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Frequent Hemodialysis Network: Rationale for Study and Study Design

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Univ. of California at San Francisco Dr. Glenn Chertow ... Dr. Gerald Beck, Cleveland Clinic (OH) In-center HD Coordinating Center PIs ... – PowerPoint PPT presentation

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Title: Frequent Hemodialysis Network: Rationale for Study and Study Design


1
Frequent Hemodialysis Network Rationale for
Study and Study Design
  • National Kidney Foundation
  • Annual Meeting April 2006
  • Michael V. Rocco, M.D., M.S.C.E.
  • Wake Forest University School of Medicine

2
Objectives
  • Introduction
  • Selective review of data in daily and nocturnal
    HD studies
  • Why a randomized trial is needed
  • FHN Nocturnal study
  • Trial objectives and study design
  • Inclusion and exclusion criteria
  • Dose of dialysis
  • Primary and secondary outcomes
  • Baseline and follow-up period
  • Schedule of measurements

3
Published data in Daily HD Trials
  • Systemic review of daily HD
  • Review of daily HD publications in 6 languages
  • More than 800 citations screened
  • 233 full text articles retrieved for detailed
    review
  • Only 25 articles met the inclusion criteria
  • Five or more adult patients
  • Follow-up of at least 3 months
  • Prescription of 1.5 3 hours 5 7 days/week
  • Published after 1989
  • Suri R et al. CJASN 133-42, 2006

4
Review of Daily HD Trials through 5/31/05
  • 14 cohorts of 268 unique patients
  • Largest cohort 42 patients
  • One randomized design, using a randomized
    cross-over trial
  • 13 observational studies
  • All studies reported continuous outcomes between
    3 and 24 months of follow-up, with the majority
    at 12 months
  • Delivered treatment time or frequency reported in
    only 6 of 14 cohorts

5
Daily HD Summary of findings
Suri R. et al. CJASN 133-42, 2006
6
Milton Roy Model A
Built by Milton Roy Company of St. Petersburg,
Florida in 1964
7
Milton Roy Model A
Features Automatic hot water Disinfection Automat
ic alarm checks Solid state logic Acoustic tiles
inside to reduce noise
8
Nocturnal Home HD Machines
Aksys PHD System
Baxter Aurora
Fresenius 2008K at home
9
Nocturnal Home HD Programs in the U.S.
From www.HomeDialysisCentral.org
10
Published data in Nocturnal HD Trials
  • Systemic review of Nocturnal HD
  • Review of nocturnal HD publications from Medline,
    Cochrane, BioAbstracts, Cinahl, Health Technology
    Assessment Database and Proceedings First
  • 270 papers and abstracts screened
  • 71 publications retrieved for detailed review
  • Only 10 papers and 4 abstracts met inclusion
    criteria
  • Prescription of at least 5 nights per week and 6
    hours per session
  • Reported on at least one of four outcomes of
    interest
  • Follow-up of at least 4 weeks
  • Included a comparator group (case-control or
    pre/post within patient comparison)
  • Walsh M et al. Kidney Int 671500-1508, 2005

11
Review of Nocturnal HD Trials through 7/03
  • 4 cohorts of unique patients
  • London, Ontario
  • Toronto, Ontario
  • Lynchburg, Virginia
  • Rochester, Minnesota
  • Average follow-up time ranged from 6 weeks to
    3.4 years
  • Study sample sizes ranged from 5 - 63 Nocturnal
    patients
  • No randomized trials
  • No comparative data on survival or occurrence of
    cardiac events

12
Nocturnal HD Summary of findings
Different tools and reporting methods used in
individual studies
Walsh M et al Kidney Int 67 1500-1508, 2006
13
Other reported improvements in patient outcomes
with NHHD
  • Improvement in sleep apnea (Hanly)
  • Increase in patient dry weight (McPhatter,
    Pierratos)
  • Decrease in serum creatinine level (McPhatter)
  • Decrease in beta-2 microglobulin levels (Raj)
  • Hanly PJ Pierratos A. NEJM 344 102-107, 2001
  • Pierratos A et al. JASN 9859-868, 1998
  • McPhatter LL et al. Adv Renal Replace Ther
    6358-365 1999
  • Raj DS et al Nephrol Dial Trans 1558-64, 2000

