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

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 )

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

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  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. 1.0 0.8 0.6 0.4 0.2 0.0 0 200 400 Primary Patency - Grafts vs AVFs US DOPPS 1997-99 Prop. Failure-free Adjusted RR=1.22, p<0.01 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 <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

  5. Native Arteriovenous Fistulae • Survival of Fistulae • Excellent survival aftersuccessful 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. Today’s 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. 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 LIFEFOR HEMODIALYSIS PATIENTS

  9. Trends in Access Type Catheter Fistula Graft USRDS ADR 2008 – ESRD CPM

  10. Access Complications Catheter Fistula Graft Note differences in the scales for the rates of complications USRDS ADR 2008 – ESRD CPM

  11. 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

  12. 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

  13. 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

  14. DAC Graft TrialRationale and Design

  15. 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) Graft Trial Rationale and Goal • Target • Pharmacological prevention of myointimal hyperplasia • Many agents considered

  16. Dipyridamole and Vascular Disease

  17. 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

  18. 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

  19. 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

  20. Graft Trial Primary Outcome Primary unassisted graft patency Time from access surgery to first thrombosis or procedure required to maintain or restore patency

  21. Graft Trial Secondary Outcomes • Cumulative graft patency (i.e., irreparable graft failure) • Patient survival • Composite of patient survival or cumulative graft patency

  22. DAC Graft Trial Results

  23. Graft Trial Enrollment and Follow-up 61.5% of 1056 planned 328 included in analysis of primary and secondary outcomes 321 included in analysis of primary and secondary outcomes

  24. Graft Characteristics

  25. DAC Graft TrialPrimary Outcome

  26. 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

  27. Graft Trial - ERDP/ASA Increases Primary Unassisted Patency HR = 0.82 95% CI 0.69 - 0.99 P=0.034 ERDP/ASA % Primary Unassisted Patency Placebo

  28. Percent of Patients Reaching the Primary Endpoint

  29. Percent of Patients in Each Component of the Primary Endpoint

  30. Graft Trial - Secondary Outcomes

  31. Graft Trial - Adverse Events

  32. 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

  33. 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

  34. DAC Fistula TrialRationale and Design

  35. Fistula Trial Rationale and Goals • Target • Pharmacological prevention of early thrombosis • Agents considered • Dipyridamole • Aspirin • Ticlopidine

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

  37. 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

  38. 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

  39. Fistula TrialNine Clinical Centers • Fistula surgeries at 27 hospitals • Dialysis at 125 facilities • Broad geographic distribution • Urban and rural centers • Academic and community practices

  40. 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

  41. 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

  42. 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

  43. DAC Fistula TrialPrimary Results

  44. 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)

  45. 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

  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%) Relative Risk 0.63 *95% CI 0.46 – 0.97 *P Value 0.018 *Adjusted for interim analyses Dember L et al. JAMA 2008

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

  48. Fistula Trial Secondary Outcome: Suitability for Dialysis Suitability ascertained in 758 of 877 subjects (86%) Dember L et al. JAMA 2008

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

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