Effect of Dipyridamole Plus Aspirin on Hemodialysis Graft Patency

Abstract

Conclusion: Use of the combination of dipyridamole plus aspirin reduces risk of stenosis and improves duration of primary unassisted patency of newly created arteriovenous grafts. Summary: Arteriovenous grafts remain a common source for dialysis access. Although it is generally possible to restore patency to arteriovenous grafts after thrombosis, such procedures are costly. The annual cost of procedures related to vascular access is estimated to exceed $1 billion in the United States (US Renal Data System. 2007 Annual data report: atlas of end-stage renal disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2007). It is postulated that because dipyridamole acts by inhibiting the proliferation of vascular smooth muscle cells and that its use in treatment of patients with newly created hemodialysis access may improve patency of the dialysis access graft. The authors therefore performed a randomized, double-blind, placebo-controlled trial to determine whether extended-release dipyridamole plus aspirin inhibited stenosis of vascular access and prolonged primary unassisted patency of newly created dialysis access grafts. Patients were randomized to receive dipyridamole at a dose of 200 mg and aspirin at a dose of 25 mg twice daily, or placebo, after placement of a new arteriovenous dialysis access graft. The primary outcome was loss of primary unassisted patency of the access graft. Secondary outcomes included cumulative graft failure and death. Thirteen centers in the United States participated in the study, and 649 patients were randomly assigned to receive dipyridamole plus aspirin (321 patients) or placebo (328 patients). The study extended for 4.5 years, with an additional 6 months of follow-up. Blood flow rates at access sites were measured each month after the patient started on hemodialysis. Measurements were done using ultrasound-indicated dilution techniques. Baseline characteristics of the two study groups were similar, as were graft blood flow rates at the time of baseline measurement. Of the grafts placed, 94% were expanded polytetrafluoroethylene, and 5% were made from some other synthetic materials. Twenty-nine percent of the grafts were forearm grafts and 44% were in the upper arm, with 6% in the leg. The rate of adherence to the study medication regimen was 83% in both groups. At 1 year, primary unassisted patency was 23% (95% confidence interval [CI], 18%-28%) in the placebo group and 28% (95% CI, 23%-35%) in the dipyridamole-aspirin group. Adjusting for prespecified factors, the hazard ratio (HR) for loss of primary unassisted graft patency in the dipyridamole plus aspirin group compared with the placebo group was 0.82 (95% CI, 0.68-0.98; P = .03). This provided a relative reduction in the rate of loss of primary unassisted graft patency of 18%. The HR for loss of primary unassisted graft patency in the dipyridamole-aspirin group compared with the placebo group was 0.76 (95% CI, 0.60-0.96; P = .02) among patients not receiving aspirin at baseline and 0.92 (95% CI, 0.68-1.24; P = .57) among those receiving aspirin at baseline. There was an overall 28% reduction in rate of stenosis of >50% from treatment with dipyridamole plus aspirin (HR, 0.72; 95% CI, 0.57-0.90; P = .005). Mean duration of primary patency was 5.8 months (95% CI, 4.3-7.1) in the extended-release dipyridamole-aspirin group and 4.3 months (95% CI, 3.6-5.4) in the placebo group. Comment: The data indicate that the combination of extended release dipyridamole plus aspirin in patients who had not previously received aspirin therapy had a statistically significant effect on extending primary patency of hemodialysis access grafts. The effect was modest and not clinically important. The aspirin and dipyridamole combination delayed by 6 weeks the median time to loss of primary patency in patients with newly created arteriovenous grafts. Put another way, the drug combination provides a reduction in the number of patients with primary graft failure by one patient for every 20 patients treated for 1 year. Because treatment with dipyridamole plus aspirin can cost between $5000 and $2200 per year, it is unclear if this therapy is cost-effective. The importance of this study is that it indicates that pharmacologic therapy targeting intimal hyperplasia potentially can improve the patency of dialysis access grafts. However, a better, more robust, effect will be needed to change practice.