Dialysis Vascular Access The Achilles Heel Still Needs Fixing Lessons from the Dialysis Access Consortium DAC Clinical Trials

1
Dialysis Vascular AccessThe 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

2
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

3
Primary Patency - Grafts vs AVFs US DOPPS 1997-99
Prop. Failure-free
Adjusted RR1.22, plt0.01
Median survival (days) Grafts 176 AVFs 236
AVFs
Grafts
600
800
1000
VA Time (days)
4
Synthetic Vascular Access Grafts

• Survival of Grafts
• Median unassisted survival 1 year
• Median cumulative patency lt2 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

5
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

6
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
7
Todays Wisdom KDOQI 2006

• Fistula placement first
• Radiocephalic
• Brachiocephalic
• Transposed brachial basilic
• Prosthetic grafts if fistula not possible
• Forearm loop
• Forearm straight
• Upper arm
• Chest wall / lower extremity
• Regular surveillance of access function
• Avoid catheters

8
(No Transcript)
9
Trends in Access Type
Catheter
Fistula
Graft
USRDS ADR 2008 ESRD CPM
10
(No Transcript)
11
Access Complications
Catheter
Fistula
Graft
Note differences in the scales for the rates of
complications
USRDS ADR 2008 ESRD CPM
12
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

13
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

14
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

15
DAC Graft TrialRationale and Design
16
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)

17
Dipyridamole and Vascular Disease
18
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

19
Graft Trial Overview
Access Placed
1st Intervention or Thrombosis
Site Loss
HD Starts
ERDP/ASA or Placebo
Monthly visits to monitor access problems,
adverse events and measure access flow rate
Randomize Start Drug
Primary Unassisted Patency
Cumulative Access Patency
Site Failure
20
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

21
Graft Trial Primary Outcome

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

22
Graft Trial Secondary Outcomes

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

23
DAC Graft Trial Results
24
Graft Trial Enrollment and Follow-up
328 included in analysis of primary and secondary
outcomes
321 included in analysis of primary and secondary
outcomes
25
Graft Characteristics
Characteristic ERDP/ASA N 318 Placebo N 326
Graft type,
ePTFE 93.7 93.3
Other synthetic material 5.3 5.2
Biograft 1.0 1.5
Graft location,
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
26
DAC Graft TrialPrimary Outcome
27
Graft Trial - One Year Primary Unassisted Patency
on Placebo 23
Predicted one-year patency 46
Primary Unassisted Patency
One-year patency 23
Median Patency 4.3 months
28
Graft Trial - ERDP/ASA Increases Primary
Unassisted Patency
HR 0.82 95 CI 0.69 - 0.99 P0.034
ERDP/ASA
Primary Unassisted Patency
Placebo
29
Percent of Patients Reaching the Primary Endpoint
Primary endpoint ERDP/ASA N 321 Placebo N 328
Overall failure of primary unassisted patency 80 84
30
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 gt50 26 28
Infection 7 4
Failure to use graft by 12 wks 1 3
Other procedure 7 6
31
Graft Trial - Secondary Outcomes
Secondary endpoints ERDP/ASA N 321 PlaceboN328 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
32
Graft Trial - Adverse Events
33
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

34
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

35
DAC Fistula TrialRationale and Design
36
Fistula Trial Rationale and Goals

• Target
• Pharmacological prevention of early
  thrombosis
• Agents considered

• Dipyridamole
• Aspirin
• Ticlopidine

37
Trials of Anti-Platelet Agents to Prevent Early
Fistula Thrombosis
Adapted from Kaufman JS. Seminars in Dial 2000
13 40-46
38
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

39
Fistula Trial Overview
Fistula Creation
Clopidogrel or Placebo
Randomization and start of study drug
Patency Assessment Week 6
Suitability Ascertainment Month 5
Clopidogrel 300 mg loading dose 75 mg
daily dose
40
Fistula TrialNine Clinical Centers

• Fistula surgeries at 27 hospitals
• Dialysis at 125 facilities
• Broad geographic distribution
• Urban and rural centers
• Academic and community practices

41
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

42
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

43
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 gt4 months after surgery

44
DAC Fistula TrialPrimary Results
45
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)

46
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
47
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 analyses
Dember L et al. JAMA 2008
48
Fistula Trial Secondary Outcome Suitability
for Dialysis

Dember L et al. JAMA 2008
49
Fistula Trial Secondary Outcome Suitability
for Dialysis

Suitability ascertained in 758 of 877 subjects
(86)
Dember L et al. JAMA 2008
50
Fistula Trial Secondary Outcome Suitability
for Dialysis
Unsuitable fistulas Clopidogrel 238 (62)
Placebo 222 (60)

Dember L et al. JAMA 2008
51
Fistula Trial Secondary Outcome Suitability
for Dialysis
Unsuitable fistulas Clopidogrel 238 (62)
Placebo 222 (60)

Relative Risk 1.05 95 CI 0.94
1.17 P Value 0.40
Dember L et al. JAMA 2008
52
DAC Fistula TrialAdverse Events
53
Fistula Trial - No Safety Concerns
Clopidogrel Placebo
54
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

55
DAC Fistula TrialInterpretation and Implications
56
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

57
What have we learned?Where to from here?
58
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?

59
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

60
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

61
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

62
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)

63
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

64
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

65
Catheters - Focus of Future Efforts

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

66
Acknowledgments

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

67

• 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

DAC Study Sites
68
Percent of Patients Having Stenosis gt50 at
Primary Endpoint
Primary Endpoint ERDP/ASA N 321 Placebo N 328
Overall failure of primary unassisted patency 80 84
Thrombosis 40 43
Stenosis gt50 26 28
Infection 7 4
Failure to use graft by 12 wks 1 3
Other procedure 7 6
Stenosis gt50 with or without thrombosis 47 51
69
Fistula TrialRationale for Outcomes

• Patency
• Clinically important
• Outcome closely related to biological effect of
  intervention
• Ascertainment highly feasible
• Supportive pilot data

• Suitability
• Clinically important