Effect of fish oil supplementation on graft patency and cardiovascular events among patients with new synthetic arteriovenous hemodialysis grafts: A randomized trial

Abstract

Context

Arteriovenous grafts, an important option for hemodialysis vascular access, are prone to recurrent stenosis and thrombosis.

Objective

To determine the effect of fish oil on arteriovenous graft patency and cardiovascular events.

Design, Setting and Patients

Randomized, double-blind, controlled clinical trial (FISH Study) conducted at 15 North American dialysis centres from November 2003-December 2010 enrolled 201 participants with stage 5 chronic kidney disease (50% female, 63% Caucasian, 53% diabetic) and followed them for 12 months after graft creation

Interventions

Random allocation to daily fish oil capsules (4×1 gram) or matching placebo on day 7 after graft creation.

Main Outcome Measure

The proportion of participants experiencing a graft thrombosis or radiological or surgical intervention during 12 months follow-up.

Results

The risk of the primary outcome did not differ between fish oil and placebo recipients (48/99 [48%] versus 60/97 [62%]; relative risk 0.78 [95% CI, 0.60–1.03; P = 0.064]). However, the rate of graft failure was lower in the fish oil group (3.43 versus 5.95 per 1,000 access days; incidence rate ratio (IRR) 0.58 [95% CI, 0.44–0.75; P < 0.001). In the fish oil group, there were half as many thrombosis events (1.71 versus 3.41 per 1,000 access days; IRR 0.50 [95% CI, 0.35–0.72; P < 0.001); fewer corrective interventions (2.89 versus 4.92 per 1,000 access days; IRR 0.59 [95% CI, 0.44–0.78; P < 0.001), improved cardiovascular event-free survival; hazard ratio 0.43 [95% CI, 0.19–0.96; P=0.035) and lower systolic blood pressure by 12 months (average −3.61 versus + 4.49 mmHg [95% CI −15.4–−0.85]; P=0.014).

Conclusions: D

aily fish oil ingestion did not reduce the proportion of patients with loss of native patency within 12 months of graft creation; however, it did reduce the rate and time to thrombosis, the need for corrective interventions to maintain patency, and was associated with improved cardiovascular outcomes.

Trial registration

controlled-trials.com Identifier: ISRCTN 15838383

Optimal hemodialysis requires a reliable vascular access. Current options include the arteriovenous fistula, synthetic arteriovenous graft (AV-graft), and central venous catheter, which are used in 55%, 21%, and 24% of prevalent US hemodialysis patients, respectively¹. The AV-graft was the predominant vascular access type in North America during the early 1990s but fell out of favor due to its high complication rates and associated costs. For example, thrombosis occurs in >50% of all AV-grafts within 1 year after placement, necessitating a salvage procedure in >75%^2,3. AV-graft thrombosis usually occurs at the venous anastomosis in proximity to a stenotic lesion resulting from aggressive neointimal hyperplasia⁴.

To date, multiple interventions have failed to convincingly or consistently reduce thrombosis rates^5–9. A large, multicenter randomized trial of Aggrenox (dipyridamole plus low-dose aspirin) demonstrated a modest improvement in AV-graft primary patency but poor cumulative AV-graft survival¹⁰. Due to their anti-proliferative, anti-oxidant, and vasodilatory effects, fish oils (omega-3 fatty acids) have theoretical appeal for preventing development of AV-graft stenosis and thrombosis^11–16. Indeed, a small, single-center prospective study of fish oil prophylaxis showed a dramatic (5-fold) improvement in 12 month graft patency¹⁶ and inspired a larger, definitive trial.

We performed a randomized, blinded, controlled trial that compared AV-graft patency and rates of thrombosis and intervention in hemodialysis patients who received oral fish oil supplementation versus placebo following AV-graft creation.

Methods

Sponsor and study oversight

Two peer-reviewed Canadian funding agencies, the Canadian Institutes for Health Research (CIHR) and the Physicians Services Incorporated (PSI) Foundation sponsored the trial. An independent data and safety monitoring committee reviewed the study for safety, data quality, and efficacy using the Lan-DeMets extension of O’Brien-Fleming stopping rules.^17,18 A planned interim analysis was performed after half of the patients were recruited to determine whether the study should be stopped early for safety concerns. Discontinuing the study was deemed unnecessary.

