Omega-3 index
The omega-3 index is EPA plus DHA as a percentage of red cell fatty acids. Its two developers proposed below 4% as high risk and above 8% as low risk for coronary death. Pooled cohorts link higher levels to fewer coronary deaths, while trials of omega-3 supplements found small or no reductions in events. Results differ between laboratory methods.
- Status
- A blood test offered by specialty laboratories, ordered by a clinician or bought direct. One of its two developers writes that the test is run in many laboratories around the world, that small differences in method produce large differences in results, and that standardization is still called for [1].
- Measures
- EPA plus DHA, the two main marine omega-3 fatty acids, as a percentage of the total fatty acids in red blood cells [2][3].
- Also called
- Omega-3 Index, omega 3 index, O3I, HS-Omega-3 Index, red blood cell EPA plus DHA, RBC omega-3, erythrocyte EPA and DHA, omega-3 blood test
- Tested for
- heart health, checking a fish oil or omega-3 supplement, low fish intake, vegetarian or vegan diet, pregnancy nutrition, brain health
Strong several reviews agree · Moderate one review or consistent trials · Limited one or a few small studies · Untested no study in people, listed with what it rests on
Linked in research2
Reported risks0
No risks sourced yet.
Reference ranges
Each range is the one its source published, in %. Where sources differ, each is shown.
Harris and von Schacky, the developers of the index, proposed risk zones, 2004 and 2008
Adults, as proposed zones of risk for death from coronary heart disease · [2], [4], [3], [5]
| Range | What the source calls it |
|---|---|
| below 4 % | "high risk" |
| 4 to 8 % | "intermediate risk" |
| above 8 % | "low risk" |
These zones were proposed by the two researchers who defined and named the index, not by a guideline body or a laboratory standards group. The wording and numbers here are from the 2008 paper [2]. The 2004 paper that introduced the index put 4% or below with the least protection and 8% or above with the greatest, so the two papers place results of exactly 4% and 8% differently. The zones came from relating the index to death from coronary heart disease, especially sudden cardiac death, in published prevention studies [4]. A 2017 paper by one developer describes the original zones as below 4% and 8% to 12%, and reports that a pooled analysis of 10 cohorts supports below 4% and above 8% [3]. An independent survey of 298 studies used the same outer cut points, above 8% as its high range and 4% or below as very low [5].
von Schacky, co-developer of the index, target range, 2020
Adults, including in pregnancy, for results from the standardized method the range was defined for · [1]
| Range | What the source calls it |
|---|---|
| below 8 % | No name given |
| 8 to 11 % | "target range" |
| above 11 % | No name given |
A target range stated by one of the two developers, for the original standardized method. He writes that results from other laboratories are frequently related to this range although their methods give different numbers, which he describes as raising ethical issues. He gives no term for results below or above the range, and reports that no person has been found with an index below 2% [1]. The basis is observational: outcomes that correlate with the index [1].
How it compares with the reference method
Matched the reference method1
Week to week variation and the effect of a recent dose
Small studies found red cell EPA plus DHA varied about 4% from week to week and did not change within 24 hours of a large fish oil dose.
The numbers and sources
- Compared with
- The same person's earlier red cell result, and EPA plus DHA measured in plasma
- Effect
- In volunteers tested weekly for 6 weeks, within-person variation was 4.1% for red cell omega-3 content, against 15.9% for plasma and 14.5% for plasma phospholipids, and the red cell measure was not altered in the fed state [13]. Six hours after 3.6 g of omega-3 fatty acids taken with breakfast, the plasma concentration of EPA plus DHA had risen 47% (95% CI 24% to 73%) and its percentage of plasma fatty acids 19%, while the red cell percentage was unchanged (-0.6%, 95% CI -2.6% to 1.5%). At 24 hours the change in plasma was 10 times that in red cells [14].
- Population
- 20 healthy volunteers tested weekly over 6 weeks [13]. 20 healthy volunteers sampled over 24 hours [14].
- Sources
- [13], [14]
- Caveats
- Two studies of 20 people each, both led by a developer of the index [13][14].
Did not match the reference method1
Agreement between laboratories and methods
Limited evidence: a developer of the index reports that small differences in method give large differences in results. A US program found 70% of fatty acid results agreed within 20%.
The numbers and sources
- Compared with
- Results from other laboratories and methods on the same samples
- Effect
- One of the two developers of the index writes that even small differences in analytical methods entail large differences in results, and that results are nonetheless frequently related to the target range defined for the original method [1]. The other wrote in 2008 that standardized laboratory methods and quality control materials had to become available before the measurement could be used in routine clinical evaluation [2]. In two rounds of a US quality assurance program for fatty acids in serum or plasma, with 11 and 14 laboratories, agreement among laboratories for individual fatty acids was within 20% for 70% of the data submitted [12].
