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Figure 1.
Consolidated Standards of Reporting Trials Diagram: Study Enrollment and Follow-up
Consolidated Standards of Reporting Trials Diagram: Study Enrollment and Follow-up

aFollowing the protocol amendment in 2011, participants unable to discontinue aspirin use were eligible for randomization to fish oil or matching placebo with continuation of open-label aspirin use.

bNumber of participants whose primary outcome was determined by imputation; fish oil n = 62 (23%), placebo n = 60 (23%).

AVF indicates arteriovenous fistula.

Figure 2.
Forest Plot for Prespecified Subgroup Analysis on Arteriovenous Fistula (AVF) Failure
Forest Plot for Prespecified Subgroup Analysis on Arteriovenous Fistula (AVF) Failure

RR indicates relative risk.

aIncludes any 1 or more of peripheral vascular disease, ischemic heart disease, and cerebrovascular disease.

bNo indicates predialysis/transplant; yes, hemodialysis or peritoneal dialysis.

Table 1.  
Patient Demographic and Baseline Characteristics for Fish Oil vs Placebo and Separately for the Subset of Aspirin vs Placebo
Patient Demographic and Baseline Characteristics for Fish Oil vs Placebo and Separately for the Subset of Aspirin vs Placebo
Table 2.  
Primary and Secondary Outcomes for Fish Oil vs Placebo and Aspirin vs Placebo
Primary and Secondary Outcomes for Fish Oil vs Placebo and Aspirin vs Placebo
Table 3.  
Adverse Events Fish Oil vs Placebo and Aspirin vs Placebo
Adverse Events Fish Oil vs Placebo and Aspirin vs Placebo
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Mori  TA, Beilin  LJ, Burke  V, Morris  J, Ritchie  J.  Interactions between dietary fat, fish, and fish oils and their effects on platelet function in men at risk of cardiovascular disease.  Arterioscler Thromb Vasc Biol. 1997;17(2):279-286.PubMedGoogle ScholarCrossref
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Rylance  PB, Gordge  MP, Saynor  R, Parsons  V, Weston  MJ.  Fish oil modifies lipids and reduces platelet aggregability in haemodialysis patients.  Nephron. 1986;43(3):196-202.PubMedGoogle ScholarCrossref
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van Acker  BA, Bilo  HJ, Popp-Snijders  C, van Bronswijk  H, Oe  PL, Donker  AJ.  The effect of fish oil on lipid profile and viscosity of erythrocyte suspensions in CAPD patients.  Nephrol Dial Transplant. 1987;2(6):557-561.PubMedGoogle Scholar
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Cartwright  IJ, Pockley  AG, Galloway  JH, Greaves  M, Preston  FE.  The effects of dietary omega-3 polyunsaturated fatty acids on erythrocyte membrane phospholipids, erythrocyte deformability and blood viscosity in healthy volunteers.  Atherosclerosis. 1985;55(3):267-281.PubMedGoogle ScholarCrossref
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Wang  Q, Liang  X, Wang  L,  et al.  Effect of omega-3 fatty acids supplementation on endothelial function: a meta-analysis of randomized controlled trials.  Atherosclerosis. 2012;221(2):536-543.PubMedGoogle ScholarCrossref
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Fox  PL, DiCorleto  PE.  Fish oils inhibit endothelial cell production of platelet-derived growth factor-like protein.  Science. 1988;241(4864):453-456.PubMedGoogle ScholarCrossref
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Endres  S, Ghorbani  R, Kelley  VE,  et al.  The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells.  N Engl J Med. 1989;320(5):265-271.PubMedGoogle ScholarCrossref
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Mori  TA.  Omega-3 fatty acids and cardiovascular disease: epidemiology and effects on cardiometabolic risk factors.  Food Funct. 2014;5(9):2004-2019.PubMedGoogle ScholarCrossref
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Lok  CE, Moist  L, Hemmelgarn  BR,  et al; Fish Oil Inhibition of Stenosis in Hemodialysis Grafts (FISH) Study Group.  Effect of fish oil supplementation on graft patency and cardiovascular events among patients with new synthetic arteriovenous hemodialysis grafts: a randomized controlled trial.  JAMA. 2012;307(17):1809-1816.PubMedGoogle ScholarCrossref
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Schmitz  PG, McCloud  LK, Reikes  ST, Leonard  CL, Gellens  ME.  Prophylaxis of hemodialysis graft thrombosis with fish oil: double-blind, randomized, prospective trial.  J Am Soc Nephrol. 2002;13(1):184-190.PubMedGoogle Scholar
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Baigent  C, Landray  M, Leaper  C,  et al.  First United Kingdom Heart and Renal Protection (UK-HARP-I) study: biochemical efficacy and safety of simvastatin and safety of low-dose aspirin in chronic kidney disease.  Am J Kidney Dis. 2005;45(3):473-484.PubMedGoogle ScholarCrossref
26.
Irish  A, Dogra  G, Mori  T,  et al.  Preventing AVF thrombosis: the rationale and design of the Omega-3 Fatty Acids (Fish Oils) and Aspirin in Vascular Access Outcomes in Renal Disease (FAVOURED) study.  BMC Nephrol. 2009;10:1.PubMedGoogle ScholarCrossref
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Viecelli  AK, Pascoe  EM, Polkinghorne  KR,  et al; FAVOURED Study Team.  Baseline characteristics of the Omega-3 Fatty Acids (Fish Oils) and Aspirin in Vascular Access Outcomes in Renal Disease (FAVOURED) study.  Nephrology (Carlton). 2016;21(3):217-228.PubMedGoogle ScholarCrossref
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Smith  GE, Gohil  R, Chetter  IC.  Factors affecting the patency of arteriovenous fistulas for dialysis access.  J Vasc Surg. 2012;55(3):849-855.PubMedGoogle ScholarCrossref
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Lok  CE, Allon  M, Moist  L, Oliver  MJ, Shah  H, Zimmerman  D.  Risk equation determining unsuccessful cannulation events and failure to maturation in arteriovenous fistulas (REDUCE FTM I).  J Am Soc Nephrol. 2006;17(11):3204-3212.PubMedGoogle ScholarCrossref
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Original Investigation
February 2017