Study Design and Patient Population

This study was a multi-center, randomized, placebo-controlled clinical trial of chronic hemodialysis patients who required a new AV-graft access. Details of the study design have been published¹⁹. Briefly, adult patients (≥18 years old) with end stage renal disease (ESRD) who required a synthetic AV-graft for chronic hemodialysis were eligible. The AV-graft could either be a “first access” ever surgically created or a “subsequent access” after a previously failed access. Major exclusion criteria were reversible renal failure, active malignancy, pregnancy, malignant hypertension, active major bleed in the prior month, receiving >2 antiplatelet agents or anticoagulants (i.e. concomitant use of aspirin and warfarin was not an exclusion), life expectancy < 6 months, surgical revision of a previous access e.g. a jump graft (i.e. the AV-graft under study needed to be a new AV-graft), AV-graft that failed prior to and including postoperative day 7, ingestion of any form of fish oil at time of randomization, allergy to fish or fish products, and enrollment in another interventional AV-graft study.

Patients were enrolled at 12 Canadian and 3 USA sites. The institutional review board of each participating study site approved the study protocol. Each patient provided written informed consent before enrollment. The study was conducted with strict adherence to good clinical practice guidelines and the Declaration of Helsinki, and is registered at Current Controlled Trials (www.controlled-trials.com) ISRCTN: 15838383.

Study Procedures

The study was initiated in November 2003; enrollment closed in December 2009. Patients were randomized (1:1) with concealed allocation to the two treatment groups after the 7^th post-operative day of their AV-graft creation by a central, independent randomization facility. Patient randomization was stratified by site and “first access” or “subsequent access”. Patients were assigned to ingesting 4 × 1 gram fish oil capsules or 4 × 1 gram matching placebo capsules to be taken daily for the 12-month duration of the study. The study capsules (fish oil or placebo) were 1-gram soft gel capsules that were steam deodorized and flavored with 1% peppermint. The fish oil was MEG-3® (Ocean Nutrition Canada Ltd) which contains 48% (400 mg/capsule) eicosapentaenoic acid (EPA) and 25% (200 mg/capsule) docosahexaenoic acid (DHA). The placebo capsule consisted of 1% peppermint flavored corn oil and was packaged identically to the fish oil. The placebo and fish oil capsules resembled each other in color, shape, odor, taste and consistency.

Patients, study coordinators, caregivers, and site pharmacists were blind to treatment allocation. Only the study independent clinical trials pharmacist that packaged the study treatment had access to the randomization assignment.

Patients initiated study treatment after randomization on day 7 following their graft creation surgery date. Baseline characteristics were collected using established definitions, where available, such as ethnicity^20,21. They were monitored biweekly with increased frequency as clinically indicated. All sites were required to abide by local graft surveillance and/or monitoring protocols that were based upon national guidelines and available evidence ^22–26. For example, Canadian sites that performed routine flow surveillance followed Canadian national guidelines for intervention; thus when AV-graft flows fell by >20% from its baseline or to <650 ml/min, and there was a clinical abnormality, a follow up angiogram was required²⁷. If the angiogram disclosed a stenotic lesion of >50%, an angioplasty was attempted. An angiogram without any intervention to change the vascular access anatomy (i.e. angioplasty, stent, revision) was not considered an endpoint. Of note, participating sites could not change their policy for graft surveillance and/or monitoring in study patients throughout the duration of the trial. Compliance with ingestion of study capsules was assessed by measurement of EPA incorporation into endogenous cells by gas-liquid chromatography (OnLine Appendix 1).

Outcomes

The pre-defined primary study endpoint was the proportion of AV-grafts with loss of native patency within 12 months. Loss of native patency was defined as the AV-graft having a primary event of thrombosis or requiring a radiological or surgical intervention following its creation. If a radiological or surgical intervention occurred, an independent assessor, unaware of treatment allocation, reviewed the radiology or surgical reports to verify the outcomes.

