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Measurement of Long-Chain Omega-3 Fatty Acids in Red Blood Cell Membranes as a Cardiac Risk Factor

Policy Number: MP-239

Latest Review Date: September 2019

Category: Laboratory

Policy Grade:

Effective July 1, 2010: Active Policy but no longer scheduled for regular literature reviews and updates.


Measurement of long-chain omega-3 fatty acids in red blood cell membranes, including but not limited to its use as a cardiac risk factor is considered not medically necessary and investigational.


Epidemiologic studies have reported that subjects who eat a diet high in fish have a reduced risk of sudden cardiac death. Fish are rich in long-chain omega-3 fatty acids, and it has been hypothesized that these fatty acids may be responsible for the beneficial effect. Long-chain omega-3 fatty acids may be detected in the red cell membrane using gas chromatography. It has been suggested this measurement may be clinically useful as a cardiac risk factor for sudden cardiac death.


A search of the literature through September 3, 2019 identified many observational studies that have explored the association between fish consumption and risk of coronary heart disease (CHD) in different populations of patients. These studies suggest that mortality from coronary heart disease may be reduced by including fish as a regular part of the diet. However, most of them have not had sufficient statistical power to provide convincing evidence for the presence or absence of the association. There are no published articles that explored how the measurement of red blood cell membrane omega-3 fatty acids may be used to improve patient management. For example, studies establishing the diagnostic parameters of omega-3 fatty acids, i.e., the definition of normal, high, and low values were not identified. It has been suggested that the measurement of omega-3 fatty acids may be incorporated into a cardiac risk panel in patients with a prior cardiac event. No studies focused on this application of this laboratory test.

Some studies were identified that examine the association between fish consumption and risk of coronary heart disease, but lack proof of clinical utility in measurement of long chain omega-3 fatty acids in red blood cell membranes, as this measurement was not taken into consideration when recommending fish consumption. No trials were identified where prospective measurement of omega-3 fatty acids (Omega-3 Index) was used to direct treatment to prevent or treat cardiac disease.

At the present time, patients with coronary artery disease are offered the general dietary recommendation to increase fish consumption, a recommendation not based on red blood cell membrane levels of omega-3 fatty acids.

The Japan Eicosapentaenoic Acid Lipid Intervention Study (JELIS) trial compared fish oil capsules plus statins to statins alone in 18,645 patients with hypercholesterolemia. In this primary and secondary prevention study, if hypercholesterolemia remained uncontrolled, the dose of the statin could be raised by protocol. No measurements of the efficacy of fish oil treatment were performed and the dose remained constant throughout the study. The fish oil plus statin group had 18% (p=0.132) and 19% (p=0.015) fewer non-fatal (primary and secondary, respectively) cardiac events over a mean of 4.6 years compared to the statin only group.

Results of analysis of eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) and fish intake in relation to incident heart failure in the population-based Rotterdam Study. The analysis comprised 5,299 participants (41% men, age approximately 68 years) free from heart failure for which dietary data were available. In the 11.4 years of follow-up, 669 developed heart failure. After adjustment for lifestyle and dietary factors the relative risk (RR) of heart failure in the top vs. bottom quintile of EPA plus DHA intake was 0.89 (95% CI 0.69-1.14), after adjustment for lifestyle and dietary factors. For fish intakes > or = 20 g/day, the RR was 0.96 (0.78-1.18) compared with no fish intake. In sex-specific analysis, a high EPA plus DHA intake tended to be protective in women (RR=0.75, 0.54-1.04) but not in men (RR= 1.00, 0.73-1.36). An inverse association for EPA plus DHA was also not observed in diabetics (RR= 0.58, 0.32-1.06), which was borderline statistically significant. The authors concluded that their findings did not support a major role for fish intake in the prevention of heart failure.

No published articles have been identified that explored how the measurement of this index may be used to improve patient outcomes.

Summary of Evidence

Trials and studies are needed to demonstrate the potential impact of measuring this index on clinical outcomes. At the current time there is insufficient evidence to support the medical necessity of measurement of long-chain omega-3 fatty acids in red blood cell membranes.


Long-chain omega-3 fatty acids, coronary heart disease, Omega-3 fatty acids, fatty acids, heart disease risk, fish oil


Not applicable


Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP contracts: FEP does not consider investigational if FDA approved and will be reviewed for medical necessity. Special benefit consideration may apply. Refer to member’s benefit plan.


