Frequent hemodialysis network nih cms daily and nocturnal hemodialysis randomized clinical trials
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Frequent Hemodialysis Network: NIH/CMS Daily and Nocturnal Hemodialysis Randomized Clinical Trials. Alan S. Kliger MD Hospital of St. Raphael Yale University School of Medicine New Haven CT. Eknoyan et al NEJM 347:2010, 2002. HEMO Study. High Dose: eKt/V 1.45 Standard Dose: eKt/V 1.05.

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Frequent Hemodialysis Network: NIH/CMS Daily and Nocturnal Hemodialysis Randomized Clinical Trials

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Frequent hemodialysis network nih cms daily and nocturnal hemodialysis randomized clinical trials

Frequent Hemodialysis Network: NIH/CMS Daily and Nocturnal Hemodialysis Randomized Clinical Trials

Alan S. Kliger MD

Hospital of St. Raphael

Yale University School of Medicine

New Haven CT


Hemo study

Eknoyan et al NEJM 347:2010, 2002

HEMO Study

High Dose: eKt/V 1.45

Standard Dose: eKt/V 1.05


Background

Mean = 2.19 Mean = 2.53

2.88

2.59

Weekly Std Kt/V

2.30

2.02

Standard

Dose

High

Dose

Background

  • Hypothesis for negative findings of HEMO Study

    Limited separation between treatment groups for unified dose measures, such as

    Standard Kt/V ≅ [urea generation rate] / [average (C0)]

Separation in Std Kt/V in HEMO Trial

Only 16% difference

in mean Std Kt/V

between dose groups


Frequent hemodialysis network nih cms daily and nocturnal hemodialysis randomized clinical trials

Effect of increasing length of dialysis

Three sessions per week

7

6

5

HEMO: High

4

Weekly Dialysis Dose (stdKt/V)

3

2

1

HEMO: Standard

0

0.0

0.5

1.0

1.5

Dialysis dose each dialysis (eKT/V)


Frequent hemodialysis network nih cms daily and nocturnal hemodialysis randomized clinical trials

Effect of increasing number of

dialysis sessions per week

7

Hemodialysis

Daily

Dialysis

6

sessions/wk

6

5

HEMO: High

4

Weely Dialysis Dose (stdKt/V)

3

3

2

1

HEMO: Standard

0

0.0

0.5

1.0

1.5

Dialysis dose each dialysis (eKT/V)


Background1

Background

  • Possibility of benefit of longer dialysis treatment suggested by Tassin experience with three 8 hr treatments per week

  • In last decade, experience with

    • Short daily hemodialysis, with 6 relatively short treatments per week

    • Nocturnal hemodialysis, with 6 long nocturnal treatments per weak

  • Proponents suggest dramatic improvements in outcome


Observational studies

Observational Studies

  • Both short daily and nocturnal dialysis regimens associated with improvements in outcomes

  • Reported effects generally larger and more

  • consistent for nocturnal dialysis, and extend to

  • hospitalization


Milton roy model a

Milton Roy Model A

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


Milton roy model a1

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

Nocturnal Home HD Machines

Aksys PHD System

Baxter Aurora

Fresenius 2008K at home


Observational studies1

Improved

BP Control

Anemia

HR QoL

Mixed Results

LVH

Mineral Metabolism

Improved

BP Control

LVH

Mixed Results

Anemia

HR QoL

Mineral Metabolism

Observational Studies

Walsh et al Review of Nocturnal Hemodialysis

Kidney Int 67:1500, 2005

Suri et al Review of Daily Hemodialysis

CJASN 1:33, 2006


Observational studies of nhd dhd

Observational Studies of NHD & DHD

  • Improved interdialytic weight gain & BP

  • Improved clearance of small and middle molecules

  • Improved Nutritional Intake


Other reported improvements in patient outcomes with nhhd

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


Gaps in knowledge in frequent hd

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 observational studies

Switch to

6x/week

Observe

Outcomes on

Conventional HD

Observe Outcomes

on Daily or

Nocturnal HD

Compare Outcomes

Limitations of Observational Studies

  • Basic observational longitudinal design:

Possible limitations:

  • Confounding with time-dependent co-factors

  • Selection bias, regression to the mean

  • Placebo effects (enthusiasm for novel therapy)

  • Dropout bias

  • Hemodilution effects

  • Publication bias

  • Small N, variable results across studies


Trial objectives

Trial Objectives

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 objectives1

Trial Objectives

Benefits

Primary and Secondary Outcomes

Incremental Cost

Objective, prospective assessment


Can we use hard endpoints of hospitalization or death

Can We Use Hard Endpoints of Hospitalization or Death?

  • Hospitalization:

    • DHD: To detect 25% effect on hospitalization with 85% power requires 882 patients with 1 yr follow-up assuming HEMO event rate

    • NHD: To detect 30% overall treatment effect requires 662 patients for 1 yr follow-up if a 20% lower event rate than HEMO is assumed


Can we use hard endpoints of hospitalization or death1

Can We Use Hard Endpoints of Hospitalization or Death?