Major secondary endpoints included the rate (events per 1,000 access days) and proportion of AV-graft thrombosis and radiological or surgical interventions, the time to each event, and cumulative AV-graft patency. Time to loss of native patency is also known as primary unassisted-patency²⁸. Cumulative AV-graft patency was defined as the time from AV-graft creation to unsalvageable AV-graft loss (when the graft was abandoned). The occurrences of minor and major bleeding episodes, changes in lipid status and blood pressure, hospitalizations for cardiovascular events, and death were determined. All endpoints reported were prespecified²⁹. Follow-up continued for 12 months regardless of whether the patient reached the primary outcome (to achieve the secondary objectives); patients were censored at kidney transplantation or transfer to a non-study facility.

Statistical Analysis

Recruitment of 232 patients (116 AV-grafts/group) was initially planned to detect a 30% reduction in the proportion of patients with loss of native patency (from 68% to 47.5%) with 80% power, using a two-sided statistical test with alpha of 0.05, and adjusted for a 12% patient loss and non-adherence to study treatment. This sample size was based on results from an earlier study that demonstrated an improvement in 12 month AV-graft patency from 14.9% to 75.6%¹⁶. Additionally, Canadian pilot data demonstrated loss of AV-graft patency to be 68% at 12 months²⁹ Due to a paucity of data at the study design phase, a 30% reduction in loss of AV-graft patency was deemed more conservative than previously observed¹⁶ and feasible from a study standpoint. If the accrual goal of 232 patients is reduced to the observed 201 patients, then the study’s power would decrease from 80% to 74%.

While both are clinically relevant endpoints, we chose a proportion primary endpoint (proportion with loss of native patency) rather than a Poisson primary endpoint (events per 1,000 days) because we could not confirm a priori that the distribution of AV-graft events would follow a Poisson distribution. The time to event endpoint was deemed to have less clinical importance from a patient perspective. Thus, the proportion endpoint was chosen as the primary endpoint and the rate of events and time to event endpoints were classified as clinically important secondary clinical endpoints. We assessed proportions, their confidence intervals and their differences using Fisher’s exact test³⁰ and compared groups using relative risk and logistic regression.³¹ Outcomes reporting the number of events per 1,000 access days were analyzed using Poisson distribution methods³² and comparisons between groups used the incidence rate ratio from a Poisson regression.³³ Quantitative values were compared between groups using the Wilcoxon rank-sum test or t-test depending on distribution. Time-to-event distributions and their confidence intervals were estimated using the Kaplan-Meier method and groups were compared using the log-rank test and hazard ratio from the Cox proportional hazards model.³⁴

Analyses were based on an intention-to-treat approach, except for the exclusion of five randomized, blinded participants who did not remain on the study long enough to get to the point where treatment would be started (Figure 1). A P-value <0.05 was considered statistically significant. All P-values are two-sided and are unadjusted for multiple comparisons, except where noted. When adjusted for multiple endpoint analyses a Bonferroni adjustment³⁵ was utilized. Analyses were performed using STATA, version 10.0 (StataCorp, College Station, Texas).

Figure 1.

Study enrollment and follow-up

Results

Study population

We assessed 497 patients for eligibility, of whom 201 were randomly assigned to fish oil capsules (101 patients) or placebo (100 patients) (Figure 1). The most common reason for ineligibility was patient refusal and creation of a fistula rather than AV-graft. There were 5 protocol deviations that occurred whereby patients were erroneously randomized (e.g. received a fistula rather than a graft) before post operative day 7, but none of them received study intervention (see Figure 1). Patient demographics and graft characteristics were well balanced between the two treatment groups (Table 1) except more patients in the fish oil group had a history of congestive heart failure (P=0.03). While not statistically significant, more patients in the fish oil group had forearm AV-grafts (P = 0.13). Both congestive heart failure and a forearm AV-graft location are factors known to increase the risk of thrombosis^36–38.

Table 1.

