Title: Frequent Hemodialysis Network: Rationale for Study and Study Design
1Frequent 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
2Objectives
- 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
3Published 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
4Review 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
5Daily HD Summary of findings
Suri R. et al. CJASN 133-42, 2006
6Milton Roy Model A
Built by Milton Roy Company of St. Petersburg,
Florida in 1964
7Milton Roy Model A
Features Automatic hot water Disinfection Automat
ic alarm checks Solid state logic Acoustic tiles
inside to reduce noise
8Nocturnal Home HD Machines
Aksys PHD System
Baxter Aurora
Fresenius 2008K at home
9Nocturnal Home HD Programs in the U.S.
From www.HomeDialysisCentral.org
10Published 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
11Review 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
12Nocturnal HD Summary of findings
Different tools and reporting methods used in
individual studies
Walsh M et al Kidney Int 67 1500-1508, 2006
13Other 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
14Nocturnal HD Renal osteodystrophy
- Multiple studies with differing results
- London, Ontario (Dr. Robert Lindsay)
- Toronto, Canada (Dr. Andreas Pierratos)
- Lynchburg, Virginia (Dr. Robert Lockridge)
15Serum phosphorus levels - London
p NS 2 nocturnal patients added phosphate to
dialysate Lindsay et al. Am J Kidney Dis
42(Suppl1) S24-S29, 2003
16Phosphate 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
17Serum phosphorus and phosphate intake - Pierratos
Mucsi et al. Kidney Int. 531399-1404, 1998
18Serum phosphorus and phosphorus intake - Lockridge
McPhatter et al. Advances Renal Replacement Ther
6358-365, 1999
19Phosphate binder dosing - Pierratos
p lt 0.05 versus baseline values pre-nocturnal
HD
Mucsi et al. Kidney Int 531399-1404, 1998
20Phosphorus binders - Lockridge
McPhatter et al. Advances Renal Replacement Ther
6358-365, 1999
21NHHD dialysis parameters
22Gaps 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
23Limitations 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
24Advantages 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
25Nightly Hemodialysis
Frequent Hemodialysis Network
26Frequent 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
27Trial 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?
28Trial 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
29Study timeline
30Inclusion 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
31Exclusion 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
32Exclusion 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).
33Nocturnal 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
34Clinical 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
35Dose 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
36Dialysis 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
37Summary of Interventions
38Daily 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
39Clinical 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
-
40Clinical 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
41Dose 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
42Summary of Interventions
43Equilibrated Kt/V
44Standardized Kt/V
Gotch F. Seminars in Dialysis 14 15-17, 2001
45Efficiency 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
46Standardized 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
47Standardized Kt/V for Daily HD
GFR 15 12 9 6 3 0
Short Daily HD Dose Range
48Standardized Kt/V for Nocturnal HD
Long Nocturnal HD Dose Range
GFR 15 12 9 6 3 0
49Standardized (weekly) Kt/V
50Phosphorus removal
51Beta-2-microglobulin clearance
52Study 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
53Primary 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
54LV 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
55PCS 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
56PCS 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
57Secondary Outcomes
58Other 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
59Other 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
60Steering 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)
61Grant 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
62FHN grant support