Introduction

A functioning vascular access is essential for patients requiring haemodialysis (HD). A native arteriovenous fistula (AVF) has the best long-term outcomes although this advantage is frequently limited by early thrombosis, maturation failure, the need for access interventions and/or placement of a central venous catheter (CVC)[1,2]. Vascular access interventions are burdensome for patients and incur significant health care costs[3]. Patients and health professionals consider the need for interventions to maintain the use of a vascular access for HD the most important adverse outcome of a vascular access[4], yet treatments to reduce intervention rates and to increase the usability of AVF have not been a major focus of randomised trials in patients requiring HD[5]. The inhibitory effects of omega-3 polyunsaturated fatty acids (fish oils) on platelet aggregation[6,7], inflammation[8,9], and neointimal hyperplasia[10], and of aspirin on platelet inhibition could be beneficial in reducing the need for interventions for acute thrombosis and maturation-enhancing procedures. Fish oil supplementation has been shown to reduce intervention and thrombosis rates in arteriovenous grafts[11] but has not previously been studied in AVF.

The omega-3 fatty acids (Fish oils) and Aspirin in Vascular access OUtcomes in REnal Disease (FAVOURED) trial found that neither fish oil nor aspirin reduced the primary outcome ‘AVF failure’, a binary composite outcome comprising AVF thrombosis and/or AVF abandonment and/or cannulation failure assessed at 12 months following AVF creation[12]. The current analysis of secondary and exploratory outcomes of the FAVOURED trial aimed to determine whether fish oil or low-dose aspirin could reduce the need for access interventions and CVC exposure and/or increase the usability of newly created AVF for HD.

Materials and methods

Results

The FAVOURED study randomised 567 participants to fish oil or placebo from August 21, 2008 to February 28, 2014, of which 536 were included in the final analysis[12]Fig 1. Table 1 shows the baseline characteristics of the 536 participants; 31 participants were excluded because they either died prior to being assessed on any outcome (n = 5 in each of the fish oil and placebo groups) or did not have an AVF created (n = 9 randomised to fish oil, n = 12 randomised to placebo)[12]. Participants had a mean age of 55 years and 64% were male. Baseline characteristics were generally well balanced although more participants treated with fish oil compared to placebo were diabetic (48% versus 43%) or smokers (53% versus 48%). At study initiation, 49% were on dialysis with 84% dialysing through a CVC. At study end, 83% received dialysis with 61% using the study AVF (167 [62%] randomised to fish oil, 159 [60%] randomised to placebo).

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Fig 1. CONSORT participant flow diagram.

https://doi.org/10.1371/journal.pone.0213274.g001

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Table 1. Patient demographics and baseline characteristics for fish oil versus placebo and separately for the subset of aspirin versus placebo.

https://doi.org/10.1371/journal.pone.0213274.t001

Of the 406 participants not taking aspirin or able to cease it prior to enrolment, 203 were randomised to aspirin and 203 to matching placebo[12] of which 388 (194 in each group) were included in the analysis (S1 Fig). The remaining 18 participants were excluded because they either did not undergo AVF creation (n = 5 randomised to aspirin, n = 8 randomised to placebo) or died before they could be assessed on any outcome (n = 4 randomised to aspirin, n = 1 randomised to placebo). As outlined in Table 1, this subset of 388 participants had a lower prevalence of cardiovascular disease (7% randomised to aspirin, 5% randomised to placebo) compared to the full set of 536 participants randomised to fish oil (14%) or matching placebo (15%).

AVF interventions

Fig 2 and S2 Table present the frequency and type of AVF interventions by treatment arms for fish oil versus placebo (A) and aspirin versus placebo (B). Overall, 22% of participants receiving fish oil supplementation required at least one AVF intervention compared to 27% treated with placebo (S2 Table). Of those, 17% treated with fish oil and 28% treated with placebo required more than one intervention. The majority of interventions occurred within the first 6 months of AVF creation (Fig 2). Neither fish oil nor aspirin reduced the risk of needing at least one rescue- or non-rescue intervention compared to their matching placebo. Similarly, the time to first intervention was not significantly reduced by fish oil or aspirin (Fig 3A and 3B; HR 0.85, 95% CI 0.57, 1.26, p = 0.41 for fish oil versus placebo; HR 0.81, 95% CI 0.51, 1.29, p = 0.38 for aspirin versus placebo). As shown in Fig 4A, intervention rates were significantly reduced by fish oil compared to placebo, driven by a significant reduction in rescue procedures (IRR 0.53 95% CI 0.34, 0.84, p = 0.005). The effect size remained similar when adjusting for pre-specified baseline characteristics and geographical regions. Of note, there was a significant reduction in the number of rescue interventions with fish oil during the active treatment period, i.e. the first 3 months, compared with placebo (p = 0.009) (Fig 2A). Similarly, the rate of rescue interventions was reduced in the participants treated with low-dose aspirin compared to matching placebo (Fig 4B). The fish oil by aspirin interaction test was not statistically significant for rescue or non-rescue interventions (p = 0.12).

