Routine Use of Clopidogrel to Prevent Failure of New Fistulas Not Supported by Data

November 8, 2007 (San Francisco) — Results of the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Dialysis Access Consortium (DAC) trial of clopidogrel for prevention of early thrombosis of hemodialysis-related arteriovenous (AV) fistulas do not support the routine use of clopidogrel to prevent the early failure of new fistulas.
Results from this trial were presented by Harold Feldman, MD, and Laura Dember, MD, here at Renal Week 2007, the American Society of Nephrology Annual Meeting. Dr. Feldman is national study chair of the DAC and a professor of medicine at the University of Pennsylvania, Philadelphia. Dr. Dember is a principal investigator for the DAC, associate professor of medicine at Boston University, and medical director of the DaVita-Boston Dialysis Center, Massachusetts.
According to Dr. Feldman, vascular access complications are a major source of morbidity in North America and worldwide. An estimated 16% of all hospitalizations for patients with end-stage renal disease are the result of vascular access complications. The DAC study was a large, multicenter clinical trial of an intervention (clopidogrel) to improve vascular access outcomes.
The rationale and design of the trial were based on the beliefs that fistulas are the preferred access type, that fewer complications and lower costs are associated with dialysis through fistulas, and that individuals dialyzed through fistulas have lower associated mortality. Early failure is a major barrier to increasing fistula prevalence, and the failure of fistula success and maturation leads to the prolonged use of catheters, with their attendant morbidity, Dr. Feldman said.
The DAC trial was designed to enroll 1284 subjects that would provide 85% power to detect a 30% reduction in thrombosis in 6 weeks.
At 6 weeks, 12.2% of the subjects in the clopidogrel group had thrombosis vs 19.5% of subjects in the placebo group. However, for the secondary outcome, suitability for dialysis, suitability failed in 63% of the clopidogrel group and in 60% of the placebo group.
"We were struck by the very high rate of fistula suitability failure, and so we performed a variety of sensitivity analyses to assess the frequency of suitability failure. Even with the least restrictive definition of fistula suitability, nearly half of the fistulas failed," Dr. Dember said.
The study was terminated early because the intervention was clearly efficacious with regard to the primary outcome of patency. Unexpectedly, however, the benefit of clopidogrel on patency was not accompanied by an improvement in fistula suitability. "From a clinical standpoint, the findings of our trial do not support the routine use of clopidogrel to prevent the early failure of new fistulas," Dr. Dember said.
"From a mechanistic standpoint, our findings suggest that patency is necessary but not sufficient for fistula maturation, and that properties not affected by clopidogrel are likely to be important for fistula maturation," he continued.
"We believe that the focus of future efforts should be on elucidating mechanisms underlying maturation failure, on determining which patients have acceptably high likelihood of fistula maturation success, and on identifying interventions to enhance fistula maturation," Dr. Dember said.
"The rate of failure, meaningful failure in terms of the suitability of these access devices, is huge. Sixty percent fail," Dr. Feldman told Medscape Nephrology after the presentation. "That's one point. The second point is that this treatment, which has a lot of attractiveness and was demonstrated to be effective with one particular outcome, meaning the thrombosis outcome, turns out unexpectedly to not be a useful clinical intervention."
"And that's really important because it helps to inform people that they should not be complacent and just treat people with this agent, even though in the short term they may believe they are doing their patients a world of good. In fact, we even showed that in the short term you can quantitate the benefit, but the long-term effect is that it has no benefit at all. It's always important to be able to inform people about what they shouldn't do, especially when there is a lot of information out there that is maybe leading them to believe that this is an effective therapy," Dr. Feldman continued.
"This was an excellently designed trial, and it was carried out with scientific rigor," said Sharon Adler, MD, one of the moderators of the session. "And it basically underscores the fact that we have more work to do in trying to provide the best access we can to hemodialysis patients." Dr. Adler is a professor of medicine at the Harbor-University of California, Los Angeles, Medical Center.
Collaborating institutions included Boston University, Duke University, the Maine Medical Center, the University of Alabama in Birmingham, the University of Iowa, the University of Texas Southwestern Medical Center, Vanderbilt University Medical Center, Washington University in St.Louis, Wake Forest University, the Cleveland Clinic Foundation, and the NIDDK.
Dr. Dember has disclosed receiving research support from Neurochem, Inc, the NIDDK, and Proteon, Inc. She has also disclosed that she is a consultant for Proteon, Inc. The clopidogrel used in the study was donated by Bristol-Myers Squibb and Sanofi-Aventis.
Renal Week 2007. Presented November 4, 2007.