Effect of Fish Oil Supplementation and Aspirin Use on Arteriovenous Fistula Failure in Patients Requiring Hemodialysis: A Randomized Clinical Trial

Author Affiliations
  • 1Department of Nephrology, Fiona Stanley Hospital, Perth, Australia
  • 2School of Medicine and Pharmacology, University of Western Australia, Perth, Australia
  • 3Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia
  • 4Australasian Kidney Trials Network, School of Medicine, University of Queensland, Brisbane, Australia
  • 5Department of Medicine and Hemodialysis Unit, Hospital Sultanah Aminah, Johor Bahru, Malaysia
  • 6Department of Nephrology, St George Hospital, Sydney, Australia
  • 7The George Institute for Global Health, Sydney, Australia
  • 8Menzies School of Health Research, Charles Darwin University, Darwin, Australia
  • 9Department of Nephrology, Monash Medical Centre, Melbourne, Australia
  • 10Department of Medicine, Monash University, Melbourne, Australia
  • 11Middlemore Renal Department, Counties-Manukau Health, Auckland, New Zealand
  • 12Department of Nephrology, Penang Hospital, Georgetown, Malaysia
  • 13School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
JAMA Intern Med. 2017;177(2):184-193. doi:10.1001/jamainternmed.2016.8029
Key Points

Question  Is fish oil or aspirin effective in preventing failure of de novo arteriovenous fistulae in patients requiring hemodialysis?

Findings  In this randomized clinical trial that included 567 adults, the occurrence of fistula failure within 12 months of surgery was high and not reduced by fish oil supplementation or aspirin use compared with placebo.

Meaning  This study suggests that neither fish oil nor aspirin can be recommended routinely for the prevention of arteriovenous fistula failure and that additional strategies to reduce the high arteriovenous fistula failure rate are required.

Abstract

Importance  Vascular access dysfunction is a leading cause of morbidity and mortality in patients requiring hemodialysis. Arteriovenous fistulae are preferred over synthetic grafts and central venous catheters due to superior long-term outcomes and lower health care costs, but increasing their use is limited by early thrombosis and maturation failure. ω-3 Polyunsaturated fatty acids (fish oils) have pleiotropic effects on vascular biology and inflammation and aspirin impairs platelet aggregation, which may reduce access failure.

Objective  To determine whether fish oil supplementation (primary objective) or aspirin use (secondary objective) is effective in reducing arteriovenous fistula failure.

Design, Setting, and Participants  The Omega-3 Fatty Acids (Fish Oils) and Aspirin in Vascular Access Outcomes in Renal Disease (FAVOURED) study was a randomized, double-blind, controlled clinical trial that recruited participants with stage 4 or 5 chronic kidney disease from 2008 to 2014 at 35 dialysis centers in Australia, Malaysia, New Zealand, and the United Kingdom. Participants were observed for 12 months after arteriovenous fistula creation.

Interventions  Participants were randomly allocated to receive fish oil (4 g/d) or matching placebo. A subset (n = 406) was also randomized to receive aspirin (100 mg/d) or matching placebo. Treatment started 1 day prior to surgery and continued for 12 weeks.

Main Outcomes and Measures  The primary outcome was fistula failure, a composite of fistula thrombosis and/or abandonment and/or cannulation failure, at 12 months. Secondary outcomes included the individual components of the primary outcome.