Patient demographics and baseline characteristics

Characteristic	Fish Oil (N = 99) [% patients]	Placebo (N = 97) [% patients]
Mean age in years (range)	62.5 (28–88)	63.4 (27–87)
Male sex	47 [47]	51 [53]
Ethnicity: Caucasian	64 [65]	59 [61]
Black	16 [16]	15 [15]
South Asian1	5 [5]	7 [7]
Southeast Asian2	9 [9]	7 [7]
Other3	5 [5]	9 [9]
Etiology of end stage renal disease
Diabetes	49 [49]	39 [40]
Glomerulonephritis	14 [14]	22 [23]
Hypertension	27 [27]	21 [22]
Tubulointerstitial disorders	1 [1]	2 [2]
Cystic or Hereditary disorders	2 [2]	5 [5]
Other/unknown	6 [6]	8 [8]
Hemodialysis duration in years (range)	2.76 (0–34)	2.84 (0–25)
Comorbidities
Diabetes	51 [52]	52 [54]
Hypertension	84 [85]	84 [87]
Coronary artery disease	32 [32]	34 [35]
Peripheral vascular disease	17 [17]	12 [12]
Congestive heart failure	26 [26]	13 [13]
Cerebrovascular Disease	12 [12]	15 [15]
Current or prior smoker	57 [58]	50 [52]
History of malignancy	14 [14]	12 [12]
Mean Lipids (range)4: Baseline LDL	1.81 (.14–4.52)	1.79 (.20–5.24)
Baseline Total Cholesterol	3.76 (1.78–6.17)	3.66 (.93–8.29)
Baseline Triglyceride	2.06 (.47–6.46)	1.80 (.40–7.8)
Medications: Lipid lowering agent	67 [68]	55 [57]
Aspirin	57 [58]	51 [53]
Warfarin	26 [26]	20 [21]
Clopidogrel	11 [11]	13 [13]
Dipyridamole and aspirin	0 [0]	1 [1]
Prior Access	63 [64]	63 [65]
Mean number of prior accesses (range)	1.1 (0–5)	1.2 (0–7)
Number >=2 prior accesses	26 [26]	27 [28]
Number with prior fistulas	73 [74]	72 [74]
Predialysis graft creation	17 [17]	12 [12]
Graft location: Upper arm	34 [34]	43 [44]
Forearm	61 [62]	49 [51]
Leg	4 [4]	5 [5]
Graft configuration: Loop	71 [72]	70 [72]
: Straight	28 [28]	27 [28]

¹South Asian: including patients of East Indian, Pakistani, and Punjabi origins; also known as “Indian sub-continent”

²Southeast Asian: including patients of Chinese, Japanese, Korean, and Indo-Chinese origins

³Others: including patients of Aboriginal, Arabic, Hispanic, Polynesian, mixed, or unknown ethnic origins

⁴ mmol/L

Due to slower than expected recruitment¹⁹ and lack of additional funds to continue the study, enrollment was terminated prematurely at 201 patients. The last patient completed study follow-up on December 15, 2010.

Study Outcomes

There was no significant difference in the proportion of fish oil recipients with loss of native patency compared to placebo recipients (48% (48/99) versus 62% (60/97), relative risk (RR) 0.78 [95% CI, 0.60 to 1.03], P = 0.064, Table 2). However, the rate of these events was significantly lower in the fish oil group (3.43 versus 5.95 per 1,000 access days, incidence rate ratio (IRR) 0.58 [95% CI, 0.44 to 0.75], P < 0.001, Table 2). The frequency of thrombosis events was reduced by half (1.71 versus 3.41 per 1,000 access days, IRR 0.50 [95% CI, 0.35 to 0.72], P < 0.001) and the frequency of corrective interventions was lower in the fish oil group (2.89 versus 4.92 per 1,000 access days, IRR 0.59 [95% CI, 0.44 to 0.78], P < 0.001). All three rate comparisons (loss of native patency, thrombosis events and corrective interventions) per 1,000 access days remained statistically significant after adjusting for multiple endpoint analyses (P < 0.001).

Table 2.

