Meta-analysis shows association between omega-3 FAs and CV outcomes
Effect of omega-3 fatty acids on cardiovascular outcomes: A systematic review and meta-analysisLiterature - Khan SU, Lone AN, Khan MS et al. - EClinicalMedicine 2021, doi:10.1016/j.eclinm.2021.100997
Introduction and methods
Conflicting results of trials evaluating the effect of omega-3 FAs in reduction ASCVD risk (including JELIS, ASCEND, VITAL, REDUCE-IT, STRENGTH, OMEMI) have resulted in uncertainty and debate on the role of omega-3 FAs in CVD risk reduction. It has been suggested that combination of DHA and EPA may counteract the beneficial effects of EPA treatment alone [1,2], because EPA and DHA have different effects on membrane structure and lipid metabolism.
A systematic review and meta-analysis was performed to examine the potential heterogeneity across omega-3 FAs trials, with a focus on effectiveness and safety of omega-3 FAs on fatal on non-fatal CV outcomes. Secondary outcome was the potential variability in effects of EPA vs. combination of EPA and DHA treatment.
Inclusion criteria of trials were 1) RCTs that compared omega-3 FA intake vs. control in adults; 2) follow-up of at least 12 months; and 3) reports of mortality and CV outcomes of interest. Efficacy outcomes of interest in this study were CV mortality, all-cause mortality, non-fatal MI, CHD events, MACE, revascularization, non-fatal stroke, ischemic stroke, and hemorrhagic stroke. Safety endpoints included AF, total bleeding, major and minor bleeding, and gastrointestinal adverse events.
38 Trials encompassing 149,051 patients were included. Four trials compared EPA vs. control and 34 trials compared a combination of EPA and DHA vs. control. Dose of omega-3 FAs ranged from 0.4 g/day to 5.5 g/day. EPA trials had dose ranges from 1.8 to 4.0 g/day and EPA plus DHA from 0.4 to 5.5/day. 22 Trials studied primary prevention. Median follow-up was 2.0 years (IQR: 1-4.2).
- Omega-3 FA was associated with reduced CV mortality (RR 0.93, 95%CI: 0.88-0.98, P=0.01), but not with all-cause mortality (RR 0.97, 95%CI: 0.93-1.02, P=0.27). With EPA monotherapy, there was a reduction in CV mortality (RR 0.82, 95%CI: 0.68-0.99, P=0.04) and EPA plus DHA combination (RR 0.94, 95%CI: 0.89-0.99, P=0.02).
- Omega-3FA was associated with reduced non-fatal MI (RR 0.87, 95%CI:0.81-0.93, P=0.0001) and CHD (RR 0.91, 95%CI: 0.87-0.96, P=0.0002). A larger risk reduction in non-fatal MI was observed with EPA monotherapy (RR 0.72, 95%CI: 0.62-0.84, P=0.00002) than the combination of EPA and DHA (RR 0.92, 95%CI: 0.85-1.00, P=0.05), as well as for CHD events (EPA monotherapy: RR 0.73, 95%CI: 0.62-0.85, P=0.00004; combination of EPA and DHA: RR 0.94, 95%CI: 0.89-0.99, P=0.01, Pinteraction for both endpoints=0.01).
- There was an association between omega-3 FA and reduced MACE (RR 0.95, 95%CI: 0.92-0.98, P=0.002) and revascularization (RR 0.91, 95%CI: 0.87-0.95, P=0.0001). With EPA monotherapy, there was a greater risk reduction in MACE (RR 0.78, 95%CI: 0.71-0.85, P=0.00000001), while combination of EPA and DHA did not reduce MACE (RR 0.99, 95%CI: 0.95-1.02, Pinteraction=0.000005). A consistent effect was observed for revascularization.
- Omega-3 FAs did not reduce non-fatal stroke, though EPA monotherapy was associated with a reduction of non-fatal stroke (RR 0.71, 95%CI: 0.54-0.94, P=0.01).
- There was an association between omega-3 FA and risk of AF (RR 1.26, 95%CI: 1.08-1.48, P=0.004) with a higher risk with EPA monotherapy (RR 1.35, 95%CI: 1.10-1.66, P=0.004). Also, a higher risk of total bleeding with EPA monotherapy was observed (RR 1.49, 95%CI: 1.20- 1.84, P=0.006).
- Omega-3 FAs did not reduce sudden cardiac death, increase GI-related adverse events, total bleeding, or major or minor bleeding.
This meta-analysis of 38 trials showed that omega-3 FAs was associated with reduced CV mortality and other CV outcomes. Moreover, EPA monotherapy was associated with a greater reduction in CV outcomes than the combination of EPA and DHA. When analyzing safety outcomes, omega-3 FAs was associated with increased risk of AF and a greater increase in risk of AF was observed with EPA monotherapy. EPA monotherapy was also associated with higher risk of bleeding.