Results  Of 1415 eligible participants, 567 were randomized (359 [63%] male, 298 [53%] white, 264 [47%] with diabetes; mean [SD] age, 54.8 [14.3] y). The same proportion of fistula failures occurred in the fish oil and placebo arms (128 of 270 [47%] vs 125 of 266 [47%]; relative risk [RR] adjusted for aspirin use, 1.03; 95% CI, 0.86-1.23; P = .78). Fish oil did not reduce fistula thrombosis (60 [22%] vs 61 [23%]; RR, 0.98; 95% CI, 0.72-1.34; P = .90), abandonment (51 [19%] vs 58 [22%]; RR, 0.87; 95% CI, 0.62-1.22; P = .43), or cannulation failure (108 [40%] vs 104 [39%]; RR, 1.03; 95% CI, 0.83-1.26; P = .81). The risk of fistula failure was similar between the aspirin and placebo arms (87 of 194 [45%] vs 83 of 194 [43%]; RR, 1.05; 95% CI, 0.84-1.31; P = .68).

Conclusions and Relevance  Neither fish oil supplementation nor aspirin use reduced failure of new arteriovenous fistulae within 12 months of surgery.

Trial Registration  anzctr.org.au Identifier: CTRN12607000569404

Introduction

Hemodialysis is the commonest renal replacement modality worldwide and requires a functioning permanent vascular access. Vascular access dysfunction is associated with substantial morbidity and mortality and presents a major health economic burden.1,2 Arteriovenous fistulae (AVFs) are recommended as the preferred vascular access by international clinical practice guidelines3-6 because of their longevity and lower complication rates compared with synthetic arteriovenous grafts (AVGs) and central venous catheters.2,7,8 However, AVFs require a longer maturation time before use and have a significantly higher risk of early failure compared with AVGs.9 Early primary failure occurs in 20% to 50% of AVFs as a result of either thrombosis or maturation failure.10,11 Although antiplatelet agents can reduce early thrombosis of AVFs, this has not translated into significant improvements in the proportion of AVFs that become suitable for dialysis.12,13

Supplementation of ω-3 polyunsaturated fatty acids found in fish oil may be beneficial in promoting vascular access maturation and reducing thrombosis by not only inhibiting platelet aggregation14,15 but also decreasing blood viscosity, improving red blood cell flexibility,16,17 promoting vasodilation,18 inhibiting smooth muscle cell proliferation,19 and reducing inflammation.20,21 Fish oil has been shown to increase patency rates in AVGs, but it has not been assessed in AVFs.22,23 Low-dose aspirin is an effective antiplatelet agent in the secondary prevention of vascular disease24 and has been used safely in patients with advanced kidney disease25; however, it has not been adequately evaluated in the prevention of AVF failure.

The primary aim of the Omega-3 Fatty Acids (Fish Oils) and Aspirin in Vascular Access Outcomes in Renal Disease (FAVOURED) trial was to test the hypothesis that fish oil supplementation will reduce AVF failure after AVF creation in patients with stage 4 or 5 chronic kidney disease. A secondary aim was to examine the efficacy of aspirin use in preventing failure of new AVFs (registration ACTRN12607000569404).

Methods
Study Design

FAVOURED is an investigator-initiated, international, double-blind, randomized, placebo-controlled trial conducted in 35 hemodialysis centers across Australia, Malaysia, New Zealand, and the United Kingdom (study protocol and statistical analysis plan in Supplement 1). Recruitment began on August 21, 2008, and ended on February 28, 2014, with the last follow-up on February 28, 2015. The original study, which commenced with a 2 by 2 factorial design, was amended in June 2011. First, the primary outcome of “early thrombosis” at 12 weeks following AVF creation was broadened to the more clinically relevant “AVF access failure,” a composite of thrombosis and/or AVF abandonment and/or cannulation failure at 12 months. Second, eligibility criteria were broadened so that patients who were previously ineligible due to medically indicated aspirin use were eligible and randomized to fish oil or matching placebo with continuation of open-label aspirin (eFigure 1 in Supplement 2). As a result of the second amendment, the primary objective of FAVOURED was to assess the efficacy of fish oil supplementation on AVF failure at 12 months and the efficacy of aspirin was assessed as a secondary objective. Details of the original and amended study protocols have been published previously.26-28

Study Oversight

The study was approved by human research ethics committees at participating centers. All patients provided written consent prior to study enrolment. A trial management committee comprising clinicians and a statistician had sole responsibility for the design and conduct of the study, analysis of data, and manuscript preparation. An independent data and safety monitoring board reviewed accumulating data. Two interim efficacy analyses using the Haybittle-Peto rule were planned after one-third and two-thirds of patients had been recruited and observed for at least 12 months. Due to early cessation of recruitment, only the first interim analysis was performed, after which the study continued as planned until terminated because of slower than anticipated accrual, funding issues, and lack of ongoing availability of trial medications. FAVOURED is registered with the Australia and New Zealand Clinical Trials Register (ACTRN12607000569404).