- Population
- 11 and 14 laboratories in two interlaboratory studies run by the National Institute of Standards and Technology with the National Institutes of Health and the Centers for Disease Control and Prevention [12].
- Sources
- [1], [2], [12]
- Caveats
- The interlaboratory program measured fatty acids in serum or plasma, not in red cells, so it is indirect evidence for this test [12]. The developers' statements give no figures for how far methods differ [1][2]. A report does not always say which method produced the result or whether the published zones were set on that method.
What studies tie it to
Linked in research2
Death from coronary heart disease
Linked to fewer coronary deaths at higher levels: an estimated 30% lower risk at an index of 8% than at 4% across 10 pooled cohorts.
The numbers and sources
- Effect
- In an analysis of 10 cohort studies, the mean omega-3 index was 6.1% (SD 2.1%) and each standard deviation higher went with a hazard ratio for fatal coronary heart disease of 0.85 (95% CI 0.80 to 0.91). The median index was 4.2% in the lowest fifth and 8.3% in the highest, from which the authors estimated about 30% lower risk at 8% than at 4% [3]. In the Framingham Offspring cohort, people in the highest fifth of the index (above 6.8%) had a 39% lower risk of a first cardiovascular event than those in the lowest fifth (below 4.2%) [6].
- Population
- 10 cohort studies drawn from a published 19-cohort meta-analysis [3]. 2,500 participants, mean age 66, 54% women, 245 cardiovascular events [6].
- Sources
- [3], [6]
- Caveats
- Observational, so confounding cannot be ruled out. Both papers were led by a developer of the index. The Framingham authors list a relatively short follow-up and a single measurement as limits [6].
Death from any cause
Linked to fewer deaths at higher blood levels of long-chain omega-3: 15% to 18% lower risk in the top fifth than the bottom across 17 pooled cohorts.
The numbers and sources
- Effect
- In a pooled analysis of 17 prospective cohorts, risk of death from any cause was 15% to 18% lower in the highest than the lowest fifth of circulating EPA, DPA and DHA after adjustment for other risk factors. Similar relations were seen for death from cardiovascular disease, cancer and other causes, and none for the plant omega-3 alpha-linolenic acid [7]. In the Framingham Offspring cohort, the highest fifth of the omega-3 index had a 34% lower risk of death from any cause than the lowest [6].
- Population
- 42,466 people with 15,720 deaths over a median 16 years [7]. 2,500 participants with 350 deaths [6].
- Sources
- [7], [6]
- Caveats
- Observational. The pooled analysis measured omega-3 fatty acids in several blood fractions, not only as the red cell index [7].
Mixed results2
Heart attack and coronary death in trials of omega-3 supplements
Mixed results: a pooled analysis of 10 supplement trials found no significant reduction in coronary events, while a later one of 13 trials found reductions of 5% to 8%.
The numbers and sources
- Effect
- In a meta-analysis of 10 trials, allocation to omega-3 supplements had no significant association with coronary heart disease death (RR 0.93, 99% CI 0.83 to 1.03), nonfatal heart attack (RR 0.97, 99% CI 0.87 to 1.08), any coronary heart disease event (RR 0.96, 95% CI 0.90 to 1.01) or major vascular events (RR 0.97, 95% CI 0.93 to 1.01) [8]. A later meta-analysis of 13 trials found, in its analysis that left out the REDUCE-IT trial of icosapent ethyl, lower risks of heart attack (RR 0.92, 95% CI 0.86 to 0.99), coronary heart disease death (RR 0.92, 95% CI 0.86 to 0.98) and total coronary heart disease (RR 0.95, 95% CI 0.91 to 0.99) [9].
- Population
- 77,917 people at high cardiovascular risk in 10 trials lasting a mean 4.4 years, EPA doses of 226 to 1,800 mg a day [8]. 127,477 participants in 13 trials, mean treatment 5.0 years [9].
- Sources
- [8], [9]
- Caveats
- These analyses compared people by the dose they were assigned, not by the omega-3 index they reached. One developer of the index argues that events track blood levels more than dose and that uptake varies from person to person, which he says makes the effects hard to show in trials of this design [1]. No trial reported here treated people to an index target.
Atrial fibrillation
Mixed results: higher blood EPA plus DHA went with slightly less atrial fibrillation in pooled cohorts, while trials of omega-3 supplements found 25% more.