Study Outcomes

Outcomes	Fish Oil [95% CI]	Placebo [95% CI]	Group comparison [95% CI] (P-value)
Primary study outcome: Proportion of patients with loss of native patency1	48/99 (48%) [0.38–0.59]	60/97 (62%) [0.51–0.72]	2 RR = 0.78 [0.60–1.03] (0.064)
Secondary and tertiary AV-graft outcomes:
Primary event rate: primary events3 per 1,000 access days	3.43 [2.78–4.19]	5.95 [5.00–7.03]	4 IRR = 0.58 [0.44–0.75] (<0.001)
Primary unassisted patency at 12-months (without loss of native patency)	0.48 [0.38–0.58]	0.32 [0.23–0.43]	5 HR = 0.68 [0.46–0.99] (0.045)
Cumulative patency at 12-months	0.72 [0.62–0.80]	0.65 [0.54–0.74]	5 HR = 0.76 [0.46–1.27] (0.30)
Thrombosis events
Proportion of patients with at least one thrombosis event	33/99 (33%) [0.24–0.44]	45/97 (46%) [0.36–0.57]	2 RR = 0.72 [0.49–1.04] (0.080)
Thrombosis rate: thromboses per 1,000 access days	1.71 [1.26–2.27]	3.41 [2.70–4.24]	4 IRR = 0.50 [0.35–0.72] (<0.001)
Thrombosis–free at 12-months	0.64 [0.53–0.73]	0.47 [0.36–0.58]	5 HR = 0.62 [0.39–0.97] (0.033)
Radiological or surgical interventions
Proportion of patients with at least one intervention	38/99 (38%) [0.29–0.49]	48/97 (49%) [0.39–0.60]	2 RR = 0.78 [0.55–1.09] (0.15)
Intervention rate: interventions per 1,000 access days	2.89 [2.30–3.59]	4.92 [4.06–5.90]	4 IRR = 0.59 [0.44–0.78] (<0.001)
Intervention-free at 12-months	0.56 [0.44–0.66]	0.38 [0.27–0.50]	5 HR = 0.68 [0.44–1.03] (0.069)
Cardiovascular Outcomes7
Proportion of patients with at least one cardiovascular event	9/99 (9%) [0.04–0.17]	17/97 (18%) [0.11–0.27]	2 RR = 0.52 [0.22–1.17] (0.10)
Cardiovascular event rate: events per 1,000 access days	0.39 [0.20–0.70]	0.95 [0.59–1.44]	4 IRR = 0.41 [0.20–0.85] (0.017)
Cardiovascular event-free at 12-months	0.88 [0.77–0.93]	0.75 [0.63–0.84]	5 HR = 0.43 [0.19–0.96] (0.035)
Blood pressure and anti-hypertensive medications
Mean change in SBP from baseline to 6 months	−5.11 [−9.90–−0.33]	+2.63 [−1.8–7.02]	6 Mean = −7.74 [−14.2–−1.30] (0.018)
Mean change in SBP from baseline to 12 months	−3.61 [−8.73–1.52]	+4.49 [−0.72–9.71]	6 Mean = −8.10 [−15.4–−0.85] (0.014)
Mean change in DBP from baseline to 6 months	−3.85 [−6.56–−1.13]	+0.63 [−2.04–3.29]	6 Mean = −4.47 [−8.25–−0.70] (0.044)
Mean change in DBP from baseline to 12 months	−2.17 [−4.77–0.42]	+0.13 [−2.43–2.68]	6 Mean = −2.30 [−5.91–1.31] (0.13)
Proportion of patients who had at least one reduction in dose or frequency of anti-hypertensive medications	63/99 (64%) [0.53–0.73]	41/97 (42%) [0.32–0.53]	2 RR = 1.51 [1.13–2.01] (0.004)
Mean reduction in number of anti-hypertensive medications	1.68 [1.25–2.10]	0.62 [0.37–0.87]	6 Mean = 1.06 [0.57–1.55] (<0.001)

¹Experienced at least one of thrombosis or radiological intervention or surgical intervention

²Relative risk group comparison, Fisher’s exact test P-value

³Primary event is a thrombosis or radiological intervention or surgical intervention