Study Population

Adults (age >19 years) with stage 4 or 5 chronic kidney disease receiving or planned to receive hemodialysis within 12 months and scheduled for AVF surgery in the arm were eligible for inclusion. Participants were excluded if they had an increased bleeding risk (bleeding disorder, recent or active gastrointestinal ulcer, platelet count <100 × 103/μL [to convert to billions per liter, multiply by 1.0], hepatic insufficiency), were taking aspirin within 2 weeks or fish oil within 4 weeks of trial commencement, were taking nonsteroidal anti-inflammatory drugs, anticoagulants, or antiplatelet agents, or had contraindications for taking the study agents. In June 2011, the exclusion criterion of current use of aspirin was removed so that patients currently taking aspirin were eligible for recruitment (eFigure 1 in Supplement 2).

Randomization and Study Intervention

Randomization of participants was dependent on aspirin-taking status: (1) not taking aspirin or able to cease; (2) taking aspirin and unable to cease (open-label aspirin). Within each group, participants were randomly assigned in a 1:1 ratio to receive either 4 g of fish oil (2 g twice daily) in the form of 4 ω-3-acid ethyl esters (Omacor) capsules (46% eicosapentaenoic acid and 38% docosahexaenoic acid) or 4 matching placebo capsules (olive oil) (BGP Products Pty Ltd, trading as Mylan EPD). Participants not taking aspirin or able to cease were further randomized in a 1:1 ratio to receive 100 mg of oral aspirin daily or matching placebo (Bayer Healthcare). Randomization was performed by a central, web-based system (Flexetrials) using an adaptive minimization algorithm with study site and planned location of the AVF (upper vs lower arm) as minimization variables. Randomization occurred up to 7 days prior to scheduled AVF surgery. Treatment commenced on the day before scheduled AVF surgery and continued for 12 weeks. Participants, caregivers, treating physicians and surgeons, laboratory staff, and members of the study team were blinded to treatment allocation.

Outcomes

The primary outcome was AVF access failure at 12 months after fistula creation and defined as a composite of any one of AVF thrombosis, AVF abandonment, and cannulation failure. Thrombosis was defined as the absence of a thrill or bruit by clinical assessment and/or requirement for rescue intervention (medical thrombolysis or surgical thrombectomy). Arteriovenous fistula abandonment was defined as no further use of, or attempt to intervene on, the study AVF. Cannulation failure was defined as failure to successfully cannulate the study AVF during 8 or more of 12 consecutive hemodialysis sessions during the cannulation assessment period28 (eTable 1 in Supplement 2). Secondary outcomes included components of the primary outcome, and safety outcomes.

Sample Size

The study was designed to detect a 30% relative reduction in AVF access failure assuming 30% AVF failure in control groups (an absolute risk reduction of 9%). At 80% power and a 2-sided significance level of 5%, 734 participants would be required (367 per group). Assuming a 5% drop-in from control to fish oil and a 5% drop-out from fish oil to placebo and a 5% loss to follow-up, a total of 954 participants needed to be recruited.

Statistical Analysis

Log binomial regression (to enable calculation of relative risks [RRs]29) was used to compare fish oil with matching placebo on the composite outcome of AVF access failure, adjusted for differences in aspirin use (randomized to aspirin, randomized to placebo aspirin, open-label aspirin). The treatment effect is expressed as RR and 95% confidence interval. The robustness of the fish oil treatment effect was assessed by additional analyses that adjusted for prespecified baseline characteristics and study region (eFigure 2 in Supplement 2). All prespecified subgroup analyses were performed using log binomial regression models adjusted for differences in aspirin use. Tests of treatment-by-subgroup variable interactions informed the interpretation of subgroup results. Secondary outcomes were analyzed using log binomial regression models as per the primary outcome. Single imputation was used to replace missing values on the separate components of the primary outcome as follows: participants with missing data were randomly allocated a value (1 = event, 0 = no event) such that the proportion of imputed events was the same as the proportion of events in participants with observed data for the component; for example, if the overall frequency of AVF thrombosis for participants with available data was 20%, then a patient with a missing value for AVF thrombosis would be randomly assigned an event in 20% of cases. A range of prespecified sensitivity analyses for imputation of missing values were performed, including a complete case analysis. Comparisons of aspirin with matching placebo were performed using the same statistical models.

Analyses were based on participants’ randomized treatment. Participants who did not receive AVF creation surgery or died within 12 months of surgery and were not assessed on any of the 3 components of the primary outcome before their death were excluded. A 2-sided P < .05 was considered statistically significant. Statistical analyses were performed using SAS version 9.4 (SAS Institute) and Stata version 13.1 (Stata Corporation).

