Dialysis Vascular Access

The Achilles Heel Still Needs Fixing

Lessons from the
Dialysis Access Consortium

DAC Clinical Trials

Harold I. Feldman, M.D., M.S.C.E.
DAC

University of Pennsylvania

Overview
The epidemic of vascular access
dysfunction
Dialysis Access Consortium (DAC)
Genesis and goal of DAC
Synthetic graft study
Native arteriovenous fistula study

Insights and future directions

Primary Patency - Grafts vs AVFs

US DOPPS 1997-99
Prop. Failure-free
1.0

Adjusted RR=1.22, p<0.01

0.8

0.6

AVFs

0.4

Median survival (days)

Grafts = 176
AVFs = 236

Grafts

0.2

0.0

200

400

600

VA Time (days)

800

1000

Synthetic Vascular Access Grafts

Survival of Grafts
Median unassisted survival ~1 year
Median cumulative patency <2 years
Require frequent patency restoring/maintaining
interventions

Pathology of Graft Failure

90% loss due to myointimal hyperplasia
Smooth muscle and endothelial proliferaton
Capillary growth with neointima
Smooth muscle (PDGF and FGF) and endothelial (VEGF)
mitogens prominent

Native Arteriovenous Fistulae

Survival of Fistulae
Excellent survival after successful maturation
Substantial loss from thrombosis shortly after
placement

Pathology of Fistula Failure

10-30% fail due to early thrombosis
Maturation rates and etiology not well-described
Late stenosis, aneurysm

Costs of Vascular Access Morbidity

10-15% hospitalization in ESRD related to
access dysfunction*
1994 - 14% -17% of all costs for
hemodialysis spent on vascular access
2003 - Annual costs well-exceed $1billion

Feldman HI et al. 1996

USRDS 2005

Todays Wisdom KDOQI 2006

Fistula placement first
1. Radiocephalic
2. Brachiocephalic
3. Transposed brachial basilic

Prosthetic grafts if fistula not possible

1.
2.
3.
4.
5.

Forearm loop
Forearm straight
Upper arm
Chest wall / lower extremity
Regular surveillance of access function

Avoid catheters

For Immediate Release:

Wednesday, April 14, 2004

CMS Office of Public Affairs,
202-690-6145

CMS LAUNCHES FISTULA FIRST INITIATIVE

TO IMPROVE CARE AND QUALITY OF LIFE
FOR HEMODIALYSIS PATIENTS

Trends in Access Type

Catheter

USRDS ADR 2008 ESRD CPM

Fistula

Graft

Access Complications
Catheter

Fistula

Note differences in the scales for the

rates of complications
USRDS ADR 2008 ESRD CPM

Graft

Genesis and Goals of DAC

Clinical practice principally has focused on
monitoring for and anatomically fixing
access failure Not on primary prevention
Identification of effective preventative
strategies to:
Save resources
Reduce morbidity
Permit achievement of current access utilization
goals, i.e., stem the tide of increasing utilization
of dialysis catheters

Two Concurrent DAC Trials

Graft Trial
Aggrenox (ERDP/ASA) for the
Prevention of AV Access Stenosis

Fistula Trial
Clopidogrel for the Prevention of
Early AV Fistula Thrombosis

Thirteen Primary Clinical Centers

Broad geographic distribution in U.S.
Urban and rural centers
Academic and community practices
Graft surgeries performed at 28 hospitals
Involved 77 vascular access surgeons

Dialysis was delivered at 88 facilities

DAC Graft Trial

Rationale and Design

Graft Trial Rationale and Goal

Target
Pharmacological prevention of myointimal hyperplasia

Many agents considered

Dipyridamole
Fish oil
HMG CoA reductase
inhibitors
ACE inhibitors
Angiotensin AT1 receptor
blockers
Heparinoids / Pentosan
phosphate

Sirolimus
Trapidil
Tranilast
Ticlopidine
Clopidogrel
Pentoxyphyllin
Anti-VEGF (phase II)

Dipyridamole and Vascular Disease

Rationale for Dipyridamole (DP)

DP inhibits VSMC proliferation in vitro
DP inhibits stenosis after experimental arterial
injury in vivo
DP + ASA inhibited late stenosis in coronary
artery bypass grafts and progression of
peripheral artery disease
ERDP reduced recurrent stroke risk
ERDP equal to low dose ASA
Additive benefit of combined ERDP + ASA

