NEW YORK (Reuters Health) – In a large randomized study of hemodialysis patients with new arteriovenous grafts, daily fish oil supplementation didn’t improve long-term graft patency.
However, those who took fish oil daily for 12 months did go a longer time without forming a blood clot, had half the rate of thrombosis, were less apt to need interventions on the graft and had improved cardiovascular outcomes (lower blood pressure and fewer cardiovascular events), the FISH study team reports online today in the Journal of the American Medical Association.
“Taking fish oil is an inexpensive, available supplement that can improve the dialysis ‘lifeline’ (synthetic graft) by reducing its common complications, and at the same time, reduce blood pressure and even potentially reduce adverse cardiovascular events,” first author Dr. Charmaine E. Lok, of the University of Toronto and Toronto General Hospital, Ontario, Canada, noted in an email to Reuters Health.
Current options for vascular access for hemodialysis are arteriovenous fistula, synthetic arteriovenous graft, and central venous catheter. Until the early 1990s, the arteriovenous graft was predominantly used in North America, when it “fell out of favor owing to its high complication rates and associated costs,” the study team notes.
Thrombosis occurs in more than half of all arteriovenous grafts within one year of placement, requiring a salvage procedure in more than 75% of cases, they say. To date, no interventions have “convincingly or consistently” cut the rate of thrombosis, they say.
Owing to their antiproliferative, antioxidant, and vasodilatory effects, omega-3 fatty acids in fish oils have theoretical appeal for preventing development of arteriovenous graft stenosis and thrombosis. A small, single-center prospective study of fish oil prophylaxis, reported by Schmitz et al in the Journal of the American Society of Nephrology in 2002, showed a significant fivefold improvement in 12-month graft patency.
The new randomized trial by Dr. Lok and colleagues evaluated the effects of fish oil supplementation on patency of newly created hemodialysis grafts in 196 patients. Beginning seven days after graft creation and for 12 months, 99 patients took four 1-gm capsules of fish oil per day (with 400 mg eicosapentaenoic acid and 200 mg of docosahexaenoic acid per capsule) and 97 took matching placebo.
Unfortunately, there was no significant difference in the primary outcome, which was the proportion of patients with loss of “primary unassisted graft patency,” i.e., the first graft thrombosis or surgical or radiological intervention on the graft. At 12 months, loss of primary unassisted graft patency occurred in 48% of patients in the fish oil arm and 62% in the placebo arm (48 of 99 patients vs 60 of 97 patients), yielding a 22% relative risk reduction (RR 0.78; p=0.06).
However, the rate of graft failure was lower in the fish oil arm than the placebo arm (3.43 vs 5.95 per 1000 access-days), yielding an incidence rate ratio (IRR) of 0.58 (p<0.001). In addition, there were half as many thromboses in the fish oil group (1.71 vs 3.41 per 1000 access-days (IRR 0.50; p<0.001) and fewer corrective interventions (2.89 vs 4.92 per 1000 access-days (IRR 0.59; p<0.001).
Analysis of cardiovascular outcomes demonstrated “superior cardiovascular event-free survival” in the fish oil group (hazard ratio 0.43; p=0.04), the authors report.
Compared with baseline, there were clinically significant reductions in systolic blood pressure at six months in the fish oil group that were sustained at 12 months (-3.61 vs 4.49 mm Hg; p=0.01). And 63 of 99 patients (64%) taking fish oil had at least one reduction in the dose or frequency of their antihypertensive medications, compared with 41 of 97 (42%) taking placebo.
“Although the risk of the primary end point was not significantly lower among fish oil recipients, this should be considered in the context of the apparent consistent clinical benefits observed for the secondary outcomes,” the authors say.
“We were pleasantly surprised by the consistency of the direction and strong degree of benefit of fish oil in improving individual synthetic graft outcomes (clotting and procedures needed to maintain patency),” Dr. Lok commented. “We are also pleased with the consistency of our blood pressure findings (reduction) with other studies (in other populations) that have shown similar benefit. We are definitely surprised by the finding of improved cardiovascular events but strongly suggest caution in this result given the small numbers in our study,” she added.
Arteriovenous grafts, while not ideal, may be necessary “for patients receiving hemodialysis whose veins are unsuitable for fistula creation or who have experienced prior problems with fistula nonmaturation,” the authors conclude in their paper. “However, compared with functioning fistulas, arteriovenous grafts may require a three- to four-fold higher frequency of interventions to maintain equivalent long-term patency. Identification of safe and inexpensive agents that prolong arteriovenous graft patency and reduce the frequency of interventions to salvage graft complications might encourage increased use of grafts.”
In an editorial, Dr. Bradley S. Dixon of the University of Iowa College of Medicine in Iowa City says the secondary outcomes measuring the rate of loss of graft patency are “important and relevant and deserve the attention of physicians caring for patients receiving a new graft.”
It’s noteworthy, he writes, that “the Kaplan-Meier curves for primary graft patency show that the hazard rates for fish oil and placebo appear to continue to diverge, even up to 12 months of therapy.”
He also notes that the large randomized, placebo-controlled DAC Graft Trial found that sustained-release dipyridamole plus low-dose aspirin modestly prolonged primary unassisted patency of new hemodialysis grafts. (See Reuters Health story of May 20, 2009.) A later analysis of the trial data suggested that aspirin alone might be as effective as dipyridamole plus aspirin.
In the FISH study, more than half of all patients were taking aspirin, and more than 10% were taking clopidogrel at baseline. This suggests that fish oil may even be effective in a population of patients receiving aspirin or other antiplatelet agents, Dr. Dixon says. However, no analysis was provided on the interaction between use of an antiplatelet agent and treatment with fish oil. “This will be an important direction for future study,” he writes.
Overall, concludes Dr. Dixon, the available data do not support increased use of hemodialysis grafts accompanied by the administration of fish oil and an antiplatelet agent to prolong graft patency.
“Despite the reduction in the rate of graft thrombosis and angioplasty procedures with fish oil, the rate of these events is still lower with arteriovenous fistulas, and fistulas remain the preferred means of hemodialysis access. However, if a patient cannot obtain a fistula and requires a graft, use of fish oil and an antiplatelet agent appears reasonable, pending the results of further studies,” Dr. Dixon writes.
The FISH trial was supported by peer-reviewed grant funding from the Physician’s Services Incorporated Foundation and the Canadian Institutes for Health Research (CIHR).
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