Results
Study Participants

Of the 4242 patients assessed for eligibility, 1415 were deemed eligible, 567 were randomized to fish oil (n = 284) or placebo (n = 283), and 536 included in the analysis (Figure 1). There were 406 participants randomized to aspirin (n = 203) or matching placebo (n = 203). Participant demographic and clinical characteristics were well balanced between each pair of treatment groups (Table 1).

AVF Failure

Arteriovenous fistula failure occurred in 128 of 270 (47%) participants assigned to fish oil and 125 of 266 (47%) assigned to placebo (RR adjusted for aspirin use, 1.03; 95% CI, 0.86-1.23; P = .78). The proportion of events in the fish oil and placebo groups was similar for each of the 3 individual components of AVF failure: thrombosis (60 [22%] vs 61 [23%]; adjusted RR, 0.98; 95% CI, 0.72-1.34; P = .90), AVF abandonment (51 [19%] vs 58 [22%]; RR, 0.87; 95% CI, 0.62-1.22; P = .43), and cannulation failure during the cannulation assessment period (108 [40%] vs 104 [39%]; RR, 1.03; 95% CI, 0.83-1.26; P = .81) (Table 2). In the assessment of the prespecified subgroups, a significant difference in the effect of fish oil on AVF failure was observed in participants with diabetes mellitus compared with those without diabetes (P = .03 for interaction; RR, 1.30; 95% CI, 0.99-1.71 vs RR, 0.85; 95% CI, 0.67-1.08), but not in other prespecified subgroups (Figure 2A).

In participants randomized to aspirin or matching placebo, the risk of AVF failure was similar (87 [45%] vs 83 [43%]; RR, 1.05; 95% CI, 0.84-1.31; P = .68). Aspirin compared with placebo did not reduce the risk of AVF thrombosis (38 [20%] vs 35 [18%]; RR, 1.09; 95% CI, 0.72-1.64; P = .70), AVF abandonment (46 [24%] vs 35 [18%]; RR, 1.31; 95% CI, 0.89-1.95; P = .17), or cannulation failure (73 [38%] vs 74 [38%]; RR, 0.99; 95% CI, 0.76-1.27; P = .92) (Table 2). There were no statistically significant subgroup effects involving the aspirin groups (Figure 2B). The fish oil by aspirin interaction test was not statistically significant for the composite outcome (P = .12); however, results for comparisons of fish oil plus aspirin with fish oil and aspirin alone and double placebo are included in eTable 2 in Supplement 2.

Analyses based on complete cases and secondary analyses adjusting for prespecified baseline characteristics and/or geographic region demonstrated results comparable to those of the primary analyses for both fish oil and aspirin (eFigure 2A and B in Supplement 2). The amounts of missing data (23% for fish oil and placebo; 22% for aspirin and 21% for placebo) and number of imputed events were similar between treatment groups (eTable 3 in Supplement 2). The majority of “missing” data were due to 81 of 122 (66%) participants who did not start dialysis within 12 months of surgery and thus could not be assessed for cannulation failure.

Post hoc analyses examining the timing of first cannulation (eTable 4 in Supplement 2), the time from fistula creation to initiation of hemodialysis (eTable 5 in Supplement 2), and the timing of renal replacement therapy initiation in predialysis participants (eTable 6 in Supplement 2) showed no differences between treatment groups.

Adverse Events

Adverse drug events, including bleeding events (16 [6%] vs 10 [4%]; P = .23) and gastrointestinal adverse effects (15 [5%] vs 14 [5%]; P = .86), were similar for the fish oil and placebo groups. Death occurred in 8 participants allocated to fish oil and 9 allocated to placebo (Table 3). Aspirin use was not associated with an increase in adverse drug events or serious adverse events (Table 3).

Adherence

After 6 and 12 weeks of treatment, the percentage of eicosapentaenoic acid and docosahexaenoic acid incorporated in erythrocytes (measured in Australian and New Zealand participants taking fish oil) doubled, but it remained at baseline levels for those taking placebo, confirming adherence to study treatment and providing evidence that the fish oil formulation was sufficient to modify lipid composition of erythrocytes (eFigure 3 in Supplement 2). For all participants, the median number of returned capsules was comparable for both the fish oil and placebo groups (47 vs 45 of 360 dispensed capsules) and the aspirin and placebo groups (7 of 90 dispensed tablets for both groups).

