Background The Dialysis Access Consortium (DAC) was developed to investigate interventions to improve hemodialysis vascular access outcomes. The autogenous arteriovenous fistula created by direct connection of native artery to vein is the recommended vascular access for hemodialysis. However, it fails frequently due to clotting after surgery.
Purpose The DAC Early AV Fistula Thrombosis Trial tests the hypothesis that clopidogrel can prevent early fistula failure and increase the number of fistulas that ultimately become usable for hemodialysis access. This is one of two initial and concurrent trials being performed by the DAC. The companion trial investigates pharmacologic approaches to prevent venous stenosis leading to AV graft failure.
Methods This is a multicenter, randomized, double-blind, placebo-controlled trial that will enroll 1284 patients over four years. Patients undergoing creation of a new native arteriovenous (AV) fistula are randomized to treatment with clopidogrel or placebo for six weeks following fistula creation surgery. The primary outcome is fistula patency at six weeks. The major secondary outcome is fistula suitability for dialysis.
Results This paper examines key aspects of this study that have broad relevance to trial design including: 1) the selection of an intermediate event as the primary outcome, 2) timing of the intervention to balance efficacy and safety concerns, 3) ethical considerations arising from required modifications of concomitant drug therapy, and 4) choosing an efficacy or effectiveness evaluation of the intervention.
Conclusions This is the first, large, multicenter trial evaluating a pharmacologic approach to prevent early AV fistula failure and promote more usable fistulas for hemodialysis. The methodologic challenges identified and addressed during the development of this trial should help to inform the design of future vascular access trials, and are relevant to clinical trials addressing a wide range of questions.
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References
1.
1. United States Renal Data System2003 Annual Data Report. Bethesda National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, 2003.
2.
2. Woods JD, Turenne MN, Strawderman RL et al.Vascular access survival among incident hemodialysis patients in the United States. Am J Kidney Dis1997; 30: 50–57.
3.
3. Feldman HI, Kobrin S, Wasserstein A. Hemodialysis vascular access morbidity. J Am Soc Nephrol1996; 7: 523–535.
4.
4. Hakim R, Himmelfarb J. Hemodialysis access failure: a call to action. Kidney Int1998; 54: 1029–1040.
5.
5. United States Renal Data System1997 Annual Data Report. Bethesda National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, 1997.
6.
6. Schwab SJ, Harrington JT, Singh A et al. Vascular access for hemodialysis. Kidney Int1999; 55: 2078–2090.
7.
7. National Kidney Foundation K/DOQI Clinical Practice Guidelines for Vascular Access: Update 2000. Am J Kidney Dis2001; 37: S137–S181.
8.
8. Allon M, Robbin ML. Increasing arteriovenous fistulas in hemodialysis patients: problems and solutions. Kidney Int2002; 62: 1109–1124.
9.
9. Prischl FC, Kirchgatterer A, Brandstatter E et al. Parameters of prognostic relevance to the patency of vascular access in hemodialysis patients. J Am Soc Nephrol1995; 6: 1613–1618.
10.
10. Culp K, Flanigan M, Taylor L, Rothstein M.Vascular access thrombosis in new hemodialysis patients. Am J Kidney Dis1995; 26: 341–346.
11.
11. Feldman HI, Held PJ, Hutchinson JT et al.Hemodialysis vascular access morbidity in the United States. Kidney Int1993; 43: 1091–1096.
12.
12. Miller PE, Tolwani A, Luscy CP et al. Predictors of adequacy of arteriovenous fistulas in hemodialysis patients. Kidney Int1999; 56: 275–280.
13.
13. Miller CD, Robbin ML, Allon M. Gender differences in outcomes of arteriovenous fistulas in hemodialysis patients. Kidney Int2003; 63: 346–352.
14.
14. Feldman HI JM, Rosas SE, Burns JE, Knauss J, Brayman K. Predictors of successful arteriovenous fistula maturation. Am J Kidney Dis2003; 42: 1000–1012.
15.
15. Silva MB, Jr, Hobson RW, 2nd, Pappas PJ et al.A strategy for increasing use of autogenous hemodialysis access procedures: impact of preoperative noninvasive evaluation. J Vasc Surg1998; 27: 302–307; discussion 307–308.
16.
16. Malovrh M. Non-invasive evaluation of vessels by duplex sonography prior to construction of arteriovenous fistulas for haemodialysis. Nephrol Dial Transplant1998; 13: 125–129.
17.
17. Robbin ML, Gallichio MH, Deierhoi MH et al. US vascular mapping before hemodialysis access placement. Radiology2000; 217: 83–88.