14
Nocturnal HD Renal osteodystrophy
  • Multiple studies with differing results
  • London, Ontario (Dr. Robert Lindsay)
  • Toronto, Canada (Dr. Andreas Pierratos)
  • Lynchburg, Virginia (Dr. Robert Lockridge)

15
Serum phosphorus levels - London
p NS 2 nocturnal patients added phosphate to
dialysate Lindsay et al. Am J Kidney Dis
42(Suppl1) S24-S29, 2003
16
Phosphate binder dosing - London
All patients prescribed calcium carbonate p 0.05 versus nocturnal HD group value p versus baseline value
Lindsay et al. Am J Kidney Dis 42(Suppl 1)
S24-S29, 2003
17
Serum phosphorus and phosphate intake - Pierratos
Mucsi et al. Kidney Int. 531399-1404, 1998
18
Serum phosphorus and phosphorus intake - Lockridge
McPhatter et al. Advances Renal Replacement Ther
6358-365, 1999
19
Phosphate binder dosing - Pierratos
p HD
Mucsi et al. Kidney Int 531399-1404, 1998
20
Phosphorus binders - Lockridge
McPhatter et al. Advances Renal Replacement Ther
6358-365, 1999
21
NHHD dialysis parameters
22
Gaps in knowledge in frequent HD
  • Improvement in serum albumin level seen in some
    but not all frequent HD studies
  • Hemoglobin levels have not improved in all
    frequent HD studies
  • Effect of frequent HD on EPO requirements
    inconsistent
  • Very small sample size does not allow for
    analysis of hospitalization rates or access
    complication rates

23
Limitations of existing frequent HD studies
  • Lack of adequate control groups
  • Most studies are pre-post case series reports
  • Selection bias
  • Population different than typical in-center
    patients
  • Dropout bias
  • Patients lost to follow-up may due worse than
    patients who continue on nocturnal modality
  • Publication bias
  • Negative studies less likely to be published
  • Small sample size

24
Advantages of a randomized trial
  • A well-designed study of six times per week
    hemodialysis with rigorous methods for data
    collection and interpretation will help to
    alleviate the limitations of prior studies
  • The preferred study design to minimize these
    limitations and biases is a randomized trial,
    analyzed in an intention to treat manner

25
Nightly Hemodialysis
Frequent Hemodialysis Network
26
Frequent Hemodialysis Network
  • Sponsored by both NIH and CMS
  • Clinical trials began in March 2006
  • Comparison of standard three times per week
    hemodialysis with more frequent therapies
  • Daily in-center hemodialysis
  • Daily nocturnal home hemodialysis

27
Trial Objectives Feasibility and Safety
  • Feasibility
  • Can we recruit and retain patients?
  • Will patients adhere to dialysis six times per
    week?
  • Why do patients become non-compliant to a six
    times per week prescription?
  • Safety
  • Are there risks associated with daily HD?

28
Trial objectives - Efficacy
  • How will daily HD affect patient outcomes in
  • Cardiovascular disease
  • Physical health
  • Mental health
  • Cognitive function
  • Nutrition
  • Blood pressure control
  • Anemia management
  • Phosphate management
  • Hospitalization and mortality

29
Study timeline
30
Inclusion Criteria
  • Patients with end stage renal disease requiring
    chronic renal replacement therapy
  • Age
  • 18 years (nocturnal HD)
  • 12 years (daily in-center HD)
  • Achieved mean eKt/V of 1.0 over 2 baseline
    sessions

31
Exclusion Criteria (1 of 2)
  • Residual kidney function (avoid confounding due
    to residual renal function)
  • GFR greater than 10 ml/min/1.73 m2 (nocturnal HD)
  • Residual urea clearance 3 ml/min per 35L urea
    volume (daily in-center HD)
  • Reversibility of renal function
  • Life expectancy of less than six months
  • Unavailability for duration of study
  • Scheduled for living donor kidney transplant
  • Change to peritoneal dialysis, or
  • Plans to relocate to an area outside of the
    referral area of one of the clinical centers
    within the next 12/14 months

32
Exclusion Criteria (2 of 2)
  • Less than 3 months since patient returned to
    hemodialysis after renal transplantation
  • Medical history that might limit the individuals
    ability to take trial treatments for the 12/14
    month duration of the study, including
  • Currently receiving chemo or radiotherapy for a
    malignant neoplastic disease other than localized
    non-melanoma skin cancer
  • Active systemic infection (including
    tuberculosis, disseminated fungal infection,
    active AIDS but not HIV
  • cirrhosis with encephalopathy
  • Current pregnancy or planning to become pregnant
    within the next 12/14 months (patients require a
    higher dose of dialysis if pregnant).

