Prescription Icosapent Ethyl vs Mixed EPA and DHA Products: Why Trial Results Differ
Why trial results differ for prescription EPA-only icosapent ethyl and mixed EPA and DHA products: ingredients, comparators, patients and safety. Clinician-led; not dosing advice.
Content last updated . This page has not been medically reviewed.
What the two products are
NCCIH says prescription omega-3 products have a composition that is not the same as typical omega-3 supplements, and that testing and regulation differ, so effects may not be the same. [3]| EPA-only (icosapent ethyl) | Mixed EPA and DHA (omega-3-acid ethyl esters) | |
|---|---|---|
| What the label says | An ethyl ester of EPA [1] | Ethyl esters of omega-3 fats, principally EPA and DHA [2] |
| Labeled use | Adjunct to reduce triglycerides in severe hypertriglyceridemia (500 mg/dL or higher); the label also lists a cardiovascular-risk use with statin therapy [1] | Adjunct to diet to reduce triglycerides in adults with severe (500 mg/dL or higher) hypertriglyceridemia [2] |
Dosing is set by the prescriber and label; this page does not give amounts to take.
Why trial results differ
Labels: trial outcome (heart events), biomarker (blood measure only).| Trial | Product and comparator | What it found | Label |
|---|---|---|---|
| REDUCE-IT | 4 g a day of icosapent ethyl (2 g twice daily) vs placebo, 8,179 statin-treated people with triglycerides 135 to 499 mg/dL, median 4.9 years [4] | Primary events 17.2% vs 22.0% (hazard ratio 0.75). Atrial fibrillation hospitalizations 3.1% vs 2.1%. Serious bleeding 2.7% vs 2.1% (P=0.06). Funded by Amarin Pharma. [4] | Trial outcome |
| STRENGTH | 4 g a day of an EPA and DHA carboxylic acid formulation vs corn oil, 13,078 statin-treated people, median triglycerides 240 mg/dL [5] | Primary events 12.0% vs 12.2% (hazard ratio 0.99); gastrointestinal events 24.7% vs 14.7%. Stopped early for low probability of benefit. [5] | Trial outcome |
The trials differ in more than the ingredient: the EPA-only trial used a placebo (a mineral oil, per a review that discussed it) and the EPA and DHA trial used corn oil, which was meant to be inert. [6] [5] A review of mineral oil as placebo noted that interest arose from suggestions it might have inflated REDUCE-IT's results, and several of its authors list Amarin Pharma, which funded REDUCE-IT, as their affiliation, so read it as one side of an ongoing debate. [6] Enrolled patients and the particular EPA and DHA formulation also differed, and STRENGTH used a carboxylic acid form, not the ethyl-ester mixed product above.
A 2024 meta-analysis of 15 trials said the cardiovascular benefit of omega-3 fatty acids was primarily attributable to prescription EPA ethyl ester, and also found more atrial fibrillation. [7] Another analysis of seven large trials linked marine omega-3 to more atrial fibrillation, with a higher hazard in trials testing more than 1 g a day. [8]
Proper evidence not found for a randomized head-to-head trial of EPA-only against EPA plus DHA in the sources we read. We searched PubMed for icosapent ethyl vs mixed EPA and DHA comparisons. So we cannot say whether the ingredient, the comparator, the patients or chance explains the different results.
Not the same as over-the-counter products
Results from these medicines should not be applied to fish oil capsules, krill oil or algal oil, and the reverse. See Fish and heart attacks: VITAL, REDUCE-IT and STRENGTH and omega-3 and triglycerides. EFSA (EU, 2012) found the data not sufficient to set an upper limit for EPA and DHA and said supplemental intakes up to 5 g a day did not raise safety concerns for adults, which is a statement about the EU, not about these medicines. [9]Questions for a clinician
Why this product, what my triglycerides and LDL are, how it interacts with my other medicines, what to do about atrial fibrillation, bleeding or fish allergy, and how my pregnancy or breastfeeding plans matter.Frequently asked questions
Is icosapent ethyl the same as fish oil?
No. It is a purified EPA ethyl ester prescription product. [1] Typical supplements differ in composition and regulation. [3]
Why did one trial find benefit and the other not?
We do not know. The products, comparators (placebo vs corn oil), patients and formulations differed. [4] [5]
Does the mixed product raise LDL?
Its label says it may increase LDL and to monitor levels. [2]
Are these safe with blood thinners?
Both labels describe bleeding cautions. [1] [2] Ask the prescriber; never stop a medicine yourself.
Can children use them?
For the mixed product, safety and effectiveness in children have not been established. [2]
More details: evidence, limits and cautions
The details behind this page: cautions, limits of the evidence and where sources disagree. Open any note to read it.
Safety and who decides
- Bleeding. The icosapent ethyl label reports more bleeding in patients taking antithrombotic medicines such as aspirin, clopidogrel or warfarin. [1] The mixed EPA and DHA label says omega-3 acids may prolong bleeding time. [2]
- Atrial fibrillation. The icosapent ethyl label links it to an increased risk of atrial fibrillation or flutter requiring hospitalization. [1] The mixed product label reports a possible association with more frequent recurrences of symptomatic atrial fibrillation. [2]
- Fish and shellfish allergy. The icosapent ethyl label says it is not known whether people with these allergies are at increased risk of a reaction. [1] The mixed product label says to use with caution in known fish or shellfish hypersensitivity. [2] Signs of a severe allergic reaction, such as trouble breathing, are an emergency: call 911.
- Liver, LDL, children. The mixed product label says to monitor liver tests and that it may increase LDL; safety and effectiveness in children have not been established. [2]
Also see medication interactions and prescription omega-3 vs supplements.