omega-3 pill decreases cardiac events (REDUCE-IT trial)

A recent trial released at the 2018 Am Heart Assn meetings found that an eicosapentanaenoic acid (EPA) derivative (a fish oil variant) decreased cardiovascular outcomes in patients with high cardiovascular risk, had high triglyceride levels, and were already on a statin with low LDL levels (see cad triglyc reduct benefit nejm2018 in dropbox, or DOI: 10.1056/NEJMoa1812792)

Details:
--8179 patients were enrolled, all with established cardiovascular disease or with diabetes and at least one other risk factor, on statin therapy with LDL 41-100 mg/dL, but had a fasting triglyceride (TG) level of 135-499 mg/dL
--median age 64, 71% male, 90% white, BMI 31, 71% from US/Canada/Netherlands/Australia/New Zealand, 26% Eastern Europe, 100% on statins/6% ezetimibe, 58% diabetes
--71% of the patients were enrolled for secondary prevention, 29% primary prevention of cardiovascular events
--median hs-CRP 2.2 mg/L, TG 217 mg/dL (61% >200 mg/dL), HDL 40, LDL 74
--randomized to 2 g of icosapent ethyl twice daily vs placebo, and followed for a median of 4.9 years
--primary end point: a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina
--secondary end point: a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke

Results:
-- trigylceride levels decreased 18.3% (-39 mg/dL) at 1 yr on treatment, and increased 2.2% in placebo (4.5 mg/dL)
--LDL levels increased 3.1% (2 mg/dL) on meds vs 10.2% (7.0 mg/dL) on placebo
--primary end-point: 17.2% on icosapent ethyl vs 22.0% on placebo group, a 25% reduction, HR 0.75 (0.68 to 0.83), P<0.001); NNT (number needed to treat)=21 over 4.9 years
    --the benefit of the meds started to become apparent at about 2 years, continued to increase til 3 years, then paralleled
--secondary end point: 11.2% vs 14.8%, a 26% reduction, HR 0.74 (0.65 to 0.83; P<0.001); NNT=28 over 4.9 years
--additional prespecified ischemic end points:
    --20% reduction in rate of cardiovascular death (4.3% vs. 5.2%), HR 0.80 (0.66 to 0.98; P = 0.03)
--adverse events:
    --increase in hospitalization for atrial fibrillation or flutter (3.1% vs. 2.1%, P = 0.004); rate of atrial fibrillation was 5.3% vs 3.9%
    --rate of peripheral edema was 6.5% vs 5%
    --increase in serious bleeding events 2.7% vs 2.1% in the placebo group (P = 0.06), and close to statistically significant.
    --but higher rates in the placebo group of: anemia (5.8% vs 4.7%), diarrhea (11.1% vs 9%), and overall GI adverse events (35.1% vs 33.0%) 
--subgroup analysis, for primary end-point:
    --secondary prevention group: 27% reduction, HR 0.73 (0.65-0.81)
    --ezitimibe use: no difference if used or not
    --more benefit in those <65yo (35% decrease) vs >65yo (13% decrease), a statistically significant difference at p=0.004
    --sex, race (though almost all white), diabetes at baseline, baseline eGFR, baseline TG < vs >200 mg/dL, baseline LDL or hs-CRP did not affect primary end-point
--secondary end-point subgroup analysis: not much different
--of note, there was no difference in efficacy if the baseline TG level was >150 vs <150, or >200 vs <200. and no difference if the achieved TG level were < vs > 150mg/dL
--also, no difference in benefit if look at placebo patients who did not increase their LDL levels

