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Genetic Testing for Lipoprotein(a) Variant(s) as a Decision Aid for Aspirin Treatment

Policy Number: MP-474

ARCHIVED – Refer to AIM Genetic Testing Guidelines Effective 3/1/20

Latest Review Date: October 2019

Category: Laboratory Testing

Policy Grade: C


The use of genetic testing for the LPA rs3798220 allele (LPA-Aspirin Genotype) is considered not medically necessary and investigational in patients who are being considered for treatment with aspirin to reduce risk of cardiovascular events.


Lipoprotein (a) (LPA) is a lipid-rich particle similar to low-density lipoprotein (LDL) and has been determined to be an independent risk factor for coronary artery disease (CAD). Patients with a positive test for the LPA genetic variant rs3798220 have a higher risk for thrombosis and therefore may derive more benefit from the anti-thrombotic properties of aspirin. As a result, testing for the rs3798220 variant has been proposed as a method of stratifying benefit from aspirin treatment.

Lipoprotein (A)

Extensive epidemiologic evidence has determined that lipoprotein (a) (LPA) blood level is an independent risk factor for cardiovascular disease. The overall risk associated with LPA appears to be modest, and the degree of risk may be mediated by other factors such as low-density lipoprotein (LDL) levels and/or hormonal status.

Over time, a person’s LPA levels remain relatively stable; however, levels have been known to vary up to 1000-fold between different people, and this is most likely due to genetics. A single-nucleotide variant in the LPA gene, LPA rs3798220, has been associated with both elevated LPA levels and an increased risk of cardiovascular disease. This variant substitutes methionine for isoleucine at amino acid position 4399 and is also called I4399M. Mendelian randomization studies have supported the hypothesis that this genetic variant, and the subsequent increase in LPA levels, are causative of cardiovascular disease.

Aspirin is a well-established treatment for patients with known coronary artery disease. It also is prescribed as primary prevention for some patients who are at increased risk of coronary artery disease. Current recommendations for primary prevention consider the future risk of cardiovascular events weighed against the bleeding risk of aspirin. The U.S. Preventive Services Task Force 2013 final guidelines recommended aspirin for men “age of 45 to 79 years when the potential benefit due to reduction in myocardial infarctions outweighs the potential harm due to an increase in gastrointestinal hemorrhage”; the Task Force made the same recommendation for women between the ages of 55 and 79 years. Given such guidelines that recommend individualizing the risk-benefit ratio of aspirin therapy, additional tools that could aid in better defining the benefits of aspirin, and/or the risk of bleeding, have potential utility for clinicians who are making decisions about aspirin therapy.

The Cardio IQ® LPA-Aspirin Genotype is a commercially available genetic test (Berkeley HeartLab, a Quest Diagnostics Service) that detects the presence of the rs3798220 allele. Patients with a positive test for rs3798220 have a higher risk for thrombosis, and therefore may derive more benefit from the anti-thrombotic properties of aspirin. It has been proposed that the additional information obtained from the LPA-Aspirin Check® test may aid physicians in better estimating the benefit/risk of aspirin therapy, and therefore may aid in deciding whether to prescribe aspirin for individual patients.


The most recent literature review was performed through August 14, 2019.

Summary of Evidence

For individuals who have a high risk of thrombosis who receive genetic testing for LPA rs3798220 variant, the evidence includes observational studies. Relevant outcomes are test validity, medication use, and morbid events. The LPA minor allele, rs3798220, is associated with higher levels of LPA and a higher risk for cardiovascular events. This allele is infrequent in the population and is associated with a modest increase in cardiovascular risk in the general population. Testing for this allele is commercially available, but performance characteristics are uncertain, and standardization of testing has not been demonstrated. The evidence is insufficient to determine the effects of the technology on health outcomes. Several observational studies have reported that LPA rs3798220 variant is an independent risk factor for cardiovascular disease, but some studies have not reported a significant association. Evidence from a post hoc analysis of the Women’s Health Study reported that carriers of the allele might derive greater benefit from aspirin therapy compared with noncarriers. It is unclear whether this information, which derives from genetic testing, leads to changes in management; in particular, it cannot be determined from available evidence whether deviating from current guidelines on aspirin therapy based on LPA genetic testing improves outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Position Statements

A number of guidelines contain recommendations for testing of lipoprotein (a) serum levels, but none were identified with recommendations for genetic testing.

American College of Cardiology/American Heart Association

The American College of Cardiology and American Heart Association (2013) issued joint guidelines on the assessment of cardiovascular risk. The guidelines were based on a systematic review conducted by an expert panel appointed by the National Heart, Lung, and Blood Institute. The panel noted that LPA was considered as a risk predictor, but its contribution to risk assessment “awaits further consideration at a later time.”

U.S. Preventive Services Task Force Recommendations

Not applicable


LPA-Aspirin Check®, rs3798220 allele genetic testing, LPA rs3798220, rs3798220, aspirin genetic testing, Lipoprotein (a) genetic testing, LPA-Aspirin Genotype


Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Berkeley HeartLab/Quest Diagnostics is certified under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.


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

ITS: Home Policy provisions apply.

FEP: FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.


