Frequent Hemodialysis Network:Rationale for Studyand Study Design

National Kidney FoundationAnnual Meeting – April 2006

Michael V. Rocco, M.D., M.S.C.E.Wake Forest University School of Medicine

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

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 1:33-42, 2006

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

Daily HD – Summary of findings

Variable Outcome Number of studies

SBP or MAP* Decrease 10 of 11

Serum phosphorus or binder dose* No change 6 of 8

Anemia (Hb, HCT or EPO dose) Improvement 7 of 11

Serum albumin Increase 5 of 10

HRQOL Improvement 6 of 12

Vascular access dysfunction No change 5 of 7

Suri R. et al. CJASN 1:33-42, 2006

Milton Roy Model A

Built by Milton Roy Company of St. Petersburg, Florida in 1964

Milton Roy Model A

Features:

Automatic hot water

Disinfection

Automatic alarm checks

Solid state logic

Acoustic tiles inside to reduce noise

Nocturnal Home HD Machines

Aksys PHD System

Baxter Aurora Fresenius 2008K at home

Nocturnal Home HD Programs in the U.S.

From www.HomeDialysisCentral.org

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 67:1500-1508, 2005

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

Nocturnal HD – Summary of findings

Variable Outcome Number of studies

SBP or MAP* Decrease 4 of 4

Number of antihypertensives* Decrease 4 of 4

Serum phosphorus or binder dose No change 1 of 2

Anemia (Hb, HCT or EPO dose)* Improvement 3 of 3

HRQOL Improvement Variable+

Walsh M et al Kidney Int 67: 1500-1508, 2006

+ Different tools and reporting methods used in individual studies

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 9:859-868, 1998

McPhatter LL et al. Adv Renal Replace Ther 6:358-365 1999

Raj DS et al Nephrol Dial Trans 15:58-64, 2000

Nocturnal HD – Renal osteodystrophy

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

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

01

234567

89

0 6 12 18

Time in months

Serum phosphorus (mg/dl)

NocturnalControl

Phosphate binder dosing - London

All patients prescribed calcium carbonate* p < 0.05 versus nocturnal HD group value; + p < 0.05 versus baseline value

Lindsay et al. Am J Kidney Dis 42(Suppl 1) S24-S29, 2003

-1000

0

1000

2000

3000

4000

5000

6000

7000

0 6*+ 12*+ 18

Time in months

Phosphate binder daily dose

(mg/day)

Nocturnal

Control

Serum phosphorus and phosphate intake - Pierratos

Mucsi et al. Kidney Int. 53:1399-1404, 1998

0

1

2

3

4

5

6

7

8

9

-3 3 5

Time in months

Serum phosphorus (mg/dl)

0

200

400

600

800

1000

1200

1400

1600

Dietary phsophate intake

(mg/day)

Serum phosphorus

Phosphorus intake

Serum phosphorus and phosphorus intake - Lockridge

McPhatter et al. Advances Renal Replacement Ther 6:358-365, 1999

0

2

4

6

8

10

12

-6 -3 3 6 12 18

Time in months

Serum phosphorus

(mg/dl)

0

200

400

600

800

1000

1200

1400

Dietary phsophate intake (mg/day)

Serum phosphrus

Phosphorus intake

Phosphate binder dosing - Pierratos

*p < 0.05 versus baseline values pre-nocturnal HD;

Mucsi et al. Kidney Int 53:1399-1404, 1998

Phosphorus binders - Lockridge

McPhatter et al. Advances Renal Replacement Ther 6:358-365, 1999

0

2

4

6

8

10

12

14

16

18

20

-6 -3 3 6 12 18

Time in months

Phosphate binders per day

Binders per day

NHHD dialysis parameters

Parameter London Pierratos Lockridge

Machine F 2008 F 2008 F 2008

Time per treatment (hrs) 6 – 8 8 – 10 4 – 9

# of nights/week 5 – 6 6 5 – 6

Blood flow rate (ml/min) 200 – 300 200 - 300 200 – 250

Dialysate flow rate (ml/min)

300 300 – 350 200 – 300

# of needles Usually 1 2 2

Reuse No No Yes

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

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

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

Frequent Hemodialysis Network

Nightly Hemodialysis

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

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?