Commentary:
-- Icosapent ethyl is a highly purified and stable EPA ethyl ester that has been shown to lower triglyceride levels and is FDA-approved as an adjunct to diet in adult patients who have triglyceride levels of at least 500 mg/dL
-- prior trials of omega-3 fatty acids have had mixed results. eg see http://gmodestmedblogs.blogspot.com/2018/02/fish-oils-cardiovasc-disease-and.html , which reviews a recent meta-analysis finding that in 78K people, there was a likely important (though at the margins of statistical significance) 7% decrease in CAD rates
    --that being said, the numbers above in REDUCE-IT are impressively higher than that.
    --most fish oil preparations are a combination of EPA and DHA (docosahexaenoic acid), though DHA does also increase LDL levels. is the benefit in REDUCE-IT related to the higher dose of EPA or the fact it has only EPA as a "highly purified and stable EPA ethyl ester"
    --another study on fish oils was just released, the VITAL study, (see cad fish oils VITAL study NEJM2018 in dropbox, or DOI: 10.1056/NEJMoa1811403), looking at supplementation of n-3 fatty acids at a dose of 1 gm/d (460mg of EPA and 380mg of DHA) in the primary prevention of cardiovascular disease or cancer, finding no benefit (though some of the results were skewed to benefit, and specific end-points such as total MI was lower) But this was a healthier (though more diverse) population put on a much lower dose of fish oils, using the combo of EPA and DHA; all of these might have made it harder to show benefit over the 5.3 year study.
--icosapent ethyl may have antiinflammatory, antioxidative, plaque-stabilizing, and membrane-stabilizing properties. Of note, neither the triglyceride level either before the intervention nor the achieved TG level on the med seemed to matter, suggesting that lowering triglycerides was not the mechanism.  And this raises the issue of whether this drug should be used more broadly for cardioprotection and independent on the triglyceride level, especially in higher risk individuals [one side issue here is that there is a long-standing debate as to whether high triglycerides are in fact a culprit in ASCVD, or is it the typically associated depressed HDL, or the higher apolipoprotein B, or the small, dense, more atherogenic LDLs, or insulin resistance, or some combo??? And, those with the rare syndrome of isolated hypertriglyceridemia do not seem to be at higher ASCVD risk (eg: see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3431581/ ). This REDUCE-IT study adds to the argument that TGs may be innocent bystanders]
--there are some important findings here:
    --though statins lower the risk of a cardiac event about the same % in those with secondary vs primary prevention, there is a substantial pool of patients with known ASCVD who have a recurrent cardiovascular event despite appropriate statin therapy (the absolute risk is so much higher in those with known ASCVD that the 30% reduction in subsequent cardiovascular events still means lots of people continue to have them). so, any further decrease with other meds is welcome (unless they deplete the federal reserves)
    --in the REDUCE-IT study in particular, they found major benefit even with an achieved median LDL of 74 mg/dL, in patients largely at very high cardiac risk. and on subgroup analysis, even those with LDL <67 had the same benefit as those with >84 mg/dL; and the highest risk group (secondary prevention) had a 27% reduction in events on subgroup analysis
--though this was a pretty large study involving many patients from sites around the world, it is rather unfortunate that there did not seem to be very much racial or ethnic diversity in the participants. Does make generalizability a bit problematic.

so, a pretty impressive study. this study does confirm the multitude of epidemiologic studies finding benefit of a high fish diet. and, with its higher doses of EPA, this study leapfrogs over the meta-analysis of fish oils above (or the VITAL study). it does bring up the generic issue: should we just prescribe this new drug (marketed with brand-name Vascepa, FDA-approved for very high triglycerides, and the funder of the REDUCE-IT study; or Lovaza, which on my internet search seems to fetch >$300/month for 4g/d. and there are pure EPA products on the internet, going for about $50-60/month at the above dose). Or should we just suggest that patients get fish oils and take higher doses. Even if their TG levels are not so high but they are at high risk???  it is a potentially real issue that pure EPA may be better than the mixture of EPA and DHA, since they are different omega-3 fatty acids and they may have pretty different metabolic effects (eg, as mentioned, DHA increases LDL levels). 

bottom line: high dose EPA does seem to have an impressive effect on cardiac outcomes, which seems to be independent of its actual effect on triglycerides. would be really great to have a big study using higher doses of EPA vs combo EPA/DHA (which seems to be more available) in both primary and secondary prevention of cardiovascular disease.

geoff​

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