Background

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 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.^1, 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 test 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 antithrombotic properties of aspirin. It has been proposed that the additional information obtained from the test may aid physicians in better estimating the benefit and risk of aspirin therapy and therefore may aid in deciding whether to prescribe aspirin for individual patients.

Regulatory Status

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.

Related Policies

• Measurement of Lipoprotein-Associated Phospholipase A2 in the Assessment of Cardiovascular Risk (Policy #014 in the Pathology Section)

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Testing for the LPA rs3798220 Variant

Clinical Context and Test Purpose

The purpose of genetic testing for the lipoprotein(a) (LPA) rs3798220 variant in patients who have a high risk of thrombosis is to confirm a diagnosis of thrombosis and select appropriate therapy.

The question addressed in this policy is: Does testing for the LPA rs3798220 variant improve the net health outcome in patients at high risk of thrombosis?

The following PICOs were used to select literature to inform this policy.

Patients

The relevant population of interest is individuals at high risk of thrombosis.

Interventions

The test being considered is testing for the LPA rs3798220 variant, which would involve a laboratory-developed test provider and outpatient cardiology. Short-term follow-up for consultation would occur once laboratory test results have been received. Long-term follow-up would occur if a therapy change is warranted based on test findings.

Comparators

The following practice is currently being used to manage thrombosis: standard clinical management without genetic testing.

Outcomes

The general outcomes of interest test validity and reducing the risk of a coronary event. Short-term follow-up for consultation would take once laboratory test results have been received. Long-term follow-up would occur if a therapy change is warranted based on test findings.

Observational Studies Assessing the LPA rs3798220 Variant as a Risk Factor for Coronary Artery Disease

Several observational studies have evaluated whether LPA rs3798220 is an independent risk factor for coronary artery disease (CAD).

Wang et al (2014) conducted a case-control study and did not report an association between rs3798220 genotype and myocardial infarction risk in a Chinese population.^2, Cases (n=2365) were patients who had experienced a first myocardial infarction, drawn from hospitals in 15 cities in China. (This was the Chinese cohort of the global INTERHEART study.^3,) Age- and sex-matched controls (n=2678) were healthy adult visitors to the hospitals; these individuals had no history of cardiovascular disease. In logistic regression analysis adjusted for age, sex, and body mass index, the odds for myocardial infarction in rs3798220 carriers compared with noncarriers was 1.12 (95% confidence interval [CI], 0.57 to 2.22; p=0.73).

In a case-control study, Koch et al (2013) evaluated 2136 cases and 1211 controls to determine whether single nucleotide variants (SNVs) rs3798220 and rs10455872 were associated with an increased risk of coronary disease.^4, Genotyping of these 2 SNVs and 7 other LPA variants believed to be associated with coronary disease was done using the TaqMan assay. After adjusting for conventional risk factors, the authors found an increased odds of myocardial infarction of 2.14 (95% CI, 1.37 to 3.33, p<0.001) for rs3798220 and 1.45 (95% CI, 1.36 to 2.24; p<0.001) for rs10455872. Two additional SNVs (rs3127599, rs9346818) also were found to be associated with risk of myocardial infarction, with an odds of 1.18 (95% CI, 1.06 to 1.32) and 0.88 (95% CI, 0.79 to 0.97), respectively.

Kamstrup et al (2013) followed a Danish cohort of 8720 participants for 10 years to determine whether LPA variants or LPA levels increased the risk of a first-time myocardial infarction or coronary heart disease (CHD) event.^5, Genotyping of rs3798220, rs10455872, and LPA kringle IV type 2 copy number variants was performed by polymerase chain reaction. The authors found that 27% of the total variation in LPA levels was explained by the rs10455872 genotype, 21% of the variation was explained by the LPA kringle IV type 2 copy number variant, and 5% of the variation was explained by the rs3798220 genotype. Hazard ratios (HRs) for rs3798220 carriers were 1.3 (95% CI, 0.8 to 2.1) for myocardial infarction and 1.4 (95% CI, 1.1 to 1.9) for CHD compared with noncarriers. LPA rs10455872 carriers had HRs of 1.3 (95% CI, 1.1 to 1.6) for myocardial infarction and 1.1 (95% CI, 0.9 to 1.3) for CHD compared with noncarriers, whereas homozygous rs10455872 patients had HRs of 1.2 (95% CI, 0.5 to 3.3) for myocardial infarction and 1.1 (95% CI, 0.5 to 2.1) for CHD compared with noncarriers.

