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DAC
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.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
Median survival (days)Grafts = 176 AVFs = 236 AVFs
Grafts
Prop. Failure-free
Adjusted RR=1.22, p<0.01
0.0
0.2
0.4
0.6
0.8
1.0
0 200 400 600 800 1000
VA Time (days)
Primary Patency - Grafts vs AVFs US DOPPS 1997-99
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
Today’s Wisdom – KDOQI 2006• Fistula placement first
1. Radiocephalic
2. Brachiocephalic
3. Transposed brachial basilic
• Prosthetic grafts if fistula not possible1. Forearm loop
2. Forearm straight
3. Upper arm
4. Chest wall / lower extremity
5. Regular surveillance of access function
• Avoid catheters
Wednesday, April 14, 2004CMS Office of Public Affairs,202-690-6145
CMS LAUNCHES “FISTULA FIRST” INITIATIVE TO IMPROVE CARE AND QUALITY OF LIFEFOR HEMODIALYSIS PATIENTS
For Immediate Release:
Access Complications
USRDS ADR 2008 – ESRD CPM
Catheter Fistula Graft
Note differences in the scales for the rates of complications
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 TrialAggrenox (ERDP/ASA) for the Prevention of AV Access Stenosis
Fistula TrialClopidogrel 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
Graft Trial Rationale and Goal
• 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)
• Target• Pharmacological prevention of myointimal hyperplasia
• Many agents considered
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
ERDP/ASA or Placebo
Primary Unassisted Patency
Monthly visits to monitor access problems, adverse events and measure access flow rate
Site Failure
Access Placed
1st Intervention or Thrombosis
Site Loss
Randomize
Start
Drug
HD Starts
Cumulative Access Patency
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
61.5% of 1056 planned
Graft Trial Enrollment and Follow-up
183 Excluded Prior to Randomization
321 Included in analysis of primary unassisted
patency
66 Discontinued study drug early
Placebo N=328 322 received treatment
328 Included in analysis of primary unassisted
patency
271 Completed study drug treatment
57 Discontinued study drug early
38 Died or lost to follow-up
40 Died or lost to follow-up
649 Randomized
ERDP/ASA N=321 318 received treatment
832 Consented
255 Completed study drug treatment
321 included in analysis of primary and
secondary outcomes
328 included in analysis of primary and
secondary outcomes
Graft Characteristics
CharacteristicCharacteristicERDP/ASA ERDP/ASA
N= 318N= 318Placebo Placebo N= 326N= 326
Graft type, %Graft type, %
ePTFEePTFE 93.793.7 93.393.3
Other synthetic materialOther synthetic material 5.35.3 5.25.2
BiograftBiograft 1.01.0 1.51.5
Graft location, %Graft location, %
Forearm loopForearm loop 50.350.3 47.247.2
Upper arm Upper arm 42.142.1 45.745.7
LegLeg 5.35.3 5.85.8
ChestChest 1.31.3 0.60.6
OtherOther 0.90.9 0.60.6
Graft Trial - One Year Primary Unassisted Patency on Placebo = 23%
Kaplan-Meier Estimate of Primary Patency for Placebo Group
Follow-up Time (Months)
% P
rim
ary
Un
as
sis
ted
Pa
ten
cy
0 2 4 6 8 10 12
10
20
30
40
50
60
70
80
90
100
10
20
30
40
50
60
70
80
90
100
Median Patency = 4.3 months
One-year patency
=23%
% P
rim
ary
Un
ass
iste
d P
ate
nc
y
Predicted one-year patency
=46%
Graft Trial - ERDP/ASA Increases Primary Unassisted Patency Kaplan-Meier Estimate of Primary Patency by Treatment Group
Follow-up Time (Months)
% P
rim
ary
Un
assi
sted
Pat
ency
0 2 4 6 8 10 12
10
20
30
40
50
60
70
80
90
100
10
20
30
40
50
60
70
80
90
100
ERDP/ASA
Placebo
HR = 0.82 HR = 0.82
95% CI 0.69 - 0.9995% CI 0.69 - 0.99
P=0.034P=0.034
% P
rim
ary
Un
ass
iste
d P
ate
nc
y
Percent of Patients Reaching the Primary Endpoint
Primary endpoint
ERDP/ASA N= 321
Placebo N= 328
Overall failure of primary unassisted patency
80% 84%
Percent of Patients in Each Component of the Primary Endpoint
Primary endpoint
ERDP/ASA N= 321
Placebo N= 328
Overall failure of primary unassisted patency
80% 84%
Thrombosis 40% 43%Stenosis >50% 26% 28%Infection 7% 4%Failure to use graft by 12 wks 1% 3%Other procedure 7% 6%
Graft Trial - Secondary Outcomes
Secondary endpoints
ERDP/ASA N= 321
PlaceboN=328
HR(95% CI)
P-value
Cumulative graft failure
49% 53%0.95
(0.76, 1.19)0.65
Death 27% 31%0.97
(0.72, 1.30)0.84
Cumulative graft failure or death
61% 63%0.97
(0.81, 1.22)0.97
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
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
Reference
N Treatment / Control
Treatment
Treatment Duration
Early Thrombosis
TTreatment Control
Andrassy, 1974 45 / 47 Aspirin 4 wks 4% 23%
Janicki, 1992 20 / 6 Sulfinpyrazone 3 wks 0% 15%
Michie, 1977 7 / 5 Sulfinpyrazone 3 mos 29% 40%
Grontoft, 1985 19 / 17 Ticlopidine 4 wks 11% 47%
Fiskerstrand, 1985 6 / 9 Ticlopidine 1 mos 6% 9%
Janicki, 1994 11 / 15 Ticlopidine 3 wks 9% 27%
Grontoft, 1998 129 /131 Ticlopidine 4 wks 12% 19%
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
Clopidogrel or Placebo
Randomization and start of study drug
Patency Assessment Week 6
Fistula Creation
Suitability Ascertainment
Month 5 Clopidogrel300 mg loading dose 75 mg daily dose
Fistula TrialNine Clinical Centers
• Fistula surgeries at 27 hospitals
• Dialysis at 125 facilities
• Broad geographic distribution
• Urban and rural centers
• Academic and community practices
Fistula TrialEligibility 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 TrialPrimary 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 TrialSecondary 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
Fistula TrialTrial 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 0.63 *95% CI 0.46 – 0.97 *P Value 0.018 *Adjusted for interim analysesDember 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 238 (62%)
Placebo 222 (60%)
Dember L et al. JAMA 2008
Fistula Trial Secondary Outcome: Suitability for Dialysis
Relative Risk 1.05
95% CI 0.94 –1.17
P Value 0.40
Unsuitable fistulas
Clopidogrel 238 (62%)
Placebo 222 (60%)
Dember L et al. JAMA 2008
Fistula Trial - No Safety Concerns
0
5
10
15
20
Any S
AE
Hospita
lizat
ion
Death
Maj
or B
leed ACS
% P
ati
en
ts
Clopidogrel
Placebo
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
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
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 procedure-based 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
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
DA
C S
tud
y S
ites
Percent of Patients Having Stenosis >50% at Primary Endpoint
Primary Endpoint ERDP/ASA N= 321
Placebo N= 328
Overall failure of primary unassisted patency
80% 84%
Thrombosis 40% 43%Stenosis >50% 26% 28%Infection 7% 4%Failure to use graft by 12 wks 1% 3%Other procedure 7% 6%Stenosis >50% with or without thrombosis
47% 51%