33
Nocturnal HD Study
  • Prospective, randomized trial
  • Three times per week in-center hemodialysis
  • versus
  • Six times per week nocturnal home hemodialysis
  • Up to 250 chronic dialysis patients
  • 125 patients per study arm
  • Follow-up of 14 months for each patient
  • Assumes training period of 2 months
  • At least 12 months of follow-up on nocturnal HD
    therapy

34
Clinical Centers for Nocturnal HD
  • Humber River Regional Hospital (Toronto)
  • Dr. Andreas Pierratos
  • Lynchburg Nephrology Associates (VA)
  • Dr. Robert Lockridge, Jr.
  • Rubin Dialysis Center, Saratoga Springs (NY)
  • Dr. Christopher Hoy
  • University of British Columbia Dr. Michael
    Copland
  • University of Iowa Dr. John Stokes and Douglas
    Somers
  • University of Toronto Dr. Chris Chan
  • University of Western Ontario Dr. Robert
    Lindsay
  • Washington University Dr. Brent Miller

35
Dose of Dialysis
  • Nocturnal home hemodialysis
  • Minimum prescription of 6 hours 6 times per week
  • Can decrease below this level if patient remains
    hypophosphatemic despite the addition of 45
    mmol/L of phosphorus to the dialysate
  • Single or double needle hemodialysis
  • Minimum standardized Kt/V of 4.0
  • Standard three times per week in-center HD
  • Equilibrated Kt/V of 1.1
  • In both arms of study, the specific dialysis dose
    is chosen by the patients nephrologist, as long
    as the minimum dose criteria above are met

36
Dialysis Prescription for Nocturnal HD
  • High flux dialyzers only
  • No reuse of dialyzers
  • Use of ultrapure dialysate
  • For patients performing two needle HD
  • Blood flow rate between 200 300 ml/min
  • Dialysate flow rate between 300 400 ml/min
  • For patients performing single needle HD
  • Blood flow rate between 500 600 ml/min
  • Dialysate flow rate between 300 400 ml/min

37
Summary of Interventions
38
Daily In-Center HD Study
  • Prospective, randomized trial
  • Three times per week in-center hemodialysis
  • versus
  • Six times per week in-center hemodialysis
  • Up to 250 chronic dialysis patients
  • 125 patients per study arm
  • Follow-up of 12 months for each patient

39
Clinical Centers Renal Research Institute
  • RRI New York City (NY) Dr. Nathan Levin
  • University of Western Ontario (London, Ontario)
    Dr. Robert Lindsay
  • Washington University (MO) Dr. Brent Miller
  • Vanderbilt University (TN) Dr. Gerald Schulman
  • Wake Forest University (NC) Dr. Michael Rocco

40
Clinical Centers UCSF
  • Univ. of California at San Francisco Dr. Glenn
    Chertow
  • Univ. of California, Davis Dr. Thomas Depner
  • Peninsula (El Camino, San Jose) Drs. John
    Moran and George Ting
  • Univ. of California at Los Angeles Drs. Allen
    Nissenson, William Goodman and Isidro Salusky
  • Univ. of California at San Diego Dr. Ravindra
    Mehta
  • University of Texas at San Antonio Drs. Juan
    Ayus and Steven Achinger

41
Dose of Dialysis Daily HD
  • Standard three times per week in-center HD
  • Equilibrated Kt/V 1.1
  • Daily in-center HD
  • Six sessions per week
  • Minimum normalized eKt/V of 0.9 per session
  • Normalized V 3.271 V 2/3
  • Minimum time of 1.50 hours/treatment
  • Ensure minimum time for volume removal
  • Maximum time of 2.75 hours/treatment
  • Assist with patient adherence to prescription