⁴Incidence rate ratio (IRR) group comparison of fish oil relative to placebo, Poisson regression P-value

⁵Hazard ratio group comparison, Log-rank test P-value

⁶Mean change from baseline to 6 and 12 month values are reported; Wilcoxon rank sum test P-value

⁷Stroke, peripheral vascular disease, myocardial infarction, congestive heart failure, cardiac related death

The 12-month event-free rate (ie. without AV-graft loss of native patency )was 48% in the fish oil group, as compared with 32% in the placebo group (hazard ratio (HR) 0.68 [95% CI, 0.46 to 0.99], P = 0.045, Table 2 and Figure 3). The median time to loss of native patency was 354 versus 176 days, respectively. The 12-month thrombosis-free rate was higher in the fish oil group (64% versus 47%, HR 0.62 [95% CI, 0.39 to 0.97], P = 0.033). There were no significant interactions between the baseline AV-graft status (first or subsequent access) (P = 0.86) or study site and treatment assignment (P = 0.90). There was no significant difference between the treatment groups with respect to cumulative graft patency; in the fish oil group, 28% had lost their AV-graft by 12 months as compared to 35% of patients who received placebo (HR 0.76 [95% CI, 0.46 to 1.27], P = 0.30, Table 2).

Figure 3. Time to loss of native graft patency (Primary unassisted patency) (Panel A), Thrombosis-free graft survival (Time to thrombosis) (Panel B), Intervention-free graft survival (Time to intervention) (Panel C) and Cardiovascular event-free (Time to cardiovascular event) (Panel D).

Kaplan-Meier estimates of time to first loss of native graft patency, time to first thrombosis, time to first radiological or surgical intervention, and time to cardiovascular event. Median time to primary unassisted patency was 354 days in the fish oil group and 176 days in the placebo group.

The reasons for AV-graft loss were similar between treatment groups, and were: thrombosis (81.4%), technical cause (surgical or cannulation injury) (3.4%), steal syndrome, (5.1%), infection (8.4%), and pseudoaneurysm (1.7%)

Analysis of cardiovascular outcomes demonstrated superior cardiovascular event-free survival in the fish oil group (HR 0.43 [95% CI, 0.19 to 0.96], P = 0.035, Table 2 and Figure 3). Compared with baseline, at 6 months in the fish oil group there were clinically significant reductions in systolic blood pressure (mean decrease of 5.11 mmHg [95% CI, −9.90 to −0.33], Table 2) that was sustained to 12 months (Table 2). Sixty–four percent (63/99) of patients in the fish oil group compared with 42% (41/97) of patients in the placebo group had at least one reduction in the dose or frequency of their antihypertensive medication(s) (RR 1.51 [95% CI, 1.13 to 2.01], P = 0.004). Additionally, patients who received fish oil were able to reduce the number of antihypertensive medications (mean reduction of 1.68 [95% CI, 1.25 to 2.10]) compared with the placebo group (mean reduction of 0.62 [95% CI, 0.37 to 0.87]) for a mean difference of 1.06 between the two treatment groups ([95% CI 0.57 to 1.55], P < 0.001).

No between-treatment differences were seen in serum levels of LDL, total cholesterol or triglycerides. There was no difference in bleeding (9 in fish oil versus 8 in placebo; P > 0.99) or other significant clinical adverse events between the two treatment groups.

Compliance

At baseline, there was no difference in omega-3 fatty acid composition between the treatment groups (see Online-only Appendix Table 1). A significant difference in EPA incorporation into endogenous cells was found between the treatment groups at 3 months (a mean increase of 1.76 in the fish oil group versus a mean decrease of 0.45 in the placebo group, mean difference of 2.21 [95% CI 1.65 to 2.77], P < 0.001, Appendix Table 1), confirming both compliance and evidence that the fish oil formulation was sufficient to modify lipid composition of endogenous cells.