DP reduces AVG thrombosis in HD patients

Graft Trial Overview

AccessPlaced
HDStarts

1stIntervention
orThrombosis

Randomize
StartDrug

ERDP/ASAorPlacebo
Monthlyvisitstomonitoraccess
problems,adverseeventsand
measureaccessflowrate
PrimaryUnassistedPatency
Cumulative
Access Patency
SiteFailure

SiteLoss

Graft Trial Eligibility Criteria

New AV graft - any type or location
Receiving chronic hemodialysis or
anticipated to start within 6 months
No contraindication to ERDP/ASA
No concurrent use of anti-coagulants or
anti-platelet agents except ASA
No recent bleeding events

Graft Trial Primary Outcome

Primary unassisted graft patency
Time from access surgery to first
thrombosis or procedure required to
maintain or restore patency

Graft Trial Secondary Outcomes

Cumulative graft patency
(i.e., irreparable graft failure)
Patient survival
Composite of patient survival or
cumulative graft patency

DAC Graft Trial

Results

Graft
Trial
Enrollmen
t and
Follow-up

832 Consented
183 Excluded Prior
to Randomization
649 Randomized

61.5% of 1056 planned

ERDP/ASA N=321

Placebo N=328

318 received treatment

322 received treatment

255
Completed
study drug
treatment

66 Discontinued
study drug early

271
Completed
study drug
treatment

57 Discontinued
study drug early

38 Died or lost to
follow-up

40 Died or lost to
follow-up

included
in
321321
Included
in analysis
of primary
unassisted
analysis
of primary
and
patency

328328
Included
in analysis
included
in
of primary
unassisted
analysis
of primary
and
patency

secondary outcomes

secondary outcomes

Graft Characteristics
Characteristic

ERDP/ASA Placebo
N= 318
N= 326

Graft type, %
ePTFE

93.7

93.3

Other synthetic material

5.3

5.2

Biograft

1.0

1.5

Forearm loop

50.3

47.2

Upper arm

42.1

45.7

Leg

5.3

5.8

Chest

1.3

0.6

Other

0.9

0.6

Graft location, %

DAC Graft Trial

Primary Outcome

Graft Trial - One Year Primary

Unassisted Patency on Placebo = 23%
% Primary Unassisted
Unassisted Patency
Patency

Kaplan-Meier Estimate of Primary Patency for Placebo Group

100

100

90

90

80

80

Predicted oneyear patency

=46%

70
60
50

One-year
patency
=23%

Median
Patency =
4.3 months

40
30
20

70
60
50
40
30
20
10

10
0

10

Follow-up Time (Months)

12

Graft Trial - ERDP/ASA Increases

Primary Unassisted Patency
%Primary
Primary Unassisted
Unassisted Patency
%

Kaplan-Meier Estimate of Primary Patency by Treatment Group

100

100

HR = 0.82

90

95% CI 0.69 - 0.99

80

80

P=0.034

70

90

70
60

60

ERDP/ASA

50
40

50
40

Placebo

30

30

20

20

10

10
0

10

Follow-up Time (Months)

12

Percent of Patients Reaching

the Primary Endpoint
Primary endpoint
Overall failure of primary
unassisted patency

ERDP/ASA Placebo
N= 321
N= 328
80%

84%

Percent of Patients in Each Component

of the Primary Endpoint
Primary endpoint
Overall failure of primary
unassisted patency
Thrombosis
Stenosis >50%
Infection
Failure to use graft by 12 wks
Other procedure

ERDP/ASA Placebo
N= 321
N= 328
80%

84%

40%
26%
7%
1%
7%

43%
28%
4%
3%
6%

Graft Trial - Secondary Outcomes

Secondary
endpoints

ERDP/ASA Placebo
N= 321
N=328

HR
(95% CI)

Pvalue
0.65

Cumulative
graft failure

49%

53%

0.95
(0.76, 1.19)

Death

27%

31%

0.97
(0.72, 1.30)

0.84

63%

0.97
(0.81, 1.22)

0.97

Cumulative
graft failure or
death

61%

Graft Trial - Adverse Events

Graft Trial - Key Findings

Primary failure rate 77% in the placebo group at
one year
Stenosis leading to thrombosis is the most
common cause of primary graft failure
ERDP/ASA produced a 18% reduction in the
failure rate of primary unassisted patency for new
AV grafts
No significant effect on cumulative graft patency
No increase in bleeding, AEs, or including death

