Steve J. Schwab

Design of the Dialysis Access Consortium (DAC) clopidogrel prevention of early AV fistula thrombosis trial

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.

Is percutaneous transluminal angioplasty an effective intervention for arteriovenous graft stenosis

Address correspondence to: Steve J. Schwab, MD, Department of Medicine, Medical College of Georgia, 1120 15th St. BI-5076, Augusta, GA 30912-3100, or e-mail: sschwab@mail.mcg.edu. End-stage renal disease (ESRD) mortality is predominantly cardiovascular, while morbidity is primarily vascular access. Access placement and problems with vascular access accounted for more than

Influence of Luminal Diameters on Flow Surveillance of Hemodialysis Grafts: Insights from a Mathematical Model

1 billion in medical costs in 1996; estimates of current expenditures double that figure. Native arteriovenous fistulas (AVFs), once established, have a very low complication rate. In contrast, synthetic AV accesses, while easier to establish, have much higher failure and intervention rates. Polytetrafluoroethylene (PTFE) arteriovenous grafts (AVGs), introduced in 1976, previously comprised some 80% of vascular procedures performed in the United States. Since the publication of the Kidney Disease Outcomes Quality Initiative (K/DOQI), the placement rate of AVFs has dramatically increased, but AVG placement remains a sizable portion. While having many advantages over tunneled catheters, AVGs remain inferior to AVFs primarily because of increased rates of stenosis/thrombosis. Intervention rates are some five times higher for AVGs than for AVFs, with patency rates of less than 50% at 3 years. The most common cause for all AV vascular access loss is access thrombosis. Thrombosis in AVGs occurs primarily in the setting of decreased access blood flow secondary to venous stenosis. Thrombosis occurs at a rate of roughly 0.5–0.8 episodes/patient/year. The primary lesion is venous outflow stenosis secondary to venous neointimal hyperplasia (VNH), occurring at the site of the venous anastomosis in approximately 60% of cases. Given the fibrotic nature of these stenoses, it was reasoned by the K/DOQI panel that waiting for graft thrombosis before intervention leads to an increased incidence of graft failure. The original data suggested that correction of a subcritical (50–70%) stenosis by percutaneous transluminal angioplasty (PTA) was more likely to be successful than correction of a critical (90–98%) fibrotic stenosis. The very short patency rates when PTA was used after AV access thrombosis supported this contention, as did evaluation of these lesions using intravascular ultrasound. Therefore, attempts have been made to predict thrombosis and arrange for early intervention. Ideally, prospective monitoring of AVGs for hemodynamically significant stenosis combined with appropriate intervention will improve graft function and decrease the incidence of graft thrombosis/failure by detecting and treating stenoses before they become critical. The Vascular Access Task Force of the K/DOQI has accepted this concept, and current guidelines recommend surveillance of AVFs and AVGs for stenosis.

Mathematical Model Demonstrates Influence of Luminal Diameters on Venous Pressure Surveillance

Randomized controlled trials have not shown that surveillance of graft blood flow (Q) prolongs graft life. Because luminal diameters affect flow resistance, this study examined whether the influence of diameters on Q can explain the limitations of surveillance. Inflow artery and outflow vein diameters were determined from duplex ultrasound studies of 94 patients. These diameters were applied to a mathematical model for determination of how they affect the relation between Q and stenosis. Also determined was the correlation between Q (by ultrasound dilution) and diameters, stenosis, and mean arterial pressure in 88 patients. Artery and vein diameters varied widely between patients, but arteries generally were narrower than veins. The model predicts that the relation between Q and stenosis is sigmoid: as stenosis progresses, Q initially remains unchanged but then rapidly decreases. A narrower artery increases flow resistance, causing a longer delay followed by a more rapid reduction in Q. In a multiple regression analysis of data from patients, Q correlated with artery and vein diameters, sum of largest stenoses from each circuit segment, and mean arterial pressure (R = 0.689, P < 0.001). This study helps to explain why Q surveillance predicts thrombosis in some patients but not others. Luminal diameters control the relation between Q and stenosis, and these diameters vary widely. During progressive stenosis, the delay and then rapid reduction in Q may impair recognition of low Q before thrombosis occurs. Surveillance outcomes might be improved by taking frequent measurements so that there is no delay in discovering that Q has decreased.

Effect of change in vascular access on patient mortality in hemodialysis patients.

BACKGROUND The reliability of dialysis venous pressure (VP) in detecting stenosis is controversial. A mathematical model may help to resolve the controversy by providing insight into the factors that influence static VP. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS This study used inflow artery and outflow vein luminal diameters from duplex ultrasound studies of 94 patients. These diameters were applied to a mathematical model, and how they affect the relation among VP, mean arterial pressure (MAP), blood flow, and stenosis was determined. Whether VP/MAP is a valid adjustment for the influence of MAP on VP, and whether the standard VP/MAP referral threshold of 0.50 is valid, were also determined. RESULTS It was found that there is an approximate one-to-one relation between MAP and VP, so VP/MAP is a valid adjustment. Also, the 0.50 threshold successfully identifies most grafts with stenosis of 65% or more. However, the ratio of artery/vein diameters varied widely between patients, and the ratio independently influences VP/MAP. When the inflow artery is relatively narrow, the VP/MAP increase is delayed followed by a more rapid increase as critical stenosis is reached. CONCLUSIONS VP/MAP is a valid adjustment for the influence of MAP on VP, and the standard VP/MAP threshold of 0.50 warns of the transition to critical stenosis. However, relatively narrow arteries cause a delay followed by a rapid increase in VP/MAP that may not be detected before thrombosis unless measurements are very frequent. Clinical trials that emphasize trend analysis with frequent measurements are needed to evaluate the efficacy of VP surveillance.