Comments

Our study of hemodialysis patients receiving a new AV-graft showed that the proportion with an AV-graft thrombosis or a radiological or surgical intervention did not significantly differ between fish oil and placebo recipients. However, fish oil recipients had a prolonged time without thrombosis, half the thrombosis rate, and a clinically meaningful reduction in frequency of radiological and surgical interventions to maintain AV-graft patency. Important other findings include an improved cardiovascular event-free survival and rate, improved blood pressure and a reduction in antihypertensive medications in the fish oil group. Overall, the primary endpoint, a binary measure of whether a patient had a graft thrombosis or needed a corrective intervention, failed to be significant; yet it should be considered in the context of other clinical measures that present a consistent trend of benefit associated with fish oil.

Better AV-graft outcomes have been demonstrated in an earlier trial of fish oil prophylaxis in 24 patients, which demonstrated a dramatic reduction in AV-graft thrombosis (24.4% with fish oil versus 85.1% with placebo¹⁶.). While this trial was small with limited generalizability¹⁶, it provided an important basis for our study. A second study randomized 29 patients with new forearm loop grafts to over-the-counter omega-3 fatty acids (0.96 g EPA/day and 0.6 g DHA/day) versus placebo and did not observe any difference in 8 month AV-graft patency³⁹. In addition to the small sample size, the lower doses of EPA and DHA might have contributed to lack of effect.

The fish oil used in our study had strict quality control with a minimum daily delivery of 1.6g EPA and 0.8 g DHA (EPA: 400mg/capsule and DHA: 200 mg/capsule)¹⁹. The EPA and DHA components of fish oils have been shown to have anti-proliferative, anti-oxidative and vasodilatory effects¹⁹ that may impact the pathogenesis of AV-graft stenosis. For example, EPA reduces platelet aggregation in hemodialysis patients⁴⁰, decreases serum viscosity³⁶ and may directly inhibit neointimal hyperplasia, which is the usual cause of AV-graft stenosis⁴.

The use of AV-grafts has declined over the last 10 years^37,38, largely driven by the emphasis on fistula use. AV-grafts may be suitable for hemodialysis patients whose veins are unsuitable for fistula creation or who have had prior problems with fistula non-maturation. However, compared to functioning fistulas, AV-grafts may require a 3 to 4 fold higher frequency of interventions to maintain equivalent long-term patency.^41–43. Identification of safe and inexpensive agents that prolong AV-graft patency and reduce the frequency of interventions to salvage AV-graft complications might encourage their increased use. Previous multi-center randomized studies using warfarin, aspirin plus clopidogrel, or dipyridamole plus aspirin^8–10 have observed limited improvement in AV-graft longevity but did not assess the rate of complications or interventions to maintain AV-graft longevity.

Large cohort studies have shown an inverse association between cardiovascular morbidity and mortality and fish oil ingestion.^44,45 Fish oil may reduce cardiovascular events by multiple mechanisms, including anti-inflammatory, anti-arrhythmic, plaque stabilizing and improved endothelial effects.^46,47 Although some have suggested that fish oil might also improve dyslipidemia,^16,48 we did not find any effect on lipid profile. However, fish oil recipients had better control of blood pressure despite reductions in the dose, frequency and pill burden of antihypertensive medications.

Our study has limitations that should be considered. First, we did not reach our enrollment goal. Perhaps due to lower than expected statistical power, we did not identify a significant difference for the primary endpoint. However, fish oil exerted a significant beneficial effect on several important and clinically relevant secondary endpoints. In retrospect, our choice of primary endpoint may not have been optimal since it yielded lower statistical power than potential alternatives. However, it was selected based on the available data at the time of study design. Lastly, the cardiovascular benefits seen in this study should be interpreted with caution, given the small number of participants and a resulting p-value that did not account for multiple comparisons. However, the use of fish oil to prevent cardiovascular events in the dialysis population should be studied further.

Conclusions

Among patients with new hemodialysis grafts, daily fish oil ingestion compared with placebo did not decrease the proportion of AV-grafts with loss of native patency within 12 months. However, fish oil secondarily prolonged AV-graft patency and reduced the rate of thrombosis and frequency of needed radiological or surgical interventions. An improvement in cardiovascular outcomes and blood pressure was also observed that require further confirmatory study.

Figure 2. Frequency of AV-graft Events.

95% confidence intervals are given.