Graft Trial - Clinical Implications

Until now only procedure-based therapies were
effective at treating graft stenosis and thrombosis
DAC Graft Trial heralds the first pharmacological
therapy effective to prolong graft patency
Findings support the use of ERDP/ASA to prolong
primary unassisted graft patency
17 treated to prevent 1 primary graft failure at
one year
No increased bleeding risk
Well tolerated

DAC Fistula Trial

Rationale and Design

Fistula Trial Rationale and Goals

Target
Pharmacological prevention of early
thrombosis
Agents considered
Dipyridamole
Aspirin
Ticlopidine

Trials of Anti-Platelet Agents to Prevent

Early Fistula Thrombosis

Adapted from Kaufman JS. Seminars in Dial 2000; 13: 40-46

Clopidogrel
Thienopyridine derivative that interferes
with ADP-mediated platelet activation
Inhibits release of platelet granule
contents, platelet-platelet interactions, and
platelet adhesion to endothelium
Tolerability and safety profile similar to
intermediate-dose aspirin

Fistula Trial Overview

Fistula Creation
Clopidogrel or Placebo
Randomization
and start of
study drug

Patency Assessment
Week 6

Clopidogrel
300 mg loading dose
75 mg daily dose

Suitability
Ascertainment
Month 5

Fistula Trial
Nine Clinical Centers
Fistula surgeries at 27 hospitals
Dialysis at 125 facilities
Broad geographic distribution
Urban and rural centers
Academic and community practices

Fistula Trial
Eligibility Criteria
New upper extremity native AV fistula
Chronic hemodialysis therapy or
anticipated to start chronic hemodialysis
within 6 months
No contraindication to clopidogrel
Able to discontinue anti-platelet agents or
anti-coagulants during study drug
administration

Fistula Trial
Primary Outcome
Fistula patency at 6 weeks
Presence of bruit throughout systole and
diastole detectable along the vein at least
8 cm proximal to the AV anastomosis

Fistula Trial
Secondary Outcome
Fistula suitability for dialysis
Ability to use the fistula for dialysis for 8 of 12
sessions during a four week period with a
dialysis machine blood flow of 300 ml/min
Ascertained during the 5th month following fistula
creation, or during 1st month of dialysis if dialysis
was initiated >4 months after surgery

DAC Fistula Trial

Primary Results

Fistula Trial
Trial Enrollment
Began January, 2003
Ended on 10/24/06 at the recommendation
of the DSMB after the 4th interim analysis
Early termination based on pre-defined
stopping rules
At termination of enrollment 877 subjects
randomized (1284 planned)

Fistula Trial Enrollment Terminated

Early for Efficacy of the Intervention on
the Primary Outcome
Thrombosis at 6 weeks
Clopidogrel
53 (12.2%)
Placebo
84 (19.5%)

Dember L et al. JAMA 2008

Fistula Trial Enrollment Terminated

Early for Efficacy of the Intervention on
the Primary Outcome
Thrombosis at 6 weeks
Clopidogrel
53 (12.2%)
Placebo
84 (19.5%)
Relative Risk
*95% CI
*P Value

0.63
0.46 0.97
0.018

*Adjusted for interim analyses

Dember L et al. JAMA 2008

Fistula Trial Secondary Outcome:

Suitability for Dialysis

Dember L et al. JAMA 2008

Fistula Trial Secondary Outcome:

Suitability for Dialysis
Suitability ascertained in
758 of 877 subjects (86%)

Dember L et al. JAMA 2008

Fistula Trial Secondary Outcome:

Suitability for Dialysis
Unsuitable fistulas
Clopidogrel
Placebo

Dember L et al. JAMA 2008

238 (62%)
222 (60%)

Fistula Trial Secondary Outcome:

Suitability for Dialysis
Unsuitable fistulas
Clopidogrel
Placebo

238 (62%)
222 (60%)

Relative Risk 1.05

95% CI
0.94
1.17
P Value

Dember L et al. JAMA 2008

0.40

DAC Fistula Trial

Adverse Events

Fistula Trial - No Safety Concerns

Clopidogrel
Placebo

Fistula Trial Findings

Clopidogrel reduced the risk of early fistula
thrombosis, but did not increase the % of
fistulas that became suitable for use
Short-term use of clopidogrel appears
safe

DAC Fistula Trial

Interpretation and Implications

Fistula Trial - Implications

A very high proportion of new fistulae do not
mature
Patency is necessary, but not sufficient for fistula
maturation
Early fistula patency - a poor proxy for suitability
Processes not affected by clopidogrel are likely to
be important for maturation
Routine use of clopidogrel to prevent early failure
of new fistulae not warranted

What have we
learned?
Where to from
here?