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

Study timeline

0 6 12 18 24 30 36 42 48 54 60 66

Months

Study close-out

Patient follow-up

Patient enrollment

Training of studypersonnel

Protocoldevelopment

March 2006 May 2009

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

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

Exclusion Criteria (2 of 2)• Less than 3 months since patient returned to

hemodialysis after renal transplantation• Medical history that might limit the individual’s 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).

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

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 CoplandUniversity of Iowa – Dr. John Stokes and Douglas SomersUniversity of Toronto – Dr. Chris ChanUniversity of Western Ontario – Dr. Robert LindsayWashington University – Dr. Brent Miller

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 patient’s nephrologist, as long as the minimum dose criteria above are met

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

Summary of Interventions

Parameter 3X week HD Nocturnal HD Difference

Sessions per week 3 6 + 100%

Hours per session > 2.5 hours 6 – 8 hours + 100%

Max time between HD sessions

68.5 hours 41 hours - 40%

Avg. interdialytic interval

52.5 hours 21.0 hours - 60%

Hours HD per week 10.5 40 + 281%

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

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

Clinical Centers – UCSF

Univ. of California at San Francisco – Dr. Glenn ChertowUniv. of California, Davis – Dr. Thomas DepnerPeninsula (El Camino, San Jose) – Drs. John Moran and

George TingUniv. of California at Los Angeles – Drs. Allen

Nissenson, William Goodman and Isidro SaluskyUniv. of California at San Diego – Dr. Ravindra MehtaUniversity of Texas at San Antonio – Drs. Juan Ayus and

Steven Achinger

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

Summary of Interventions

Parameter 3X week HD 6X week HD Difference

Sessions per week 3 6 + 100%

Hours per session > 2.5 hrs Median = 3.5

1.5 – 2.75 hrs

Median = 2.4

- 33%

Max time between HD sessions

68.5 hours 45.6 hours - 33%

Avg. interdialytic interval

52.5 hours 25.6 hours - 51%

Hours HD per week(5th – 95th percentile)

10.5

(9.0 – 13.1)

14.2

(11.5 – 16.5)

+ 35%

Equilibrated Kt/V

1.7

0.92

1.39

0

0.5

1

1.5

2

2.5

Control Daily HD Nocturnal HD

eKt/V

-34% +22%

Standardized Kt/V

Gotch F. Seminars in Dialysis 14: 15-17, 2001

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

Standardized Kt/V for Conventional HD

1.50

2.00

2.50

3.00

3.50

4.00

4.50

0.50 1.00 1.50 2.00

eKt/V

stdKt/V

GFR

15

12

9

6

3

0

Gotch F, FHN analysis

HEMO StudyStandard Arm

HEMO StudyHigh Dose Arm

Standardized Kt/V for Daily HD

3.00

4.00

5.00

6.00

7.00

0.50 1.00 1.50 2.00

eKt/V

stdKt/V

GFR 0 GFR 3 GFR 6 GFR 9 GFR 12 GFR 15

Short Daily HD Dose Range

GFR1512 9 6 3 0

Standardized Kt/V for Nocturnal HD

3.00

4.00

5.00

6.00

7.00

0.50 1.00 1.50 2.00

eKt/V

stdKt/V

GFR 0 GFR 3 GFR 6 GFR 9 GFR 12 GFR 15GFR1512 9 6 3 0

Long Nocturnal HD Dose Range

Standardized (weekly) Kt/V

5.12

3.82

2.46

0

1

2

3

4

5

6

7

Control Daily HD Nocturnal HD

sKt/V

+55% +108%

Phosphorus removal

299415

1218

0

200

400

600

800

1000

1200

1400

1600

Control Daily HD Nocturnal HD

Phosphate removal (mg/day) +39%+328%

Beta-2-microglobulin clearance

9.03

4.884.73

0

2

4

6

8

10

12

Control Daily HD Nocturnal HDEquivalent B2 microglobulin clearance

(ml/min)

+ 3%+39%

+91%

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

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

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, 2001London GM et al. J Am Soc Nephrol 12: 2759-2767, 2001

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

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

Secondary Outcomes

Outcome domain Main secondary outcome

Depression Change in Beck Depression Index

Nutritional status Change in serum albumin level

Cognitive function Change in Trailmaking Test B

Mineral metabolism Change in pre-HD phosphorus level

Hypertension Review of BP level and medications

Anemia Review of hemoglobin level, ESA dose and iron parameters

Clinical events Rates of death and hospitalizations

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

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

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)

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

FHN grant support