CPT codes:

For dates of service 1/1/21 and after, there are no specific codes related to this test.  An unlisted code would be submitted, such as:


Unlisted chemistry procedure


CPT codes:


Long chain (C 20-22) omega-3 fatty acids in red blood cell membranes (Deleted 12/31/2020)


  1. Albert CM, et al. Blood levels of long-chain n-3 fatty acids and the risk of sudden death, New England Journal of Medicine, April 2002; 346(15): 1113-1118.
  2. Albert CM, et al. Fish consumption and risk of sudden cardiac death, Journal of the American Medical Association, January 1998; 279(1): 23-28.
  3. Appel L, et al. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease, Circulation, November 2002; 106: 2747-2757.
  4. Ascherio A, et al. Dietary intake of marine n-3 fatty acids, fish intake, and the risk of coronary disease among men, New England Journal of Medicine, April 1995; 332(15): 977-982.
  5. Blue Cross Blue Shield Association. Measurement of long-chain omega-3 fatty acids in red blood cell membranes as a cardiac risk factor. Medical Policy Reference Manual, March 2008.
  6. Covington, M. Omega-3 fatty acids, American Family Physician, July 2004, Vol. 70, No. 1.
  7. Daviglus ML, et al. Fish consumption and the 30-year risk of fatal myocardial infarction, New England Journal of Medicine, April 1997; 336(15); 1046-1053.
  8. Gillum RF, et al. The relation between fish consumption, death from all causes, and incidence of coronary heart disease. The NHANES I epidemiologic follow-up study, Journal of Clinical Epidemiology, March 2000; 53(3): 237-244.
  9. Goff, DC, Lloyd-Jones DM, Bennett G, et al. ACC/AHA Prevention Guideline 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk a Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014; 129: S49-S73.
  10. Grieger JA, Miller MD, et al. Investigation of the effects of a high fish diet on inflammatory cytokines, blood pressure, and lipids in healthy older Australians. Food Nutr Res January 2014 15; 58.
  11. He K, et al. Accumulated evidence on fish consumption and coronary heart disease mortality: A meta-analysis of cohort studies, Circulation, June 2004; 109(22): 2705-2711.
  12. He K, et al. Fish consumption and incidence of stroke: A meta-analysis of cohort studies, Stroke, July 2004; 35(7): 1538-1542.
  13. He K, et al. Fish consumption and risk of stroke in men, Journal of the American Medical Association, December 2002; 288(24): 3130-3136.
  14. Holub B, et al. Clinical nutrition: 4 Omega-3 fatty acids in cardiovascular care, Canadian Medical Association Journal, March 2002, Vol. 166, No. 5.
  15. Hu FB, et al. Fish and long-chain omega-3 fatty acid intake and risk of coronary heart disease and total mortality in diabetic women, Circulation, April 2003; 107(14): 1852-1857.
  16. Hu FB, et al. Fish and omega-3 fatty acid intake and risk of coronary heart disease in women, Journal of the American Medical Association, April 2002; 287(14): 1815-1821.
  17. Lee KW, et al. The role of omega-3 fatty acids in the secondary prevention of cardiovascular disease, QJM, July 2003; 96(7): 465-480.
  18. Lemaitre RN, et al. n-3 Polyunsaturated fatty acids, fatal ischemic heart disease, and non-fatal myocardial infarction in older adults: The cardiovascular health study, American Journal of Clinical Nutrition, February 2003; 77(2): 319-325.
  19. Mozaffarian D, et al. Cardiac benefits of fish consumption may depend on the type of fish meal consumed: The cardiovascular health study, Circulation, March 2003; 107(10): 1372-1377.
  20. Ness AR, et al. The long-term effect of dietary advice in men with coronary disease : Follow-up of the diet and reinfarction trial (DART), European Journal of Clinical Nutrition, June 2002; 56(6): 512-5
  21. Pietinen P. Intake of fatty acids and risk of coronary heart disease in a cohort of Finnish men. The alpha-tocopherol, beta-carotene cancer prevention study, American Journal of Epidemiology, May 1997; 145(10): 876-887.
  22. Superko, HR, Superko, AR, et al. Omega-3 Fatty Acid Blood Levels Clinical Significance Update. Curr Cardiovasc Risk Rep. 2014: 8:407.
  23. Whelton S, et al. Meta-analysis of observational studies on fish intake and coronary heart disease, The American Journal of Cardiology, May 2004, Vol. 93, No. 9.
  24. Yokoyama M. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): A randomised open-label, blinded endpoint analysis. Lancet, March 2007; 369(9567): 1090-1098.
  25. Yuan JM, et al. Fish and shellfish consumption in relation to death from myocardial infarction among men in Shanghai, China, American Journal of Epidemiology, November 2001; 154(9): 809-816.


Medical Policy Group, July 2005 (3)

Medical Policy Administration Committee, August 2005

Available for comment August 13-September 26, 2005

Medical Policy Group, July 2008 (1)

Medical Policy Group, July 2010 (1): Key points updated, Policy retired

Medical Policy Group, July 1, 2010; Active Policy but no longer scheduled for regular literature reviews and updates.

Medical Policy Group (9): September 2019: Literature review completed with updates made to Key Points, Description, and References. Added key words: heart disease risk, fish oil. No change to policy statement.

Medical Policy Group, October 2020:  2021 Annual Coding Update. Moved CPT code 0111T from Current coding section. Created Previous Coding section to include code 0111T.

Medical Policy Group, November 2020: 2021 Annual Coding Update. Added CPT code 84999 to the Current coding section.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

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As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

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1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.