In this systematic review and meta-analysis of omega-3 PUFA in adults with peripheral arterial disease, we found no evidence to suggest a protective association between omega-3 PUFA supplementation and clinical cardiovascular outcomes, including myocardial infarction, cardiovascular death, angina, stroke, amputation, revascularization, pain-free walking distance or quality of life. One trial indicated that omega-3 PUFA intake may be associated with increased gastrointestinal side effects.
The effect of omega-3 PUFA supplementation in cardiovascular disease is controversial. Some reviews and meta-analyses have demonstrated reductions in adverse events with both plant-based ALA and marine-sourced EPA and DHA supplementation in cardiovascular [9–14, 39] and cerebrovascular disease , and marine omega-3 PUFA may be effective in preventing atrial fibrillation after cardiac surgery [41, 42], although this finding remains controversial . Other reviews have demonstrated mixed [6, 15–18] or no benefits [19–21] following marine and/or plant-based omega-3 PUFA supplementation. In peripheral arterial disease populations, supplementation with EPA and DHA has been shown to significantly reduce measures of arterial stiffness in several cohorts, including healthy and overweight individuals, and individuals with cardiovascular risk factors, type 2 diabetes, or hypertension [23–25, 44]. Even so, adequate long-term data on serious adverse events in peripheral arterial disease populations is lacking.
In this review, the small number of trials available and the lack of uniformity in population and design of the included trials contributed to the relatively high statistical heterogeneity for some outcomes, and thus caution must be exercised in interpreting these results. Some of the key differences among the included trials included geographic differences (e.g., the Japanese population’s omega-3 PUFA consumption is up to 15 times greater than in Western countries [45, 46]), variable intervention durations (from 16 weeks up to several years), differences in doses of omega-3 PUFA (doses of 0.13 g/day DHA and 0.2 g/day EPA are probably too low to have an effect), and concomitant statin and vitamin therapy in some trials (which may have provided beneficial effects on cardiovascular function ). Finally, the potential influence of the trial sponsor should also not go unnoticed as trials conducted by Carrero et al. [35, 36] were sponsored by the manufacturers of omega-3 PUFA.
Only two of the included trials [37, 38] supplied therapeutic omega-3 PUFA doses of >1 g/day, according to the recommendations from the American Heart Association and the World Health Organization [48, 49]. Subgroup analyses suggest that a longer period of treatment (6 months or longer) even at a low omega-3 PUFA dose may improve walking distance. This exploratory finding must be confirmed in future studies. It should also be noted that only two trials [34, 37] reported on adverse side effects: while the trial by Gans et al.  reported no significant adverse effects, half of the individuals in the omega-3 PUFA group in the trial conducted by Leng et al.  experienced gastrointestinal upset. Growing recognition for nutritional components and supplements as therapeutic agents highlights the need for thorough safety testing during clinical trials.
The internal validity of the trials was often unclear due to underreporting of methods, which potentially could have biased the results. All of the trials rated poorly in the risk of bias assessment, mostly due to a lack of detailed reporting and uncertainty around the true effect of omega-3 PUFA alone (Table 3). If meaningful and reliable results are to be obtained from future randomized controlled trials, substantial improvements in trial design must be made to reduce the risk of bias, ensure sufficient statistical power, and test for the effect of omega-3 PUFA without confounding factors.
Strengths of this review include the broad bibliographic screening of multiple citation databases and trial registries, and rigorous testing for bias. We focused on patient-centred outcomes and evaluated efficacy in the context of relevant side effects. We used an a priori published protocol and followed established methodological guidelines in the conduct and reporting of this review. It should be noted that the results of the recent update to the Cochrane review on omega-3 PUFA supplementation in individuals with intermittent claudication  are in agreement with our findings, with very little indication for recommending omega-3 PUFA as a therapeutic approach in individuals with peripheral arterial disease. However, the focus of the Cochrane review was primarily on marine omega-3 PUFA, and the presence of ALA in some of the interventions was not acknowledged.
Limitations of this review include the restricted amount of clinical outcome data available for pooling among trials, which may have affected the overall findings. We chose to pool data from trials that were variable in intervention design and population.