Similarly, Anderson et al (2013) did not find an association between rs3798220 genotype and prevalence of CAD in 1235 patients in the Intermountain Heart Collaborative Study Registry who underwent coronary angiography.^6, CAD was defined as stenosis of 70% or more in coronary artery diameter, and non-CAD as stenosis less than 10% plus no history of CAD, myocardial infarction, or coronary artery revascularization. By these definitions, 801 (65%) patients had CAD, and 434 (35%) did not. In logistic regression analysis adjusted for age, sex, body mass index, hyperlipidemia, hypertension, diabetes, smoking history, and family history of premature CAD, the odds for CAD in rs3798220 carriers compared with noncarriers was 1.74 (95% CI, 0.84 to 3.59; p=0.36). In contrast, the rs10455872 genotype was significantly associated with CAD (odds ratio in rs10455872 carriers vs noncarriers, 1.77; 95% CI, 1.22 to 2.57; p=0.003).

Clarke et al (2009) used a case-control design to examine the association between the rs3798220 variant and CAD in 3145 case patients and 3352 controls from 4 European countries.^7, They initially examined 48,742 SNVs in 2100 genes that had some association with heart disease, including 40 SNVs from the LPA gene. The rs3798220 SNV was found in 2% of patients and had the strongest association with CAD, with an HR of 1.92 (95% CI, 1.48 to 2.49). This association was then replicated in 3 independent patient samples from cohort studies, with a total of 4846 patients and 4594 controls. In these patients, the rs3798220 variant remained an independent risk factor for CAD, with odds that was somewhat lower than in the derivation population (odds ratio, 1.68; 95% CI, 1.43 to 1.98).

In a similar case-control design, Shiffman et al (2008) examined the association between the rs3798220 allele and myocardial infarction in 3 case-control studies totaling 762 cases and 857 controls.^8, Starting from a total of 1949 SNVs associated with myocardial infarction, the authors identified 5 SNVs that were most strongly associated with myocardial infarction. One of these was rs3798220, which had odds in the 3 separate studies of 1.59 (95% CI, 1.03 to 2.48), 1.72 (95% CI, 1.19 to 2.49), and 3.52 (95% CI, 1.85 to 6.69).

The risk associated with genetic variants of LPA in diabetic patients may differ from that in the general population. A large prospective study performed by Qi et al (2012) evaluated LPA variants in 2308 patients who had diabetes.^9, There was no significant association between genetic variants and cardiovascular risk or mortality. Odds ratios for CHD, cardiovascular disease, and cardiovascular death were 0.94 (95% CI, 0.69 to 1.28), 0.97 (95% CI, 0.72 to 1.29), and 1.23 (95% CI, 0.79 to 1.92), respectively. The authors also examined the degree of variability in risk between diabetic and nondiabetic patients and reported that there was significant heterogeneity between groups (p=0.006).

Shiffman et al (2008) used data from the Cardiovascular Health Study, a prospective cohort study of risk factors for myocardial infarction in 4522 subjects who were 65 years or older, to examine the association between the rs3798220 variant and myocardial infarction.^10, These authors tested 74 SNVs that had been genotyped as part of the Cardiovascular Health Study. After 13 years of follow-up, 539 (12%) patients had developed myocardial infarction. Eight SNVs were independent predictors of myocardial infarction, with HRs ranging from 1.13 to 1.62. The rs3798220 variant was one of the independent predictors and had the highest HR (1.62; 95% CI, 1.09 to 2.42). The authors calculated the false-positive reporting rate for each SNV and estimated the rate to be 1% for rs3798220.

Luke et al (2007) examined the association between SNVs and severe CAD as determined by coronary angiography.^11, They used patient samples from 3 case-control studies in sequence to determine the SNVs most strongly associated with severe CAD. Starting with more than 12,000 SNVs, the authors identified 302 SNVs associated with severe disease; after verification in the second study, 5 SNVs remained independent predictors; and after verification in the third study, only rs3798220 remained as the SNV most strongly associated with severe CAD. The adjusted odds for rs3798220 was 3.14 (95% CI, 1.51 to 6.56).

Section Summary: The LPA rs3798220 Variant as a Risk Factor for Coronary Artery Disease

The data on the clinical validity of testing for the LPA rs3798220 allele is sufficient to conclude that it is an independent risk factor for cardiovascular disease. It has not been determined whether detection of this genetic variant is superior to measurement of LPA levels as an independent risk factor for cardiovascular disease.

Prospective Studies Assessing Therapy Guided by the Presence of the LPA rs3798220 Variant

The Women’s Health Study examined the comparative efficacy of aspirin and placebo for primary prevention of cardiovascular events in healthy women. Chasman et al (2009) published a post hoc analysis of 28,345 participants in the Women’s Health Study who were genotyped for the presence of the LPA rs3798220 minor allele.^12, The allele was present in 3.7% of the population, 3.6% of which were heterozygotes and 0.06% who were homozygotes. As expected, LPA levels in carriers of the allele were markedly elevated compared with noncarriers, and carriers had a 2-fold increased risk for subsequent cardiovascular events compared with noncarriers.