18.
18. Allon M, Lockhart ME, Lilly RZ et al. Effect of preoperative sonographic mapping on vascular access outcomes in hemodialysis patients. Kidney Int2001; 60: 2013–2020.
19.
19. Beathard GA, Settle SM, Shields MW. Salvage of the nonfunctioning arteriovenous fistula. Am J Kidney Dis1999; 33: 910–916.
21. Andrassy K, Malluche H, Bornefeld H et al.Prevention of p.o. clotting of av. cimino fistulae with acetylsalicyl acid. Results of a prospective double blind study. Klin Wochenschr1974; 52: 348–349.
22.
22. Janicki K, Dmoszynska A, Janicka L, Stettner S, Jesipowicz J. Influence of antiplatelet drugs on occlusion of arteriovenous fistula in uraemic patients. Int Urol Nephrol1992; 24: 83–89.
23.
23. Michie D, Wombolt D. Use of sulfinpyrazone to prevent thrombus formation in arteriovenous fistulas and bovine grafts of patients on chronic hemodialysis. Curr Ther Res1977; 22: 196–204.
24.
24. Albert F. Prevention of early thrombus formation in arteriovenous fistulae. Dial Transplant1981; 10: 167C–167D.
25.
25. Gröntoft KC, Mulec H, Gutierrez A, Olander R.Thromboprophylactic effect of ticlopidine in arteriovenous fistulas for haemodialysis. Scand J Urol Nephrol1985; 19: 55–57.
26.
26. Gröntoft KC, Larsson R, Mulec H, Weiss LG, Dickinson JP. Effects of ticlopidine in AV-fistula surgery in uremia. Fistula Study Group. Scand J Urol Nephrol1998; 32: 276–283.
27.
27. Fiskerstrand CE, Thompson IW, Burnet ME, Williams P, Anderton JL. Double-blind randomized trial of the effect of ticlopidine in arteriovenous fistulas for hemodialysis. Artif Organs1985; 9: 61–63.
28.
28. Janicki K, Janicka L, Dmoszynska A, Marczewski K, Smarz I. Effects of ticlopidine on platelet activity and occlusion of arteriovenous fistulas in IPD patients. Dial Transplant1994; 23: 576–579.
29.
29. Hirth RA, Turenne MN, Woods JD et al. Predictors of type of vascular access in hemodialysis patients. Jama1996; 276: 1303–1308.
30.
30. Healthcare Financing Administration. 2000 Annual Report, End Stage Renal Disease Clinical Performances Measures Project. Baltimore, MD: Office of Clinical Standards and Quality, Health Care Financing Administration, Department of Health and Human Services, 2000.
31.
31. Bender MH, Bruyninckx CM, Gerlag PG. The brachiocephalic elbow fistula: a useful alternative angioaccess for permanent hemodialysis. J Vasc Surg1994; 20: 808–813.
32.
32. Hakaim AG, Nalbandian M, Scott T. Superior maturation and patency of primary brachiocephalic and transposed basilic vein arteriovenous fistulae in patients with diabetes. J Vasc Surg1998; 27: 154–157.
33.
33. O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics1979; 35: 549–556.
34.
34. Jeste DV, Palmer BW, Harris MJ. Neuroleptic discontinuation in clinical and research settings: scientific issues and ethical dilemmas. Biol Psychiatry1999; 46: 1050–1059.
35.
35. Rosenstein DL. IRB review of psychiatric medication discontinuation and symptom-provoking studies. Biol Psychiatry1999; 46: 1039–1043.
36.
36. Kaufman JS, O'Connor TZ, Zhang JH et al.Randomized controlled trial of clopidogrel plus aspirin to prevent hemodialysis access graft thrombosis. J Am Soc Nephrol2003; 14: 2313–2321.
37.
37. Pearson TA, Blair SN, Daniels SR et al. AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke: 2002 Update: Consensus Panel Guide to Comprehensive Risk Reduction for Adult Patients Without Coronary or Other Atherosclerotic Vascular Diseases. American Heart Association Science Advisory and Coordinating Committee. Circulation2002; 106: 388–391.
38.
38. Beving H, Zhao C, Albage A, Ivert T. Abnormally high platelet activity after discontinuation of acetylsalicylic acid treatment. Blood Coagul Fibrinolysis1996; 7: 80–84.
39.
39. Bombardier C, Maetzel A. Pharmacoeconomic evaluation of new treatments: efficacy versus effectiveness studies?Ann Rheum Dis1999; 58(Suppl 1): I82–I85.
