Coverage Policy Manual
Policy #: 2011057
Category: Laboratory
Initiated: August 2011
Last Review: July 2018
  Genetic Test: Aspirin Treatment, Lipoprotein(a) Variant(s) as a Decision Aid

Description:
Lipoprotein(a) (LPA) is a lipid-rich particle similar to low-density lipoprotein (LDL). A large amount of epidemiologic evidence has determined that LPA blood level is an independent risk factor for cardiovascular disease. The overall degree of risk associated with LPA levels appears to be modest, and the degree of risk may be mediated by other factors such as LDL levels and/or hormonal status.
 
Levels of LPA are relatively stable in individuals over time but vary up to 1,000-fold between individuals, presumably on a genetic basis. A single nucleotide polymorphism (LPA rs3798220) has been identified in the LPA gene that has been associated with both elevated levels of Lipoprotein(a) and an increased risk of cardiovascular disease. Mendelian randomization studies have supported the hypothesis that these genetic variants, 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 (CAD). It is also prescribed as primary prevention for some patients who are at increased risk of CAD. Current recommendations for primary prevention consider the future risk of cardiovascular events weighed against the bleeding risk of aspirin. U.S. Preventive Services Task Force (USPSTF) guidelines from 2009 recommend aspirin for men between the ages of 45-79 years when the benefit in reducing myocardial infarction (MI) exceeds the risk of bleeding, particularly gastrointestinal hemorrhage; and for women between the ages of 55-79 years when the benefit in reducing stroke exceeds the risk of gastrointestinal bleeding. Given guidelines such as these that recommend individualizing the risk/benefit ratio of aspirin therapy, additional tools that would aid in better defining the benefits of aspirin, and/or the risk of bleeding, have potential utility for clinicians who are making decisions on aspirin therapy.
 
LPA-Aspirin Check® is a commercially available genetic test (Berkeley HeartLab) 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 LAP-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.
 
Coding
There is no specific CPT code for this test. The unlisted molecular pathology code would be reported 81479.
  

Policy/
Coverage:
The use of genetic testing for the rs3798220 allele (LPA-Aspirin Check®) does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in patients who are being considered for treatment with aspirin.
 
For contacts without primary coverage criteria, the use of genetic testing for the rs3798220 allele (LPA-Aspirin Check®) is considered investigational in patients who are being considered for treatment with aspirin. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 

Rationale:
Genetic testing for the LPA rs3798220 can be evaluated in a similar framework as other novel cardiac risk factors. There are several conditions that must be met in order for a cardiovascular risk factor to demonstrate clinical utility. A 2002 Blue Cross and Blues Shield Association TEC Assessment summarized three steps necessary for clinical utility:
 
  • Standardization of measurement of the risk factor.
  • Determination of its contribution to risk assessment. As a risk factor, it is important to determine whether the novel risk factor contributes independently to risk assessment compared to established risk factors.
  • Determination of how the novel risk factor will be used in the management of the patient, compared to standard methods of assessing risk, and whether any subsequent changes in patient management result in an improvement in patient outcomes.
 
1) Is the measurement of the LPA rs3798220 allele standardized?
Testing for the LPA rs3798220 allele is commercially available through Berkeley HeartLab® under the name LPA-Aspirin Check®. DNA is extracted from a buccal swab sample taken from the inner cheek. Genetic testing is performed by real-time polymerase chain reaction (PCR) in conjunction with several control samples . Real-time PCR is expected to be more accurate than traditional PCR, since it preserves the exquisite sensitivity of PCR, while reducing the probability of cross-contamination that can result in false-positive results (Valasek, 2005). According to Valasek and Repa, (Valasek, 2005) the main limitations to real-time PCR accuracy are human factors such as improper assay development, incorrect data analysis, or unwarranted interpretation.
 
There were no published studies identified that evaluated the accuracy of real-time PCR testing for the specific rs3798220 allele. According to the manufacturer’s website,  “The Real-Time PCR assay is extremely reproducible and has been validated for LPA genotyping by testing over 1000 specimens from patients whose LPA status was already known. The test accuracy was 100% in validation studies.”
 