The authors reported on an interaction between the presence of the LPA rs378220 allele and response to aspirin therapy. In carriers, a significant risk reduction was associated with aspirin treatment, with cardiovascular events occurring in 4.8% of patients in the placebo group compared with 2.1% in the aspirin group (HR=0.44; 95% CI, 0.20 to 0.94; p=0.03). For noncarriers of the allele, there was no significant reduction in cardiovascular events associated with aspirin treatment, with cardiovascular events occurring in 2.3% of the placebo group compared with 2.1% of the aspirin group (HR=0.91; 95% CI, 0.77 to 1.08; p=0.30).

Shiffman et al (2009) reported on the relation between the LPA rs3798220 variant and aspirin use from the Atherosclerosis Risk in Communities (ARIC) study.^13, The ARIC study assessed a prospective cohort of risk factors for CAD in 15,792 subjects. The subanalysis of ARIC included 6752 subjects who had data available for LPA genotype and aspirin use, including 221 subjects with the LPA rs3798220 genotype. Among carriers of rs3798220, the risk of cardiovascular events was compared in aspirin users and nonusers. The HR for nonaspirin users (n=168) was elevated at 1.57 but was not statistically significant (95% CI, 0.92 to 2.69); HR for aspirin users was not elevated at 0.86 (95% CI, 0.38 to 1.95).

Section Summary: Therapy Guided by the Presence of the LPA rs3798220 Variant

The data are supportive, but not conclusive, of the hypothesis that carriers of the rs3798220 allele may derive greater benefit from aspirin therapy than noncarriers. It is unclear how this information would be used in clinical care. For patients who are currently recommended to receive aspirin, a negative genetic test is probably insufficient to warrant withholding aspirin. Similarly, for patients who are not currently recommended to receive aspirin, a positive genetic test is probably insufficient to warrant starting aspirin. Therefore, it remains to be determined whether results of rs3798220 testing lead to changes in management and whether these management changes improve outcomes.

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. Several observational studies have reported that this 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.

SUPPLEMENTAL INFORMATION

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.^14,

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.^15, The guidelines were based on a systematic review conducted by an expert panel appointed by the National Heart, Lung, and Blood Institute.^16, The panel noted that lipoprotein(a) was considered 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.

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in August 2019 did not identify any ongoing or unpublished trials that would likely influence this review.]
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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Genetic Testing for Lipoprotein(a) Variant(s) as an Decision Aid for Aspirin Treatment
LPA-Aspirin Check
Aspirin, Genetic Testing
Lipoprotein(a), Genetic Testing
LPA-Aspirin Genotype

References:
1. U.S. Preventive Services Task Force. Archived Final Recommendation Statement: Aspirin for the Prevention of Cardiovascular Disease: Preventive Medication. 2013; https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/aspirin-for-the- prevention-of-cardiovascular-disease-preventive-medication. Accessed September 25, 2018.

2. Wang Y, Wang L, Liu X, et al. Genetic variants associated with myocardial infarction and the risk factors in Chinese population. PLoS One. Jan 2014;9(1):e86332. PMID 24475106.

3. 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. Sep 11-17 2004;364(9438):937- 952. PMID 15364185.

4. 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. Jan 2013;77(1):47-55. PMID 23278389.

5. Kamstrup PR, Tybjaerg-Hansen A, Nordestgaard BG. Extreme lipoprotein(a) levels and improved cardiovascular risk prediction. J Am Coll Cardiol. Mar 19 2013;61(11):1146-1156. PMID 23375930.

6. 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. Sep 15 2013;112(6):799-804. PMID 23735648.

7. Clarke R, Peden JF, Hopewell JC, et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med. Dec 24 2009;361(26):2518-2528. PMID 20032323.

8. 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. Aug 06 2008;3(8):e2895. PMID 18682748.

9. Qi Q, Workalemahu T, Zhang C, et al. Genetic variants, plasma lipoprotein(a) levels, and risk of cardiovascular morbidity and mortality among two prospective cohorts of type 2 diabetes. Eur Heart J. Feb 2012;33(3):325-334. PMID 21900290.

10. 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. Jan 2008;28(1):173-179. PMID 17975119.

11. 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. Arterioscler Thromb Vasc Biol. Sep 2007;27(9):2030-2036. PMID 17569884.

12. Chasman DI, Shiffman D, Zee RY, et al. Polymorphism in the apolipoprotein(a) gene, plasma lipoprotein(a), cardiovascular disease, and low-dose aspirin therapy. Atherosclerosis. Apr 2009;203(2):371-376. PMID 18775538.

13. 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. Jul 2009;102(1):179- 180. PMID 19572086.

14. 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. Feb 2013;29(2):151-167. PMID 23351925.

15. 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. Jul 01 2014;63(25 Pt B):2935-2959. PMID 24239921.

16. American College of Cardiology/American Heart Association, Assessment of Cardiovascular Risk Full Work Group. 2013 report on the assessment of cardiovascular risk: full work group report supplement. 2013; https://www.ahajournals.org/doi/suppl/10.1161/01.cir.0000437741.48606.98. Accessed August 14, 2019.

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

81479