Background

AV fistulas and grafts are the two most common methods of gaining repetitive access to the central circulation of patients on hemodialysis. While a substantial number of clinical epidemiological studies have shown that AV fistulas are less prone to failure and complications than AV grafts, in 1996 only about 18 percent of ESRD patients had a functioning AV fistula 60 days after initiating hemodialysis. Although our knowledge about the factors that precipitate failure of both fistula and graft AV access is incomplete, a positive and strong relationship exists between the percentage of stenosis observed at the access site and the risk of thrombosis.

A substantial number of clinical epidemiological studies have been conducted using a variety of methods to monitor the early events associated with vascular access dysfunction. These studies have shown that both AV fistula and AV graft failure are most often attributed to development of stenotic lesions resulting from neointimal hyperplasia, which places the patient at high risk for developing access-related thrombosis.

Few interventional studies have been performed to evaluate pharmacologic therapies that might improve this aspect of hemodialysis patient care. Of the small number of clinical trials conducted, many were carried out over a decade ago, before the introduction of other therapies for ESRD patients that may have an impact on the survival and functioning of AV grafts and fistulas. These therapies include the use of erythropoietin and the increased use of high-flux dialysis membranes.

The patient population in these older clinical trials was also different from the current hemodialysis patient population since the proportion of patients with ESRD due to diabetes (and other co-morbid medical conditions) has escalated during the past 10 years. Importantly, novel anti-thrombotic agents and drugs to inhibit cytokines that have been developed over the past several years have not been systematically and rigorously evaluated for their effect on the rate of access survival and complications in hemodialysis patients. The few trials that have been performed more recently have suffered from numerous methodological shortcomings, including small sample sizes. Maintenance of vascular access for hemodialysis is one of the major challenges in the care of the hemodialysis patient. Access-related problems are among the most frequent reasons for hospitalization in the end-stage renal disease (ESRD) population, and the cost of vascular access placement and repair in the United States exceeds $700 million per year. Despite the substantial medical and economic impact of arteriovenous (AV) graft and fistula failure in hemodialysis patients, few randomized, controlled, clinical trials have been conducted that examine the effects of drugs and other therapies aimed at prolonging the survival of these types of vascular accesses.

Vascular Access Study

To identify effective therapies that will reduce the rate of graft and fistula failure in hemodialysis patients, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) established a multi-center consortium in September 2000 that will design and implement a series of randomized, controlled, clinical trials over a five-year period. Participating institutions are Boston University, University of Iowa, Duke University, Maine Medical Center, University of Alabama, University of Texas Southwestern Medical School, Washington University, and Cleveland Clinic Foundation.

Two randomized placebo-controlled clinical trials have been designed and are currently recruiting patients. The first trial, Clopidogrel Prevention of Early Fistula Thrombosis Trial, will recruit 1,284 participants who are on hemodialysis and who will undergo creation of a new, native arteriovenous fistula. For six weeks after surgery, participants will be treated with clopidogrel or placebo and will be evaluated for fistula patency. A second clinical trial conducted on approximately the same number of hemodialysis patients will study the effects of dipyridamole (Aggrenox) on the prevention of stenosis in new arteriovenous grafts. The primary study outcome is primary unassisted patency, which is defined as the time from access creation until the first occurrence of either access thrombosis or an access procedure such as angioplasty. Because more than 40 percent of the new cases of end-stage renal disease (ESRD) are attributed to diabetes mellitus and both AV fistulas and grafts are more likely to fail in these patients, special emphasis has been given to recruit a study population that is at least 50 percent diabetic patients.