CPT Codes:


Unlisted molecular pathology procedure


  1. American College of Cardiology/American Heart Association. 2013 report on the assessment of cardiovascular risk: full work group report supplement, based on a systematic review from the National Heart, Lung, and Blood Institute. Available online at: Accessed September 25, 2018.
  2. Anderson TJ, Gregoire J, Hegele RA et al. 2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol 2013; 29(2):151-167.
  3. Anderson JL, Knight S, May HT et al. Validation and quantification of genetic determinants of lipoprotein-a levels and predictive value for angiographic coronary artery disease. Am J Cardiol 2013; 112(6):799-804.
  4. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). C-Reactive Protein as a Cardiac Risk Marker (Special Report). TEC Assessments 2002; Volume17, Tab 23.
  5. Berkeley HeartLab® LPA-AspirinCheck Web site. 2011. Available online at:
  6. Cardiovascular risk reduction in atherogenic dyslipidemia: beyond LDL-C and statins: recommendations from the European Atherosclerosis Society Consensus. 2012.
  7. Chasman DL, Shiffman D, Zee RY et al. Polymorphism in the apolipoprotein(a) gene, plasma lipoprotein(a), cardiovascular disease, and low-dose aspirin therapy. Atherosclerosis 2009; 203(2):372-376.
  8. Clarke R, Peden JF, Hopewell JC et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med 2009; 361(26):2518-252
  9. Goff DC, Jr., Lloyd-Jones DM, Bennett G et al. 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. J Am Coll Cardiol 2013.
  10. Helfand M, Buckley DI, Freeman M et al. Emerging risk factors for coronary heart disease: a summary of systematic reviews conducted for the U.S. Preventive Services Task Force. Ann Intern Med 2009; 151(7):496-507.
  11. Kamstrup PR, Tybjaerg-Hansen A, Nordestgaard BG. Extreme lipoprotein (a) levels and improved cardiovascular risk prediction. J Am Coll Cardiol 2013; 61(11):1146-1156.
  12. Koch W, Mueller JC, Schrempf M et al. Two rare variants explain association with acute myocardial infarction in an extended genomic region including the apolipoprotein (A) gene. Ann Hum Genet 2013; 77(1):47-55.
  13. Luke MM, Kane JP, Liu DM et al. A polymorphism in the protease-like domain of apolipoprotein (a) is associated with severe coronary artery disease. Thromb Vasc Biol 2007; 27(9):2030-2036.
  14. Qi Q, Workalemahu T, Zhang C et al. Genetic variants, plasm lipoprotein (a) levels, and risk of cardiovascular morbidity and mortality among two prospective cohorts of type 2 diabetes. Eur Heart J 2012; 33(3):325-334.
  15. Shiffman D, Chasman DI, Ballantyne CM et al. Coronary heart disease risk, aspirin use, and apolipoprotein (a) 4399Met allele in the Atherosclerosis Risk in Communities (ARIC) study. Thromb Haemost 2009; 102(1):179-180.
  16. Shiffman D, Kane JP, Louie JZ et al. Analysis of 17,576 potentially functional SNPs in three case-control studies of myocardial infarction. PLoS One 2008; 3:e2895.
  17. Shiffman D, O’Meara ES, Bare LA et al. Association of gene variants with incident myocardial infarction in the Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 2008; 28(1):173-179.
  18. U.S. Preventive Services Task Force. Archived Final Recommendation Statement: Aspirin for the Prevention of Cardiovascular Disease: Preventive Medication. 2013; Accessed September 25, 20
  19. Valasek MA, Repa JJ. The power of real-time PCR. Adv Physiol Educ 2005; 29(3):151-9.
  20. Wang Y, Wang L, Liu X et al. Genetic variants associated with myocardial infarction and the risk factors in Chinese population. PLoS One 2014; 9(1):e86332.
  21. Yusuf S, Hawken S, Ounpuu S et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004; 364(9438):937-52.


Medical Policy Panel, May 2011

Medical Policy Group, May 2011 (2)

Medical Policy Administration Committee, June 2011

Available for comment June 8 – July 25, 2011

Medical Policy Panel, May 2012

Medical Policy Group, June 2012 (2): Updated Description, Key Points, Key Words, References

Medical Policy Group, December 2012 (3): 2013 Coding Update – Added Code 81479 and deleted CPT code range 83890 to 83914, effective 01/01/2013.

Medical Policy Panel, May 2013

Medical Policy Group, September 2013 (1): Update to Key Points and References; no change to policy statement

Medical Policy Panel, May 2014

Medical Policy Group, June 2014 (1): Update to Key Points, Governing Bodies and References; no change to policy statement

Medical Policy Panel, May 2015

Medical Policy Group, June 2015 (3): Name change of LPA Aspirin Check® to LPA-Aspirin Genotype. Update to Description, Key Points, Key Words, and Approved Governing Bodies. Updated policy statement to reflect new name of LPA-Aspirin Genotype. Policy intent unchanged.

Medical Policy Panel, October 2017

Medical Policy Group, October 2017 (3): 2017 Updates to Description & Key Points; no new references added; no change to policy statement; removed Previous Coding section for codes deleted 01/01/13.

Medical Policy Panel, October 2018

Medical Policy Group, November 2018 (3): Updates to Description, Key Points and References. No change to policy statement or intent.

Medical Policy Panel, October 2019

Medical Policy Group, October 2019 (9): 2019 Updates to Description, Key Points. No change to policy statement.

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.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

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.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

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.