Discussion

In patients with chronic kidney disease undergoing creation of an AVF, 3 months’ treatment with fish oil at a dose of 4 g per day did not reduce the composite primary outcome of AVF failure nor any of the individual components, which included AVF abandonment, thrombosis, and cannulation failure, assessed at 12 months. The trial finished before reaching the planned recruitment target but was able to show that fish oil is unlikely to reduce the risk of AVF failure by 30%; results were consistent with, at best, a 14% RR reduction. In a smaller subset of patients, the use of low-dose aspirin was similarly ineffective in improving AVF outcomes. This large, international trial confirmed the high AVF failure of nearly 50% at 12 months after surgery and emphasizes the pressing need to improve AVF outcomes.

Previous studies regarding the benefits of fish oil supplementation in vascular access outcomes have been confined to AVGs, in which the results are conflicting. Lok and colleagues22 found no significant difference in the primary outcome measure, proportion of patency loss of newly created AVGs within 12 months, in 201 patients treated with 4 g of fish oil or placebo. However, the study demonstrated improvements in secondary outcomes including rates of patency loss, interventions, and thrombosis in addition to cardiovascular benefits. One small randomized clinical trial of 24 participants treated with 4 g of fish oil or placebo had a 12-month patency of 76% in the fish oil–treated group compared with 15% in the placebo group,23 which was not confirmed in another small randomized trial using lower doses of eicosapentaenoic and docosahexaenoic acids.30 Variability in these results may be due to differences in sample size, and dose and duration of therapy.

While participants receiving fish oil during the FAVOURED trial had increased erythrocyte ω-3 polyunsaturated fatty acids, supporting medication adherence, a clinically relevant effect of fish oil on AVF failure was not demonstrated. It remains unknown whether the lack of efficacy is due to achieved levels of eicosapentaenoic and docosahexaenoic acids being insufficient to promote adequate vasodilatory, antiproliferative, anti-aggregatory, and anti-inflammatory effects at the site of the AVF formation to improve clinical outcomes. However, the doses of eicosapentaenoic and docosahexaenoic acids used in the FAVOURED trial were higher than doses used in studies assessing AVG outcomes and studies in patients with chronic kidney disease using a comparable dose of fish oil achieved significant reductions in blood viscosity, platelet aggregation, and blood pressure consistent with biological effects.15,16,31 Three months of therapy was selected because it corresponds with the expected maturation time and early failure of AVF.32,33 However, the possibility that a longer duration of treatment may have resulted in a delayed benefit on maturation and usability cannot be excluded. It is also possible that risk factors such as age, diabetes mellitus, cardiovascular disease, and peripheral vascular disease that affect characteristics of the conduit vessel34,35 may limit any beneficial effects of fish oil supplementation on AVF failure. Although there was no difference in AVF failure between the fish oil and placebo groups, participants with diabetes mellitus had a higher risk of AVF failure when treated with fish oil than those without diabetes mellitus. The biological plausibility of this finding is uncertain, although differences in lifestyle factors associated with diabetic status or a type I statistical error are possible explanations.

Aspirin is a well-established antiplatelet agent with wide clinical efficacy in preventing vascular thrombotic events.24 One small randomized clinical trial had previously shown a beneficial effect of aspirin use on early AVF thrombosis using 1 g of aspirin every other day for 28 days.36 In our study, 3 months of low-dose aspirin use did not reduce AVF failure or thrombosis. In contrast, 6 weeks of clopidogrel bisulfate therapy reduced early access thrombosis from 20% to 12% although this did not increase the proportion of usable AVF.13 The lower dose of aspirin used in FAVOURED may have been inadequate for thrombosis prevention.

Consistent with contemporary international studies,9,13,37,38 we report 47% AVF failure. Both thrombosis and failure to mature were unaffected by the interventions at 12 months, suggesting that modifying vascular conduit function to improve vascular access outcomes requires additional research focus. This high failure rate remains the most important impediment to successful hemodialysis and is considered a critical priority by patients and clinicians.39 A substantial proportion of patients undergoing fistula creation with the expectation of requiring hemodialysis did not commence dialysis within 12 months of surgery. This uncertainty in predicting dialysis commencement and timing of AVF surgery in patients with advanced chronic kidney disease may have implications for both resource use and future trial considerations.40

To our knowledge, FAVOURED is the first trial evaluating fish oil supplementation and the largest trial evaluating aspirin use and AVF outcomes. Relevant clinical end points to define vascular access failure were included, and participants were from diverse health care settings and geographic regions. Treatment groups were well balanced with respect to baseline characteristics.

Limitations

The trial population was younger with less vascular disease than anticipated because we excluded patients with medical requirements for antiplatelet agents or anticoagulants. There were missing data on the primary outcome, mainly because patients had not commenced dialysis and therefore could not be assessed for cannulation failure; however, the proportion of missing values was balanced across treatment groups and imputation is unlikely to have biased the results.