42
Summary of Interventions
43
Equilibrated Kt/V
44
Standardized Kt/V
Gotch F. Seminars in Dialysis 14 15-17, 2001
45
Efficiency of more frequent hemodialysis
0 to 60 minutes BUN drops from 75 to 47
mg/dl 60 120 minutes BUN drops from 47 to
34 mg/dl
46
Standardized Kt/V for Conventional HD
GFR 15 12 9 6 3 0
HEMO Study Standard Arm
HEMO Study High Dose Arm
Gotch F, FHN analysis
47
Standardized Kt/V for Daily HD

GFR 15 12 9 6 3 0
Short Daily HD Dose Range
48
Standardized Kt/V for Nocturnal HD
Long Nocturnal HD Dose Range
GFR 15 12 9 6 3 0
49
Standardized (weekly) Kt/V
50
Phosphorus removal
51
Beta-2-microglobulin clearance
52
Study Outcomes
  • Insufficient power to perform a mortality
    analysis
  • Need more than 1000 patients
  • Insufficient power to perform an analysis of
    hospitalization rates
  • Need for more than 600 patients to detect a 25
    decrease in hospitalization rates

53
Primary Outcomes
  • Composite endpoints
  • Change in LV mass as measured by cardiac MRI or
    death
  • Change in RAND Physical Health Composite (PHC)
    score from the SF-36 or death

54
LV mass and Outcomes
  • LVH is a potent marker of cardiovascular death
    risk in patients with ESRD
  • By Cox proportional hazards modeling, each 1.0
    g/m2 increase in LV mass was associated with a
  • 1 increase in all-cause death or
  • 1 increase in cardiovascular death Zoccali
  • By Cox modeling, a 10 decrease in LV mass was
    asssociated with a
  • 22 decrease in all-cause mortality
  • 28 decrease in cardiovascular mortality
    London
  • Zoccali C et al. J Am Soc Nephrol 12 2768-2774,
    2001
  • London GM et al. J Am Soc Nephrol 12 2759-2767,
    2001

55
PCS score and outcomes in DOPPS
N 10,030 patients Minimum of 6 months F/U
Mapes DL et al. Kidney Int 64 339-349, 2003
56
PCS score and outcomes in Fresenius database
  • 13,592 prevalent dialysis patients
  • 6 month observation period
  • Odds ratio for death in multivariate model
  • 0.98 for each 1 point increase in PCS score
  • 0.98 for each 1 point increase in MCS score
  • Lowrie EG et al. Am J Kidney Dis 41 1286-1292,
    2003

57
Secondary Outcomes
58
Other measures (slide 1 of 2)
  • Cardiovascular
  • Cardiac deaths and hospitalizations
  • Interdialytic weight gains
  • Cognitive function
  • Modified mini mental status exam
  • Physical functioning
  • Lower extremity performance battery
  • Gait speed
  • Timed chair stands
  • Standing balance

59
Other measures (slide 2 of 2)
  • Kinetic modeling for
  • Phosphate
  • Creatinine
  • ?2-microglobulin
  • Quality of life
  • SF-36
  • Health Utilities Index (QALY)
  • Nutrition and inflammation
  • Bioimpedance
  • Protein catabolic rate
  • C reactive protein levels
  • Economic

60
Steering Committee
  • Chair
  • Dr. Alan Kliger, Yale University (CN)
  • NIDDK representatives
  • Dr. Paul Eggers
  • Dr. Robert Star
  • Data Coordinating Center
  • Dr. Gerald Beck, Cleveland Clinic (OH)
  • In-center HD Coordinating Center PIs
  • Dr. Nathan Levin, Renal Research Institute (NY)
  • Dr. Glenn Chertow, Univ. of California at San
    Francisco
  • Nocturnal HD Coordinating Center PI
  • Dr. Michael Rocco, Wake Forest Univ. (NC)

61
Grant support
  • National Institutes of Health (16 million)
  • Data Coordinating Center
  • Nine clinical centers and the Clinical
    Coordinating Center
  • Funding for additional dialyzers and for training
    for patients who do not have Medicare as primary
    insurer
  • Centers for Medicare and Medicaid (1.5 million)
  • Additional reimbursement for training of 75
    home nocturnal HD patients
  • Additional reimbursement for 4th treatment per
    week for 75 home nocturnal HD patients and 75
    daily in-center patients

62
FHN grant support
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