This limited information is sufficient to conclude that real-time PCR is an accurate method for identifying genetic polymorphisms such as the rs3798220 allele but is not sufficient to conclude that the measurement of LPA rs3798220 is standardized.
 
2) Is LPA rs3798220 an independent risk factor for coronary artery disease?
Several observational studies have evaluated whether LPA rs3798220 is an independent risk factor for coronary artery disease (CAD). Shiffman et al. used data from the Cardiovascular Health Study, a prospective cohort study of risk factors for myocardial infarction (MI) in 4,522 individuals who were 65 years or older, to examine the association of rs3798220 with MI (Shiffman, 2008). These authors tested 74 single nucleotide polymorphisms (SNPs) that had been genotyped as part of the Cardiovascular Health Study. After 13 years of follow-up, 539 patients (12%) had developed MI. There were 8 SNPs that were independent predictors of MI, with hazard ratios (HRs) varying from 1.13-1.62. The rs3798220 variant was one of the independent predictors and had the highest HR (1.62 95% confidence interval [CI]: 1.09-2.42). The authors also calculated the false-positive reporting rate for each SNP and estimated this to be 1% for rs3798220.
 
Clarke et al. used a case-control design to examine the association of rs3798220 with CAD in 3,145 case patients and 3,352 control subjects from four European countries (Clarke, 2009). They initially examined 48,742 SNPs in 2,100 genes that had some association with heart disease, including 40 SNPs from the lipoprotein(a) (LPA) gene. The rs3798220 SNP was found in 2% of patients and had the strongest association with CAD, with a HR of 1.92 (95% CI 1.48-2.49). This association was then replicated in three independent populations from cohort studies, with a total of 4,846 case patients and 4,594 controls. In these populations, the rs3798220 variant remained an independent risk factor for CAD, with an odds ratio (OR) that was somewhat lower than in the derivation population (OR 1.68 95% CI 1.43-1.98).
 
Luke et al. examined the association of SNPs with severe CAD as determined by coronary angiography. These authors used populations from 3 case control studies in sequence to determine the SNPs that were most strongly associated with severe CAD (Luke, 2007). Starting with over 12,000 SNPs, the authors identified 302 SNPs associated with severe disease; following verification in the second study, there were 5 SNPs that remained independent predictors; and after verification in the third study, only rs3798220 remained as the SNP most strongly associated with severe CAD. The adjusted OR for rs3798220 was 3.14 (95% CI 1.51-6.56).
 
In a similar case-control design, Shiffman et al. examined the association between the rs3798220 allele and MI in three case-control studies totaling 762 cases and 857 controls (Shiffman, 2008). Starting from a total of 1,949 SNPs associated with MI, the authors identified 5 SNPs that were mostly strongly associated with MI. One of these was rs3798220, which had ORs in the three separate study populations of 1.59 (95% CI 1.03-2.48), 1.72 (95% CI 1.19-2.49), and 3.52 (95% CI 1.85-6.69).
 
This information is sufficient to conclude that the genetic variant rs3798220 is an independent risk factor for cardiovascular disease. It has not been determined whether measurement of the genetic variant is superior to measurement of LPA levels as an independent risk factor for cardiovascular disease.
 
3) Will identification of the rs3798220 variant lead to changes in management, and will these changes in management lead to improved patient outcomes?
The Women’s Health Study (WHS) examined the efficacy of aspirin treatment versus placebo for primary prevention of cardiovascular events in healthy women. Chasman et al. published a post hoc analysis of 28,345 participants in the WHS who were genotyped for the presence of the LPA rs3798220 minor allele (Chasman, 2009). The allele was present in 3.7% of the population, 3.6% who were heterozygotes and 0.06% who were homozygotes. As expected, LPA levels in carriers of the allele were markedly elevated compared to non-carriers, and carriers had a 2-fold increased risk for subsequent cardiovascular events compared to non-carriers.
 
