Trail Making Test, Part B; for the domain
of nutrition, the outcome was the serum albumin
concentration before dialysis; for the domain of
mineral metabolism, the outcome was the serum
phosphorus concentration before dialysis; for the
domain of anemia, the outcome was the dose of
an erythropoiesis-stimulating agent; and for the
domain of death and hospitalization, the outcome
was the rate of the composite of death or the first
hospitalization unrelated to vascular access. For
the ninth domain, hypertension, we specified two
main secondary outcomes: systolic blood pres-
sure before dialysis and the number of antihyper-
tensive agents the patient was taking. We focused
on several potential risks, including the need for
interventions related to vascular access. Deaths,
hospitalizations, and complications related to vas-
cular access were adjudicated by an outcomes
committee whose members were unaware of the
patients’ intervention assignment. Complications
related to vascular access were defined as access
failure, infection requiring a procedure, thrombec-
tomy, angioplasty, and fibrin stripping of cathe-
ters or replacement of catheters.
Statistical Analysis
We used the Hochberg modification of the Bonfer-
roni procedure to provide a studywide two-sided
significance level approximating 0.05 when con-
sidering the two coprimary composite outcomes.
21
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The
new engla nd jour na l
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n engl j med 363;24 nejm.org december 9, 2010
2290
Assuming a 20% reduction in mortality with fre-
quent hemodialysis, we estimated that a sample
size of 250 participants would give the study 90%
power to detect clinically meaningful mean reduc-
tions in left ventricular mass of 12.1 to 13.3 g and
increases in the physical-health composite score
of the RAND-36 (in which scores range from 0 to
100 and higher scores indicate better physical
status) of 4.6 to 5.0 points, with the detectable
effect on each coprimary outcome varying slight-
ly depending on the size of the treatment effect
on the other coprimary end point.
Table 1. Baseline Characteristics of the Study Participants.*
Characteristic
Conventional
Hemodialysis
(N = 120)
Frequent
Hemodialysis
(N = 125) P Value
Age (yr) 52.0±14.1 48.9±13.6 0.07
Female sex (%) 39.2 37.6 0.80
Race or ethnic group (%)† 0.32
Black 44.2 39.2
White 38.3 34.4
Native American, Aboriginal Canadian, Alaskan Native,
or First Nation
3.3 3.2
Asian 4.2 8.8
Native Hawaiian or other Pacific Islander 2.5 0.8
Other or mixed 7.5 13.6
Body-mass index‡ 27.5±7.1 27.3±6.5 0.82
Weight after dialysis (kg) 78.7±20.5 77.6±20.6 0.68
Anthropometric volume (liters)§ 39.5±8.3 39.3±8.1 0.90
Cause of end-stage renal disease (%) 0.89
Diabetic nephropathy 32.5 36.0
Glomerulonephritis 19.2 19.2
Hypertensive nephrosclerosis 20.0 21.6
Polycystic kidney disease 5.0 3.2
Other 23.3 20.0
Duration of end-stage renal disease (%) 0.38
<2 yr 16.7 16.0
2–5 yr 42.5 35.2
>5 yr 40.8 48.8
Coexisting medical conditions (%)
Hypertension 87.3 91.5 0.12
Myocardial infarction 13.3 8.8 0.26
Heart failure 20.0 20.0 1.00
Atrial fibrillation 7.5 4.0 0.24
Peripheral arterial disease 8.3 12.0 0.34
Abdominal aortic aneurysm repair or bypass grafting 1.7 2.4 0.68
Stroke 7.5 7.2 0.93
Dementia 0.8 0.0 0.31
Tumor without metastases 6.7 1.6 0.04
Diabetes and complications of diabetes 41.7 40.0 0.79
Hemiplegia 0.8 1.6 0.59
Chronic pulmonary disease 4.2 4.8 0.81
Moderate or severe liver disease 0.8 0.8 0.98
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