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Fig 2.

Number of rescue- and non-rescue interventions by time period for fish oil versus placebo (A) and aspirin versus placebo (B). *p = 0.009 (Fisher’s Exact Test) for comparison of rescue intervention during first 3 months (active treatment phase) and beyond 3 months.

https://doi.org/10.1371/journal.pone.0213274.g002

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Fig 3.

Time to first AVF intervention for fish oil versus placebo (A) and aspirin versus placebo (B). Kaplan-Meier curve for active therapy (solid line with 95% confidence interval in light gray) and matching placebo (dashed line with 95% confidence interval in dark gray).

https://doi.org/10.1371/journal.pone.0213274.g003

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Fig 4.

AVF intervention rates for fish oil versus placebo (A) and aspirin versus placebo (B). Overall interventions: Surgical or radiological revision or dilatation of the AVF from or proximal to the anastomosis to the ipsilateral central vein, dilation of central venous stenosis, ligation of tributaries, superficialisation of AVF, thrombolysis or thrombectomy, ligation of fistula or salvage by distal reconstruction and interval ligation, others. Rescue interventions: Thrombolysis or thrombectomy. Non-rescue interventions: Surgical or radiological revision or dilatation of the AVF from or proximal to the anastomosis to the ipsilateral central vein, dilation of central venous stenosis, ligation of tributaries, superficialisation of AVF, ligation of fistula or salvage by distal reconstruction and interval ligation. Regions included Australia and New Zealand, Malaysia and the United Kingdom. Pre-specified baseline characteristics included planned AVF site (lower arm, upper arm), diabetes mellitus, age group (quartiles), cardiovascular comorbidity, including any one or more of peripheral vascular disease, ischaemic heart disease and cerebrovascular accidents, and renal replacement therapy at baseline (no [pre-dialysis/transplant], yes [haemodialysis or peritoneal dialysis]). ^aAdjusted for differences in aspirin use (no aspirin, randomized to aspirin, open-label aspirin).

https://doi.org/10.1371/journal.pone.0213274.g004

Primary patency loss and AVF abandonment

The proportion of participants with primary patency loss within 12 months of their AVF creation was not significantly reduced by fish oil (70/270 [26%] participants) compared to placebo (81/266 [31%]; RR 0.85, 95% CI 0.65, 1.12, p = 0.25). Similarly, the time to primary patency loss was not significantly improved in the fish oil treated group compared to placebo (HR 0.81, 95% CI 0.51, 1.29, p = 0.38), as shown in Fig 5A. In participants treated with aspirin or matching placebo, primary patency loss occurred in 27% of participants in both treatment arms and the time to primary patency loss was similar for aspirin and placebo treated participants (Fig 5B; HR 1.01, 95% CI 0.69, 1.47, p = 0.98). Fig 6 shows that neither fish oil (6A) nor aspirin (6B) led to a significant prolongation in the time to AVF abandonment. Similarly, time to either primary patency loss or AVF abandonment was not altered by fish oil (HR 0.92, 95% CI 0.69–1.21, p = 0.53) or aspirin (HR 1.01, 95% CI 0.73–1.42, p = 0.94).

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Fig 5.

Time to primary AVF patency loss for fish oil versus placebo (A) and aspirin versus placebo (B). Kaplan-Meier curve for active therapy (solid line with 95% confidence interval in light gray) and matching placebo (dashed line with 95% confidence interval in dark gray).

https://doi.org/10.1371/journal.pone.0213274.g005

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Fig 6.

Time to AVF abandonment for fish oil versus placebo (A) and aspirin versus placebo (B). Kaplan-Meier curve for active therapy (solid line with 95% confidence interval in light gray) and matching placebo (dashed line with 95% confidence interval in dark gray).