Global Lessons Learned

Access failures continue to occur at an
alarming rate even in the idealized
research setting
Current rates of fistula failures and a
dearth of effective interventions
emphasize the risks of an overly narrow
focus on fistula placement
Do we need to rethink the strategy of
Fistula First? Is Catheter Last more
appropriate?

Global Lessons Learned

We need more comprehensive access
strategies recognizing the cumulative
individual-level exposure to varied access
types over time that optimize care through
minimization of risk and toxicity
Broader performance metrics are needed that
do not focus solely on the proportion of any
one access type

Lessons Learned - Fistulae

Expanded selection criteria for fistula
placement probably account, in part, for
continued poor outcomes
The pathophysiology underlying failure of
fistula maturation is not well-enough
understood
Peri-operative fistula patency necessary,
but not sufficient for fistula maturation
Early imaging and anatomical correction of
failing fistulas may hold particular promise

Fistulae - Focus of Future Efforts

Elucidating mechanisms underlying
maturation failure for new targets for
intervention
Assessing the prognostic value of early
imaging algorithms
Developing predictive models to reduce rate
of fistula non-maturation
NIH-NIDDK Arteriovenous Fistula Maturation
Cohort Study initiated summer 2008

Lessons Learned - Grafts

Anti-hyperplasia agents appear to have the
ability to reduce graft dysfunction, but impact
to date has been small
A shift from restorative therapies to prevention
of graft stenosis appears increasingly feasible
A focus on prolonging cumulative patency
(grafts) should not detract from targeting
reductions in recurrent access dysfunction
(chronic disease model)

Grafts - Focus of Future Efforts

Examine other pharmacological
agents/strategies to shift from procedurebased treatment of access failure to
preventive and safe pharmacological
therapies

Lessons Learned - Catheters

Use continues to rise as does associated
toxicities. We can not afford to exclude
this observation from our metrics of quality
performance

Catheters - Focus of Future Efforts

Global risk minimization strategies
Better catheter technologies that reduce
infection risk and vascular trauma

Acknowledgments
NIDDK / NIH
Bristol-Myers Squibb / Sanofi-Aventis
Nephrologists, vascular surgeons and
dialysis unit staff
Participating patients

DAC Study Sites

Clinical Centers

Principal Investigators

Boston Univ / Baystate Med Ctr

L. Dember, G. Braden
Charlestown Area MC
A. Rahman, B. Reyes
Duke University A. Greenberg
Emory University J. Work
Maine Medical Center
J. Himmelfarb
St. Louis University
K. Martin
Tyler Nephrology Assoc, TX
J. Cotton
Univ Alabama Birmingham
M. Allon
Univ Iowa / Renal Care Assoc, Peoria IL
B. Dixon, T. Pflederer
Univ Texas S.W. / Baylor Med Ctr
M. Vazquez, A. Fenves
Vanderbilt University
T.A. Ikizler
Vascular Surgery Assoc, LA
J. McNeil
Washington University
J. Delmez
Data Coordinating Center
Cleveland Clinic Foundation

G. Beck

Steering Committee Chair

Harold Feldman, Univ. of Pennsylvania
NIDDK
Catherine Meyers and John Kusek

Percent of Patients Having Stenosis

>50% at Primary Endpoint
Primary Endpoint
Overall failure of primary
unassisted patency
Thrombosis
Stenosis >50%
Infection
Failure to use graft by 12 wks
Other procedure
Stenosis >50% with or without
thrombosis

ERDP/ASA
N= 321

Placebo
N= 328

80%

84%

40%
26%
7%
1%
7%

43%
28%
4%
3%
6%

47%

51%

Fistula Trial
Rationale for Outcomes
Patency

Suitability

Clinically important

Clinically important

Outcome closely related

to biological effect of
intervention
Ascertainment highly
feasible
Supportive pilot data