  • Death: Requires thousands of patients in each study


Co primary outcomes

Co-Primary Outcomes

  • Composite of 1-year mortality and change in LV mass by cardiac cine-MRI

  • Composite of 1-year mortality and change in RAND PHC from SF- 36


Lv mass and outcomes

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

  • 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

  • 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


9 main outcome domains

9 Main Outcome Domains


Trial design

Trial Design

  • Randomized, unblinded study comparing NHD to 3HD; and DHD to 3HD

  • Enroll 250 patients in each study, equal allocation to daily and 3HD arms

  • Feasibility Phase - “Vanguard” design

  • Efficacy Phase - primary and secondary outcomes


Vanguard phase

Vanguard Phase

  • First year of study

  • Explicit benchmarks for recruitment and adherence

    • Recruitment Goal: Randomize 120 patients

    • Adherence Goal:

      • DHD Arm: 80% of subjects attend at least 80% of scheduled dialysis sessions within each arm

        If subjects unable to attend 6 times per week, encouraged to attend 5 times per week


Fhn study designs

Compare outcomes

after 1 year

Compare outcomes

after 1 year

FHN Study Designs

Patients from 9

regional centers

Patients from 8-12

regional centers

250 pts

randomized

over 2 yrs

250 pts

randomized

over 2 yrs

1.5 months

training +

12 months

6x/Week

Nocturnal HD

12 months

3x/Week

Conventional

Home HD

12 months

6x/Week

Daily

In-center HD

12 months

3x/Week

Conventional

In-center HD


Inclusion criteria

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


Key exclusions

Key Exclusions

  • Medical conditions requiring > 3 times per week HD

  • History of poor adherence to HD

  • Currently on daily or nocturnal HD

  • Residual renal clearance

    • Urea clearance > 3 ml/min per 35 L in daily study

    • GFR > 10 ml/min/1.73m2 in nocturnal study

  • Medical conditions that preclude MRI


Daily study interventions

Daily Study Interventions

6x/Week Daily HD Group

  • Target eKt/Vn = 0.9 for each of 6 treatments

  • Treatment time between 1.5 and 2.75 hrs

    • Average treatment time per session reduced by

      approximately 1/3 vs. conventional HD

    • Average treatment time per week increased by approximately 1/3 vs. conventional HD

      3x/Week Conventions HD Group

  • Patient may remain on any 3x/week dialysis prescription with per treatment eKt/V ≥ 1.10


Nocturnal study interventions

Nocturnal Study Interventions

6x/Week Nocturnal HD Group

  • Home dialysis

  • Treatment time  6 hrs

  • Weekly standard Kt/V  4

  • Relatively High efficiency dialysis(Qd  300 ml/min)

    3x/Week Group

  • Home dialysis

  • Prescription: 3x/week dialysis with per treatment eKt/V ≥ 1.10 (equivalent to weekly standard Kt/V  2.2)


Projected characteristics of designs

Projected Characteristics of Designs*

* Simulated median values and (%  vs. control)


Projected characteristics of designs1

Projected Characteristics of Designs*

* Simulated median values and (%  vs. control)


Standard weekly kt v

Standard weekly Kt/V


Phosphorus removal

Phosphorus removal


Beta 2 microglobulin clearance

Beta-2-microglobulin clearance


Clinical centers for nocturnal hd

Clinical Centers for Nocturnal HD

Univ. of British Columbia – Dr. Michael Copland

Univ. of Calgary

- Dr. Bruce Culleton

Humber River Hosp

– Dr. Andreas Pierratos

University of Toronto – Dr. Chris Chan

Univ. of Western Ontario – Dr. Robert Lindsay

Rubin Dialysis (NY) – Dr. Christopher Hoy

University of Iowa – Dr. John Stokes

Lynchburg Nephrology – Dr. Robert Lockridge Jr.

Wake Forest University

– Dr. John Burkart

Washington University – Dr. Brent Miller


Clinical centers for daily in center hd renal research institute and ucsf cores

Clinical Centers for Daily In-center HDRenal Research Institute and UCSF Cores

Univ. of Western Ontario – Dr. Robert Lindsay

Washington Univ. (MO) – Dr. Brent Miller

RRI: New York City (NY) – Dr. Gary Handelman

Vanderbilt University (TN) – Dr. Gerald Schulman

Wake Forest University (NC) – Dr. Michael Rocco

UCSF – Dr. Glenn Chertow

Univ. California, Davis – Dr. Thomas Depner

Peninsula Dialysis: (CA) –Dr. George Ting

Univ. California, Los Angeles – Dr Allen Nissenson

Univ. California, San Diego – Dr. Ravindra Mehta

Univ. Texas at San Antonio – Dr Juan Ayus


Dhd study timeline

DHD Study Timeline

Initiation of Enrollment:June 2006

Vanguard Phase:June 2006 –

May 2007

Completion of Recruitment:December 2008

Completion of Follow-up:December 2009

Reporting Study Results:Early 2010

Nocturnal Study later by 7 months


Steering committee

Steering Committee

  • Chair

    • Dr. Alan Kliger, Yale University (CT)

  • NIDDK representatives

    • Dr. Paul Eggers

    • Dr. Andrew Narva

  • 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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