Frequent Hemodialysis Network: Rationale for Study and Study Design

1
Frequent Hemodialysis NetworkRationale for
Studyand Study Design

• National Kidney Foundation
• Annual Meeting April 2006
• Michael V. Rocco, M.D., M.S.C.E.
• Wake Forest University School of Medicine

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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

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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

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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

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Daily HD Summary of findings
Suri R. et al. CJASN 133-42, 2006
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Milton Roy Model A
Built by Milton Roy Company of St. Petersburg,
Florida in 1964
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Milton Roy Model A
Features Automatic hot water Disinfection Automat
ic alarm checks Solid state logic Acoustic tiles
inside to reduce noise
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Nocturnal Home HD Machines
Aksys PHD System
Baxter Aurora
Fresenius 2008K at home
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Nocturnal Home HD Programs in the U.S.
From www.HomeDialysisCentral.org
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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

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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

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Nocturnal HD Summary of findings
Different tools and reporting methods used in
individual studies
Walsh M et al Kidney Int 67 1500-1508, 2006
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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

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Nocturnal HD Renal osteodystrophy

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

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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
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Phosphate binder dosing - London
All patients prescribed calcium carbonate p lt
0.05 versus nocturnal HD group value p lt 0.05
versus baseline value
Lindsay et al. Am J Kidney Dis 42(Suppl 1)
S24-S29, 2003
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Serum phosphorus and phosphate intake - Pierratos
Mucsi et al. Kidney Int. 531399-1404, 1998
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Serum phosphorus and phosphorus intake - Lockridge
McPhatter et al. Advances Renal Replacement Ther
6358-365, 1999
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Phosphate binder dosing - Pierratos
p lt 0.05 versus baseline values pre-nocturnal
HD
Mucsi et al. Kidney Int 531399-1404, 1998
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Phosphorus binders - Lockridge
McPhatter et al. Advances Renal Replacement Ther
6358-365, 1999
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NHHD dialysis parameters
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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

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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

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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

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Nightly Hemodialysis
Frequent Hemodialysis Network
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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

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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?

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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

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Study timeline
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Inclusion Criteria

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

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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 gt 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

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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).

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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

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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

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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 gt 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

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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

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Summary of Interventions
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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

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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

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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

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Dose of Dialysis Daily HD

• Standard three times per week in-center HD
• Equilibrated Kt/V gt 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

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Summary of Interventions
43
Equilibrated Kt/V
44
Standardized Kt/V
Gotch F. Seminars in Dialysis 14 15-17, 2001
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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
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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
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Standardized Kt/V for Daily HD

GFR 15 12 9 6 3 0
Short Daily HD Dose Range
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Standardized Kt/V for Nocturnal HD
Long Nocturnal HD Dose Range
GFR 15 12 9 6 3 0
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Standardized (weekly) Kt/V
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Phosphorus removal
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Beta-2-microglobulin clearance
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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

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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

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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
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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

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Secondary Outcomes
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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

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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

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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)

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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

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FHN grant support