The numbers and sources
- Effect
- Across 17 cohorts, higher levels of EPA plus DHA in blood or fat tissue had a hazard ratio for new atrial fibrillation of 0.93 (95% CI 0.87 to 0.99), comparing the 90th with the 10th percentile. EPA alone showed no association (HR 1.00, 95% CI 0.95 to 1.05) [10]. In a meta-analysis of 7 trials with cardiovascular outcomes, marine omega-3 supplements were associated with more atrial fibrillation (HR 1.25, 95% CI 1.07 to 1.46), with a hazard ratio of 1.49 (95% CI 1.04 to 2.15) in trials testing more than 1 g a day and 1.12 (95% CI 1.03 to 1.22) at 1 g a day or less [11].
- Population
- 54,799 participants in 17 cohorts, 7,720 cases over a median 13.3 years [10]. 81,210 patients in 7 trials, mean age 65, weighted average follow-up 4.9 years [11].
- Sources
- [10], [11]
- Caveats
- The cohorts measured levels in blood or fat tissue under habitual intake and are observational. The trials tested supplements, with more atrial fibrillation at higher doses [10][11].
Sources
- von Schacky C. Omega-3 index in 2018/19. Proceedings of the Nutrition Society. 2020. https://doi.org/10.1017/S0029665120006989
- Harris WS. The omega-3 index as a risk factor for coronary heart disease. The American Journal of Clinical Nutrition. 2008. https://doi.org/10.1093/ajcn/87.6.1997S
- Harris WS, Del Gobbo L, Tintle NL. The Omega-3 Index and relative risk for coronary heart disease mortality: Estimation from 10 cohort studies. Atherosclerosis. 2017. https://doi.org/10.1016/j.atherosclerosis.2017.05.007
- Harris WS, von Schacky C. The Omega-3 Index: a new risk factor for death from coronary heart disease? Preventive Medicine. 2004. https://doi.org/10.1016/j.ypmed.2004.02.030
- Stark KD, Van Elswyk ME, Higgins MR, Weatherford CA, Salem N. Global survey of the omega-3 fatty acids, docosahexaenoic acid and eicosapentaenoic acid in the blood stream of healthy adults. Progress in Lipid Research. 2016. https://doi.org/10.1016/j.plipres.2016.05.001
- Harris WS, Tintle NL, Etherton MR, Vasan RS. Erythrocyte long-chain omega-3 fatty acid levels are inversely associated with mortality and with incident cardiovascular disease: The Framingham Heart Study. Journal of Clinical Lipidology. 2018. https://doi.org/10.1016/j.jacl.2018.02.010
- Harris WS, Tintle NL, Imamura F, et al. Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies. Nature Communications. 2021. https://doi.org/10.1038/s41467-021-22370-2
- Aung T, Halsey J, Kromhout D, et al. Associations of Omega-3 Fatty Acid Supplement Use With Cardiovascular Disease Risks: Meta-analysis of 10 Trials Involving 77 917 Individuals. JAMA Cardiology. 2018. https://doi.org/10.1001/jamacardio.2017.5205
- Hu Y, Hu FB, Manson JE. Marine Omega-3 Supplementation and Cardiovascular Disease: An Updated Meta-Analysis of 13 Randomized Controlled Trials Involving 127 477 Participants. Journal of the American Heart Association. 2019. https://doi.org/10.1161/JAHA.119.013543
- Qian F, Tintle N, Jensen PN, et al. Omega-3 Fatty Acid Biomarkers and Incident Atrial Fibrillation. Journal of the American College of Cardiology. 2023. https://doi.org/10.1016/j.jacc.2023.05.024
- Gencer B, Djousse L, Al-Ramady OT, et al. Effect of Long-Term Marine Omega-3 Fatty Acids Supplementation on the Risk of Atrial Fibrillation in Randomized Controlled Trials of Cardiovascular Outcomes: A Systematic Review and Meta-Analysis. Circulation. 2021. https://doi.org/10.1161/CIRCULATIONAHA.121.055654
- Schantz MM, Powers CD, Schleicher RL, Betz JM, Wise SA. Interlaboratory analytical comparison of fatty acid concentrations in serum or plasma. Clinica Chimica Acta. 2016. https://doi.org/10.1016/j.cca.2016.09.013
- Harris WS, Thomas RM. Biological variability of blood omega-3 biomarkers. Clinical Biochemistry. 2010. https://doi.org/10.1016/j.clinbiochem.2009.08.016
- Harris WS, Varvel SA, Pottala JV, Warnick GR, McConnell JP. Comparative effects of an acute dose of fish oil on omega-3 fatty acid levels in red blood cells versus plasma: Implications for clinical utility. Journal of Clinical Lipidology. 2013. https://doi.org/10.1016/j.jacl.2013.05.001