Our systematic review and meta-analysis assessed the effect of omega-3 fatty acids on all-cause mortality and coronary artery restenosis following PCI among high-risk cardiovascular patients. Omega-3 fatty acids were not associated with a statistically significant reduction in all-cause mortality or restenosis but the probability of a modest benefit remains considerable. Omega-3 fatty acids also had generally favorable effects on other cardiovascular outcomes, but definitive conclusions are not forthcoming due to the small number of studies that reported these outcomes. Unfortunately, the majority of trials did not systematically record adherence and side effects. Nevertheless, the available data suggest a favorable side-effect profile.
Our meta-regression identified some important sources of heterogeneity among mortality trials, including trial size and follow-up time. Specifically, larger and longer trials had smaller mortality benefits, suggesting that the overall observed benefit may be at least partially inflated due to bias. Similarly, restenosis benefits were smaller in larger, better quality trials. These findings temper our enthusiasm for this intervention despite a relatively favorable risk profile. Definitive results about the efficacy and safety of omega-3 fatty acid supplementation will benefit from the results of currently ongoing clinical trials, including ORIGIN [58
] and ASCEND [59
The effect of omega-3 fatty acids has been examined in previous systematic reviews and meta-analyses. However, these earlier meta-analyses [19
] were not limited to high-risk cardiovascular patients, included a scientifically questionable study [51
], did not have access to the most recently published large studies of 15,000 high-risk cardiovascular patients [47
], and importantly, did not explicitly investigate potential sources of heterogeneity which permits a more nuanced interpretation of the totality of evidence. Our results are similar to previous focused meta-analysis examining restenosis [62
] and ICD shocks [61
]. However, our credible intervals are slightly wider as our Bayesian methods account for uncertainty in the between-study variability.
Strengths and Limitations
Our systematic review and meta-analysis has a number of strengths. First, it provides a complete and comprehensive review of the current state of the omega-3 fatty acid literature. In several cases, the published data of this systematic review have been complimented by additional data furnished by the principal investigators of the original studies. Second, our Bayesian models, unlike their frequentist counterparts, allow for the calculation of probabilities and therefore have a more intuitive and informative interpretation. Third, our systematic review and meta-analysis was conducted according to a pre-specified protocol, including pre-specified subgroup analyses, and without language restrictions. Fourth, we have addressed not only the efficacy but also the safety of omega-3 fatty acids. Finally, although previous reports have discussed the role of heterogeneity in the literature [64
], we examined the sources of heterogeneity analytically. Consequently, we have provided a thorough and methodologically rigorous synthesis of the available evidence thereby facilitating informed decision making.
Nevertheless, our systematic review and meta-analysis does have potential limitations. First, as is true with all systematic review and meta-analyses, our study may be affected by publication bias, although we did not find evidence of its occurrence. Second, there was some heterogeneity in study design, including in dosage of omega-3 fatty acid used and patient populations. In particular, there is much uncertainty regarding the potency and purity of over-the-counter formulations while the proprietary formulation is both expensive and has been infrequently used in the clinical trials. Moreover, the control groups were exposed to varying amounts of fish oils according to national dietary habits, and we could not account for this variability. Our random-effects models attempt to account for between-study variability, and the effects of this heterogeneity were examined in our meta-regression models. Third, safety data were not reported in all studies. Fourth, due to the fish odor of omega-3 fatty acid supplements, complete blinding of fish oil studies may not be feasible. This imperfect blinding was not considered in our quality assessment. Fifth, most restenosis studies only presented data among those who completed their follow-up angiogram. Consequently, restenosis data were generally analyzed using a modified intention-to-treat, which may result in biased results. Finally, due to the lack of individual-level data, we were not able to estimate the change in risk of mortality or cardiovascular outcomes over time. We therefore assumed that the risk of the outcome remained the same across the duration of each study and that any censoring was random. Availability of individual-level data would also have allowed us to estimate the effect of patient-level covariates and to examine which subgroups may derive the greatest benefit from the use of these agents.