Conclusions

The proportion of new AVFs that failed within 12 months of surgery was nearly 50% and was not reduced by 12 weeks of fish oil supplementation or low-dose aspirin therapy. This study suggests that neither fish oil nor aspirin can be recommended for the prevention of AVF failure and that additional strategies to reduce the high AVF failure rate are required.

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Article Information

Corresponding Author: Ashley B. Irish, MD, Department of Renal Medicine, Fiona Stanley Hospital, 102-118 Murdoch Dr, Murdoch, Western Australia 6150, Australia (ashley.irish@health.wa.gov.au).

Accepted for Publication: October 19, 2016.

Published Online: January 3, 2017. doi:10.1001/jamainternmed.2016.8029

Author Contributions: Dr Hawley and Ms Pascoe had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Irish and Viecelli are co–first authors, with equal contribution to the manuscript.

Study concept and design: Irish, Hawley, Pascoe, Paul-Brent, Mori, Cass, Kerr, Polkinghorne.

Acquisition, analysis, or interpretation of data: Irish, Viecelli, Hawley, Hooi, Pascoe, Paul-Brent, Badve, Mori, Kerr, Voss, Ong, Polkinghorne.

Drafting of the manuscript: Irish, Viecelli, Hawley, Hooi, Paul-Brent, Badve, Voss, Polkinghorne.

Critical revision of the manuscript for important intellectual content: Irish, Viecelli, Hawley, Hooi, Pascoe, Badve, Mori, Cass, Kerr, Voss, Ong, Polkinghorne.

Statistical analysis: Hawley, Pascoe, Badve.

Obtained funding: Irish, Hawley, Paul-Brent, Mori, Kerr, Polkinghorne.

Administrative, technical, or material support: Viecelli, Hawley, Hooi, Pascoe, Paul-Brent, Mori, Kerr, Voss, Ong, Polkinghorne.

Study supervision: Irish, Hawley, Hooi, Pascoe, Badve, Mori, Cass, Kerr, Voss, Polkinghorne.

Group Information: The FAVOURED Study Collaborative Group comprises the Trial Steering Committee: Chen Au Peh, CNARTS, Royal Adelaide Hospital, Adelaide, Australia; Elaine Beller, Faculty of Health Services and Medicine, Bond University, Gold Coast, Australia; Alan Cass, Menzies School of Health Research, Darwin, Australia; Sharan Dogra, Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, Australia; David Gracey, Department of Renal Medicine, Royal Prince Alfred Hospital, Sydney, Australia; Elvie Haluszkiewicz, Department of Vascular Surgery, Royal Perth Hospital, Perth, Australia; Carmel Hawley, Department of Nephrology, Princess Alexandra Hospital, Brisbane, Queensland, Australia; Lai-Seong Hooi, Hemodialysis Unit, Hospital Sultanah Aminah, Johor Bahru, Malaysia; Colin Hutchison, Renal Services, Hawkes Bay Hospital, Hawke’s Bay, New Zealand; Ashley Irish, Department of Nephrology Fiona Stanley Hospital, Perth, Western Australia, Australia; Peter Kerr, Department of Nephrology, Monash Medical Centre, Melbourne, Australia; Amanda Mather, Royal North Shore Hospital, Sydney, Australia; Stephen McDonald, CNARTS, Royal Adelaide Hospital, Adelaide, Australia; Chris McIntyre, London Health Sciences Centre, Ontario, Canada; Trevor Mori, Medicine and Pharmacology RPH Unit, University of Western Australia, Perth, Australia; Elaine Pascoe, Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia; Kevan Polkinghorne, Department of Nephrology, Monash Medical Centre, Melbourne, Victoria, Australia; Amanda Robertson, Nephrology Surgery, Royal Melbourne Hospital, Melbourne, Australia; Johan Rosman, Medicine and Pharmacology RPH Unit, University of Western Australia, Perth, Australia; David Voss, Middlemore Renal Department, Counties-Manukau Health, Auckland, New Zealand.

The Data and Safety Monitoring Board: Andrew Tonkin and Andrew Forbes, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia; Adeera Levin, Department of Medicine, University of British Columbia, Vancouver, Canada; David C. Wheeler, Center for Nephrology, Royal Free and University College Medical School, London, England.