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AVF usability

Of the 356 participants who required HD within 6 months of AVF surgery, 36% on fish oil and 34% on placebo were unable to use the AVF for HD (RR 1.05, 95% CI 0.79, 1.39, p = 0.73). Aspirin was similarly ineffective in reducing late dialysis suitability failure compared to placebo (47/135 [35%] versus 38/124 [31%], RR 1.14, 95% CI 0.80, 1.61, p = 0.48). By 12 months following AVF surgery, 444 participants received dialysis and 74% of participants in the fish oil group and 73% of those in the placebo group had three consecutive successful cannulations of their AVF. Neither fish oil (HR 1.03, 95% CI 0.83–1.28, p = 0.77) nor aspirin (HR 0.89, 95% CI 0.69–1.15, p = 0.37) reduced the time to first successful cannulation of the study AVF (Fig 7A and 7B).

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Fig 7.

Time to first successful cannulation for fish oil versus placebo (A) and aspirin versus placebo (B). Kaplan-Meier curve for active therapy (solid line with 95% confidence interval in light gray) and matching placebo (dashed line with 95% confidence interval in dark gray).

https://doi.org/10.1371/journal.pone.0213274.g007

Discussion

Secondary and exploratory outcome analyses of the FAVOURED trial showed that a quarter of participants required at least one AVF intervention within the first year of AVF creation, almost 30% experienced primary patency loss and 50% required at least one CVC. Three months of fish oil supplementation reduced the rate of AVF interventions, principally driven by a 47% relative reduction in rescue procedures for acute thrombosis. Similarly, low-dose aspirin reduced the incidence of rescue interventions by 55%. However, neither fish oil nor aspirin was effective in reducing the frequency and duration of CVC use, the frequency of late dialysis suitability failure or the time to first successful cannulation. Similarly, the time to first AVF intervention, primary patency loss or AVF abandonment did not differ significantly between treatment groups.

Fish oil had no effect on the primary composite outcome of AVF failure[12], defined as the proportion of participants with AVF thrombosis, AVF abandonment and/or cannulation failure within 12 months of access creation. However, these secondary outcome analyses suggested a significant treatment benefit of fish oil in reducing the rate of AVF interventions. Similar findings were reported in arteriovenous grafts by Lok and colleagues[11], whereby fish oil did not significantly reduce the proportion of AVG thrombosis or interventions to maintain patency but did lead to a clinically meaningful reduction in rates of thrombosis and access interventions. These observations suggest that count outcomes (i.e. rates) are more sensitive to the detection of changes by interventions compared to binary outcomes (i.e. proportions). In addition, a reduction in intervention rates but not in either the proportion of AVFs requiring intervention or time to first intervention suggests that fish oil may be beneficial in reducing recurrent interventions. Interventions, such as angioplasties, thrombectomies and revisions, can increase the risk of recurrent thrombosis and stenosis due to disruption of the endothelial layer and subsequent vasoconstrictive, pro-inflammatory and pro-coagulative responses[18]. The vasodilatory[19], anti-inflammatory[8,9], anti-aggregatory[6,7], and anti-proliferative effects[10] of fish oil may be beneficial in reducing this risk and hence the need for recurrent interventions. Additional studies might further explore the potential benefit of fish oil supplementation in secondary prevention of AVF interventions.

High-dose aspirin given as 1000 mg every other day has previously been shown to reduce access thrombosis within the first 28 days of AVF creation[20]. To minimize the risk of bleeding complications, a lower dose of aspirin (100 mg) was used in the FAVOURED trial. Low-dose aspirin, while not associated with increased bleeding, did not reduce the frequency of access thrombosis during the first 12 months of AVF creation as previously shown[12]. However, similar to fish oil there may be a potential role for low-dose aspirin to reduce intervention rates for access thrombosis that warrants confirmation in larger trials.

Vascular access function is the most frequently reported vascular access outcome but is very heterogeneous with almost 900 measures used to assess the usability and function of an access[5]. These additional analyses from the FAVOURED study provide novel information across a broad range of outcomes related to dysfunction of a newly created AVF including patency loss, need for interventions, CVC exposure, cannulation failure and access abandonment. Patients, caregivers and health professionals all consider the need for access interventions the most important clinical outcome measure of the function of a vascular access[21]. From a patient’s perspective, the number of interventions and intervention-free time have a dramatic impact on their quality of life and well-being because access procedures are burdensome and time-consuming[21,22]. Financial costs associated with AVF procedures account for more than half of the expenditure in the first year of AVF creation even without accounting for secondary expenditure for prolonged hospitalisation or procedure-related complications[3]. It is possible that inexpensive interventions including fish oil or low-dose aspirin to reduce AVF-related procedures may be cost-saving and have a positive impact on the patients’ well-being and warrants evaluation in future studies.

