omega-3 fatty acids and cardiovascular disease

AHRQ (Agency for Healthcare Research and Quality) just released their updated systematic review on omega-3 fatty acids and cardiovascular disease (see https://www.effectivehealthcare.ahrq.gov/ehc/products/609/2261/fatty-acids-cardiovascular-disease-executive-160812.pdf ).

background:

--omega-3 fatty acids (n-3 FA) include both marine oils, predominantly EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) which come from fish, seafood, other ocean life; and ALA (alphalinolenic acid) which comes from vegetable oils (esp soybean, canola and flaxseed oils) and nuts (esp walnuts)

--there are large differences in consumption of these n-3FAs overall: though ALA ingestion is pretty consistent across developed countries at about 0.3-1.0% of energy (in the US it is 0.6%), EPA and DHA consumption vary a lot (0.13 g/d combined in the US, vs 0.4 g/d in South Korea)

--older epidemiological observational studies have found significantly less cardiovascular disease in those on high fish diets. The rates of cardiovascular disease in the US has declined sharply in the past several decades, likely related to more use of statins, antihypertensives and aspirin

results:

--RCTs (essentially all done with marine oils):

    --for many of these trials, there were very mixed results, with a few studies finding efficacy, others none, and the meta-analyses combining them therefore not finding significant benefit

    --all-cause death: 2 of 17 trial found lower all-cause death, others not, so overall no benefit

    --Major Adverse Cardiovascular Events (MACE): 2 of 10 trials found significant reductions, so meta-analysis found no significant benefit

    --total MI: no trials found benefit

    --CVD death: 2 of 7 trial found significant benefit, so meta-analysis found no significant benefit in those with existing CVD

    --sudden cardiac death: no trials found benefit

    --angina: 1 trial found benefit along with statins for unstable angina after 5 years in patients with dyslipidemia, other trials without benefit. Same for heart failure

    --no benefit in RCTs for total stroke death, revascularization, CHD deaths, atrial fibrillation, heart failure deaths

    --BP: no  benefit for blood pressure, in 19 RCTs

    --lipids: many trials. Increase in LDL of 1.98 mg/dL, increase of HDL of 0.92 mg/dL. Triglycerides more complex: each increase in baseline Tg level by 1 mg/dL was associated with a net decrease by marine oils of -0.15 mg/dL; and each increase of EPA+DHA dose by 1 g/d was associated with a greater decrease in Tg of -5.9 mg/L (ie: more effect of marine oils if higher Tg level to start with, and with higher doses marine oils.) And EPA may be more effective than DHA

--observational studies (meta-analysis of 21 studies):

    --CVD death: statistically significant benefit with marine oil intake

    --CHD death: non-significant

    --all-cause death: overall non-significant, but there was decrease in those on high dose marine oil intake. same with CHD itself

    --stroke: significant, and more protective at higher doses of marine oils. Same for ischemic stroke. No change in hemorrhagic strokes

    ​--heart failure: significant benefit of marine oils

--there was insufficient evidence of benefit in studies looking at only EPA or DHA individually (or other n-3FAs DPA, SDA; or if look at marine oils vs ALA (though very few studies looked at ALA, and not many looking at the individual marine oils)

--adverse events: no serious adverse events felt to be related to the study interventions in 25 RCTs.

--overall conclusions

    ​--omega-3 fatty acids raised HDL and LDL a little (<2gm/dL) but did lower triglycerides, more so in those with higher baseline triglyceride levels and higher doses of n-3 FAs, based on RCTs

    --in those at increased risk of cardiovascular disease, RCTs found that omega-3 fatty acids do not change one's risk for: overall major adverse cardiovascular events, all-cause death, sudden cardiac death, coronary revascularization, or atrial fibrillation

    ​--observational studies do find that those with higher intake of fish high in omega-3 fatty acids may lower one's risk of ischemic stroke due to atherosclerosis

    --RCTs and observational studies differ in benefit for cardiovascular death, and total stroke (fatal and nonfatal, ischemic and hemorrhagic stroke) outcomes. RCTs show no benefit, observational studies show some possible benefit.

    

commentary:

--meta-analyses are often hard to interpret. They are usually considered the definitive determination of benefit by including lots more patients and then averaging all of the studies with their individual biases and differing patient characteristics to achieve a real, representative average, and one which might compensate for the individual biases of the different studies. But the reality is that meta-analyses are usually trying to combine mathematically very different studies, often with mathematical correction for comorbidities, etc (eg, propensity scoring). In the above case, the meta-analysis used different n-3 FAs, in different doses, in different patients from different backgrounds, with different comorbidities, and for different follow-up times. So, it might be that an individual well-done study which more closely reflects the patient you are seeing might be much more useful than a meta-analysis which dilutes the effect by adding in other non-applicable studies (which perhaps exclude patients like you are seeing, have too small a dose of n-3FAs, don't last long enough to see an effect....). So, a meta-analysis of 7 trials with 2 showing benefit (as in CVD death above), may be meaningless: perhaps the 2 trials with benefit are much more rigorous, with longer followup, higher dose of meds, etc, are really more useful and applicable than the mathematical combination with less appropriate studies. [another issue, not in the above meta-analysis, is that sometimes a huge study will dwarf many smaller studies by being disproportionately represented in the mathematical combination. The bottom line: don’t just accept the meta-analysis; it is important to look at the individual studies to see if the meta-analysis makes sense to you. And it is not so uncommon that there are almost simultaneous meta-analyses on a subject, printed in different journals, coming out with different conclusions, based on how they do their statistics or which studies they decide to include as appropriate]

--One reason why observational studies and RCTs may differ in their results on omega-3 fatty acids is that almost all of the observational studies were done in healthy populations and almost all of the RCTs were in those at high risk of CVD. And so many people in the US in the high risk group are on statins, antihypertensives, and low-dose aspirin;  these drugs act on metabolic and biochemical pathways that the n-3FAs also impact (anti-lipid, anti-inflammatory, anti-coagulant, improved endothelial function). So the studies on patients at high cardiovascular risk are less likely to show benefit from n-3FAs, since the patients are likely on the above drugs, and any incremental benefit of the n-3’s may have been too small to measure. For low risk patients not on these medications (as in the observational studies), it would take a very long and large study of these patients randomized to n-3 FAs vs placebo to show clinical benefit (the event rate is so low in the short- to moderate-term), and I suspect this study will never happen. The data on intermediate outcomes (lipids, blood pressure) were from both average and high cardiovascular risk populations.

--nonetheless, it is pretty clear to me that n-3 FAs do have a role in those with high triglycerides, and I have had some success in lowering Tg levels in some patients with very high Tg’s. And I do encourage increased fish consumption when possible and do not discourage the use of supplemental fish oil to patients who ask about them (the concern with fatty fish, as mentioned in prior blogs, is that many environmental toxins released into the water are lipid-soluble and concentrated in the fat of fish, eg PCBs, or mercury. So I do encourage eating wild fish, when possible)