The Investigators: Australia: Australian Capital Territory: Canberra Hospital, Krishna Karpe, Patricia Johnson; New South Wales: Concord Repatriation General Hospital, Martin Gallagher, Jenny Burman; John Hunter Hospital, Alistair Gillies, Leanne Garvey; Liverpool Hospital, Michael Suranyi, Belinda Yip; Prince of Wales Hospital, Grant Luxton, Debbie Pugh, Kathleen McNamara; Royal North Shore Hospital, Bruce Cooper, Cheryl Macadam; Royal Prince Alfred Hospital, Kate Wyburn, Samantha Hand; Sydney Adventist Hospital, Meg Jardine, Anne Heath; Queensland: Gold Coast Hospital, Dakshinamurthy Divi, Tammy Schmidt; Greenslopes Private Hospital, Andrew Bofinger, Leanne Glancy; Princess Alexandra Hospital, David Mudge, Amanda Coburn; Toowoomba Hospital, Sree Krishna Venuthurpali, Elizabeth Coroneos, Suzi Hanna; Townsville Hospital, George Kan, Vicki Hartig; South Australia: Royal Adelaide Hospital, Karen Katil, Meg Hockley; Victoria: Austin Health, Peter Mount, Pascal Bisscheroux, Maree Ross-Smith; Geelong Hospital, Rob McGinley, Anthony Perkins; Monash Medical Centre, Kevan Polkinghorne, Mechelle Seneviratne; Royal Melbourne Hospital, Eugenie Pedagogos, Connie Karchimkus; Alfred Hospital, Solomon Menahem, Suzanne Douglas; Western Health, Vicki Levidiotis, Debra Broomfield, Jason Bennier; Western Australia: Fremantle Hospital, Paolo Ferrari, Ulrich Steinweadel; Royal Perth Hospital, Ashley Irish, Maria Martin, Monika Chang; Sir Charles Gairdner Hospital, Sharan Dogra, Susan Pellicano, Helen Herson; Malaysia: Kuala Lumpur Hospital, Ravindran Visvanathan, Norlida Omar, Zanariah Arsat; Pulau Pinang Hospital, Loke-Meng Ong, Ah-Heong Ang; Raja Perempuan Zainab II Hospital, Sukeri Mohamad, Najhah Md Nawi; Seberang Jaya Hospital, Anita Bhajan Manocha, Norhaniza Bt Adom; Sultanah Aminah General Hospital, Lai-Seong Hooi, Wen Jiun Liu, Mohd Rais Bin Periman, Norisham Bin Mohd Dom; Sultanah Nur Zahirah Hospital, Zawawi Nordin, Suhaizan Bt Mohd Rasidi; Taiping Hospital, Indralingam Vaithilingam, Ramli Zaraee; University Malaya Medical Centre, Lim Soo Kun, Tiviyah Sinniah; New Zealand: Dunedin Hospital, John Schollum, Liz Berry; Counties-Manukau Health, David Voss, Penelope Eadie; United Kingdom: Royal Derby Hospital, Chris McIntyre, Marie Appleby.

The Australasian Kidney Trials Network Executive Committee Members: Neil Boudville, Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, Australia; Alan Cass, Menzies School of Health Research, Darwin, Australia; Carmel Hawley, Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia; Meg Jardine, George Institute of Global Health, Sydney, Australia; David Johnson, Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia; Vlado Perkovic, George Institute of Global Health, Sydney, Australia.

The Australasian Kidney Trials Network Project Management Team: Carmel Hawley, David Johnson, Alicia Morrish, Elaine Pascoe, Peta-Anne Paul-Brent, Donna Reidlinger, Liza Vergara, Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia; Elaine Beller, Faculty of Health Services and Medicine, Bond University, Gold Coast, Australia; Sunil Badve, Department of Nephrology, St George Hospital, Sydney, New South Wales, Australia; Anish Scaria, George Institute of Global Health, Sydney, Australia; Stephane Heritier, Epidemiology and Preventative Medicine, Monash University, Melbourne, Australia.

Conflict of Interest Disclosures: Drs Irish and Hawley, Mss Pascoe and Paul-Brent, and Drs Mori, Cass, Kerr, and Polkinghorne report having received grant support from the National Health and Medical Research Council (NHMRC) project grant, grants from Mylan EPD (at the time of funding was Abbott Products Operations AG), and grants from Amgen Australia Pty Ltd. Dr Viecelli reports having received grant support from the National Health and Medical Research Council (Medical Postgraduate Scholarship) and the Royal Australasian College of Physicians (Jacquot National Health and Medical Research Council Medical Award for Excellence). No other disclosures are reported.

Funding/Support: The FAVOURED trial was funded by grants from National Health and Medical Research Council of Australia Project Grant (APP458652), Amgen Australia Pty Ltd and Mylan EPD (at the time of funding was Abbott Products Operations AG). Study medication was supplied by Mylan EPD (at the time of supply was Abbott Products Operations AG) (fish oil and placebo) and Bayer Healthcare (aspirin and placebo) free of charge.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Previous Presentation: The findings of this trial were presented at the annual meeting of the American Society of Nephrology; November 7, 2015; San Diego, California.

Additional Contributions: The authors listed in the byline constitute the FAVOURED Trial Writing Committee. The authors gratefully acknowledge the contributions of all members of the FAVOURED Study Collaborative Group, dialysis nursing staff, trial coordinators, research staff, and most especially trial participants.

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