More than a third of participants were unable to use their study AVF for dialysis by 6 months after access creation. This is comparable to the national average of AVF use of 36% in prevalent HD patients of the United States (U.S.)[23] and 39% reported in the U.S. Haemodialysis Fistula Maturation study[24]. Of note, in the North American study investigating the effect of clopidogrel on early fistula thrombosis and dialysis suitability failure[25], 61% of participants were unable to use their fistula reliably for HD. The higher prevalence of cardiovascular disease (25%) and participants of black ethnicity (50%), and the use of a more stringent definition that included a minimum machine blood flow rate of 300 mL/min may have contributed to the higher frequency of dialysis suitability failure in the clopidogrel trial. Neither fish oil nor aspirin in our study, or clopidogrel in the North American study[25], were effective in improving dialysis suitability despite reducing rescue intervention rates and early thrombosis, respectively. Dialysis suitability, while a clinically meaningful and relevant outcome, is multifaceted and not only the result of a complex fistula maturation process but also that of a multidisciplinary team effort comprising different surgical techniques, variations in fistula care and cannulation skills. A single treatment agent may therefore not be sufficient to alter such a complex outcome. Multipronged health service intervention studies that include pharmacological, patient- (e.g. vein preservation, AVF care) and clinician-directed (e.g. surgical technique, cannulation skills, access surveillance) interventions to improve AVF outcomes may be required and warrant further exploration.

Our study addresses multiple clinically meaningful and relevant outcomes to assess AVF function, particularly the need for intervention. However, the study has some limitations that should be considered. Considering the 95% CI, the treatment benefits of fish oil in reducing intervention rates might have been as low as 16% or as large as 76% and a reduction in late dialysis suitability failure by up to 21% cannot be excluded. For enhanced precision in treatment estimates, a larger study would be required. It is possible that fish oil supplementation or aspirin use beyond the first three months may have had prolonged benefits in reducing the need for access interventions or CVCs. Three months of therapy were selected because early thrombosis and physiologic maturation (i.e. AVF flow and vein diameter) typically occur within the first few weeks of AVF creation[26,27]. However, there is significant variability in the time to successful clinical maturation. Studies have shown a range in median time from AVF creation to cannulation of 25 days in Japan to 98 days in the U.S. based on the Dialysis Outcomes and Practice Patterns Study[28]. These observations reflect differences in case-mix, care processes, AVF complications (e.g. infiltrations), and AVF procedures[24] and are not expected to be influenced by fish oil or aspirin use.

Supporting information

Acknowledgments

The authors listed on the first page of this article 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 co-ordinators, research staff and most especially trial participants.

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 [School 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 [Haemodialysis 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 [Department of Renal Medicine, Royal North Shore Hospital, Sydney, Australia], Stephen McDonald [CNARTS, Royal Adelaide Hospital, Adelaide, Australia], Chris McIntyre [London Health Sciences Centre, Ontario, Canada], Trevor Mori [Medical School, RPH Unit, The University of Western Australia, Perth, Australia], Elaine Pascoe [Australasian Kidney Trials Network, The 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, The 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 [Chair; Department of Epidemiology & Preventive Medicine, Monash University, Melbourne, Australia], Andrew Forbes [Statistician; Department of Epidemiology & 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]);

The Investigators: Australia: Australian Capital Territory: The 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]; The 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]; The 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 AKTN Executive Committee Members: Neil Boudville [Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, Australia], Alan Cass [School Menzies School of Health Research, Darwin, Australia], Carmel Hawley [Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia], Meg Jardine [The George Institute of Global Health Australia, Sydney Australia], David Johnson [Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia], Vlado Perkovic [The George Institute of Global Health Australia, Sydney Australia].

The AKTN Project Management Team: Carmel Hawley, David Johnson, Alicia Morrish, Elaine Pascoe, Peta-Anne Paul-Brent, Donna Reidlinger, Liza Vergara [Australasian Kidney Trials Network, The 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 [The George Institute of Global Health Australia, Sydney Australia], Stephane Heritier [Epidemiology & Preventative Medicine, Monash University, Melbourne, Australia].