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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

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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:

Trends in Access Type

Catheter Fistula Graft

USRDS ADR 2008 – ESRD CPM

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

DAC Graft Trial

Rationale and Design

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

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

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

DAC Graft Trial Results

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

DAC Graft Trial

Primary Outcome

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 - 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

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

DAC Fistula Trial

Primary Results

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

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 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

DAC Fistula Trial

Adverse Events

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

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 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%

Fistula TrialRationale for Outcomes

Patency

• Clinically important

• Outcome closely related to biological effect of intervention

• Ascertainment highly feasible

• Supportive pilot data

Suitability

• Clinically important