13-29% death reduction further benefit was seen in adults utilizing higher doses of omega 3, and in those with higher baseline cardiovascular risk, elevated triglycerides, LDL-cholesterol, and non-statin users.
Results are to some degree in accordance with recent Science Advisory from the American Heart Association suggesting omega 3 use for secondary prevention of coronary heart disease, heart failure, and sudden cardiac death.
Randomized controlled trials investigating use of long chain omega 3 polyunsaturated fatty acids, primarily docosahexaenoic acid and/or eicosapentaenoic acid have shown mixed results. Objectives were designed to update and further explore available randomized controlled trial data regarding LC-OM3 supplementation and risk for cardiac death to propose testable hypothesis for mixed results obtained. Literature search was conducted using PubMed and Ovid/MEDLINE for randomized controlled trials assessing LC-OM3 pharmaceuticals or supplements with interventions periods of 6 months or more reporting outcomes of cardiac death. Meta analysis was conducted to compare cumulative data including sensitivity and subset analyses.
14 RCTS were identified for primary analysis consisting of 71,899 subjects. 1613 cardiac deaths were recorded in the LC-OM3 arms with 1746 in control groups, pooled relative risk estimate shows an 8% lower risk in the LC-OM3 group. Subset analyses showed greater effects of 12.9-29.1% lower risks, supporting LC-OM3 supplementation association with reduction in cardiac death.
Several randomized controlled trials assessed effects of long chain omega-3 polyunsaturated fatty acids supplements on risks for cardiovascular disease, with findings being of mixed results some of which neutral others suggesting benefits. Outcomes for observational evidence on intake or status and randomized controlled trials of supplements shows most consistent associations with cardiac death. Rizos et al conducted a meta analysis of effects of these supplements on outcomes of all cause mortality with the only outcome which the 95% confidence interval didn’t null value was cardiac death with pooled relative risk from 13 randomized controlled trials of 0.91. Findings are in agreement with that from pooled analysis consisting of data from 19 observational cohort studies evaluating biomarkers, coronary heart disease, and assessment of LC-OM3 status using biomarkers.
Purpose of meta analysis and review of research gaps was conducted for two reasons: To update and further explore available randomized controlled trials data regarding LC-OM3 supplementation and risk of cardiac death; and to review evidence regarding effects of LC-OM3 intake in cardiac event risk and propose testable hypotheses for mixed results. Results are supportive of the recent Science Advisory from the American Heart Association concluding LC-OM3 treatment is reasonable for secondary prevention of CHD and sudden cardiac death; and secondary prevention of adverse outcomes in patients with heart failure, low risk for adverse effects make even a modest benefit clinically meaningful, results are consistent with hypothesis that the supplements may be most efficacious for reducing cardiac death in high risk individuals.
Findings are also concordant with those of Alexander et al. findings of coronary death being significantly lower in a pooled analysis of 4 secondary prevention randomized controlled trials of LC-OM3, results do not agree with conclusions of AHRQ systematic review of which only the largest studies were evaluated excluding smaller studies. Alexander et al. additionally analyzed results from cohort studies and reported significantly lower risks for coronary death and sudden cardiac death. Observational cohort studies results suggest that higher LC-OM3 intake is associated with lower risks for nonfatal and fatal CHD events. For cardiac death the aggregate randomized controlled trials and observational evidence is fairly consistent showing benefits of higher LC-OM3 intake, especially in higher risk subjects. Prospective cohort and randomized controlled trials are discordant for the effects of LC-OM3 on nonfatal CHD events.
A large randomized controlled trial in Japan showed statistically significant reductions of 19% in major coronary event risk but no significant reduction in cardiac death. Taken together with current meta-analysis and those of Alexander et al.findings are consistent with hypothesis of higher intakes of LC-OM3 may be required to observe some of the effects that could contribute to lower risks for nonfatal and fatal CHD events.
28% of subjects included in the primary meta-analysis dataset participated in the randomized controlled trials with higher doses. Most of the randomized controlled trials assessing cardiovascular outcomes provided no data on baseline and on-treatment biomarkers of LC-OM3 status, making it not possible to evaluate relationships between baseline or on-treatment LC-OM3 statue and event risk. Additional research is required to assess larger doses on risks with inclusions of biomarker analyses to define both baseline status and change in status during treatment. Mechanisms through which LC-OM3 intake may alter cardiovascular risks have been reviewed in detail. Dose response characteristics for most effects have not been fully described, randomized controlled trials generally have not been designed to test specific mechanism hypotheses.
Recently published meta-analysis of effects of TG lowering drug therapies on cardiac or CVD event risk showed overall benefit in 10 studies as relatively small but was larger in subsets with elevated TGs. 2 ongoing randomized controlled trials are investigating effects of higher doses of LC-Om3 pharmaceutical products on major adverse cardiovascular event rates in high risk subjects with elevated TGs.
Present meta-analysis results are optimistic, studies in which subjects had higher baseline LDL-C or TG concentrations showed greater benefits on incidence of cardiac death than those of overall primary analysis. Higher doses have been shown to increase LDL and HDL particle size in addition to lowering TGs, DHA and EPA showed some differences regarding effects on lipoprotein lipid levels: DHA and EPA lower TGs; DHA raises HDL-C and LDL-C levels; and EPA does neither. Differences in effects in lipoprotein lipids clinical relevance is uncertain.
Current meta analysis of studies involving low statin use larger benefit was shown than in primary analysis. Recent randomized controlled trials have had higher prevalence values for statins and other cardioprotective agents such as aspirin and other pharmaceuticals reflecting changes in standards of care. Overlap in mechanisms of action of some of the agents and pathways affected make it difficult to demonstrate benefit of supplementation, especially at low doses when added to other therapies. Results from present meta-analysis combined with those from Alexander et al. suggest higher risk groups may be more likely to experience reductions in risk for cardiac death with supplementations especially at higher doses.
Limitation of results from the present meta-analysis are that several of the studies included were small or had suboptimal trial designs, such as 2 of the larger trials were not placebo controlled, and raises possibility of bias in ascertainment of event status which is likely to be less of a concern in outcomes of cardiac death than with nonfatal events. Sensitivity analyses and results from observational studies are aligned for cardiac death and suggests lower risk associated with higher LC-OM3 intake.
Present meta-analysis of randomized controlled trials showed modest benefits of LC-OM3 supplementation on risk for cardiac death, supporting recent Science Advisory from the American Heart Association concluding LC-OM3 treatment is reasonable for for secondary prevention of CHD and sudden cardiac death; and secondary prevention of adverse outcomes in patients with heart failure. Because of the low risk for adverse effects even a modest benefit is clinically meaningful.
Subgroup analysis shows larger benefits in studies using higher doses in high risk groups, including those with greater mean or median levels of TG or LCL-C, secondary prevention study samples, and studies with lower baseline use of statins. Results suggest that additional research is required to further investigate potential risk reduction with LC-OM3 supplementation of biomarkers of omega-3 status at baseline and during treatment, studies should be designed to test specific hypotheses about mechanisms through which benefits might be produced.
Four randomized controlled trials evaluating cardiovascular event risks with LC-OM3 interventions are ongoing and should help to provide helpful additional information to guide clinical use of supplementation or drug therapies.