The authors reported an interaction between the presence of the LPA rs378220 allele and response to aspirin therapy. In carriers there was a significant risk reduction associated with ASA treatment, with cardiovascular events occurring in 4.8% of patients in the placebo group compared to 2.1% in the aspirin group (HR 0.44, 95% CI 0.20-0.94, p=0.03). For non-carriers 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 to 2.1% of the aspirin group (HR 0.91, 95% CI 0.77-1.08, p=0.30).
 
Shiffman et al. reported data on the interaction of the LPA rs3798220 variant and aspirin use from the Atherosclerosis Risk in Communities (ARIC) study (Shiffman, 2009). The ARIC study was a prospective cohort study of risk factors for CAD in 15,792 individuals. The LPA genetic substudy of ARIC included 6,752 individuals with data available for LPA genotype and ASA use, including 221 individuals with the LPA rs3798220 genotype. Among carriers of rs3798220, the risk of cardiovascular events was compared in aspirin users and non-users. The HR for non-aspirin users (n=168) was elevated at 1.57 but did not reach statistical significance (95% CI 0.92-2.69), while the HR for users of aspirin was not elevated at 0.86 (95% CI 0.38-1.95).
 
This data is supportive, but not conclusive, of the hypothesis that carriers of the rs3798220 allele may derive greater benefit from aspirin therapy compared to non-carriers. It is not clear how this information would be used in clinical care. For patients who are currently recommended to receive aspirin, a negative genetic test is probably not sufficient to warrant withholding aspirin. Similarly, for patients who are not currently recommended to receive aspirin, a positive genetic test is probably not sufficient to warrant starting aspirin. Therefore, it remains to be determined whether results of rs3798220 testing leads to changes in management and whether these changes in management improve outcomes.
 
Summary
The LPA minor allele rs378220 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. Testing for this allele is commercially available, but the performance characteristics are uncertain and standardization of testing has not been demonstrated. Several observational studies have established that this genetic variant is an independent risk factor for cardiovascular disease.
 
Evidence from a post-hoc analysis of the Women’s Health Study reported that carriers of the allele may derive greater benefit from aspirin treatment compared to noncarriers. It is unclear whether this information derived from genetic testing leads to changes in management. In particular, it cannot be determined from the available evidence whether deviating from current guidelines on treatment with ASA based on LPA genetic testing improves outcomes.
 
2012 Update
A literature search was conducted through September 2012.  There was no new randomized trials, practice guidelines, position statements or other publications identified that would prompt a change in the coverage statement.
 
A large prospective study performed in 2011 evaluated 2,308 patients with diabetes for LPA variants (Qi. 2012). There was no significant association between genetic variants and cardiovascular risk or mortality. Odds ratios for coronary heart disease, cardiovascular disease, and cardiovascular death were 0.94 (95% CI: 0.69-1.28), 0.97 (95% CI: 0.72-1.29), and 1.23 (95% CI: 0.79-1.92), respectively. The authors also examined the degree of variability in risk between the diabetic and non-diabetic populations and reported that there was significant heterogeneity between the 2 groups (p=0.006).
 
There remains insufficient evidence that using LPA genetic testing as a decision aid for aspirin treatment improves health outcomes.  The policy statement is unchanged.
 
2013 Update
A literature search was conducted using the MEDLINE database through September 2013.  No new information was identified that would prompt a change in the coverage statement. The following is a summary of the key identified literature.
 
A case-control study of 2,136 cases and 1,211 controls evaluated if SNPs rs3798220 and rs10455872 were associated with an increased risk of coronary disease (Koch, 2013). Genotyping of these SNPs rs3798220 and rs10455872 and 7 other LPA variants believed to be associated with coronary disease was done by Taqman assay. After adjusting for conventional risk factors, the authors found an increased odds of MI of 2.14 (95% CI: 1.37-3.33, p=0.00080) and 1.45 (95% CI: 1.36-2.24, p <0.00001) for rs3798220 and rs10455872 respectively. Two additional SNPs, rs3127599 and rs9346818, were also found to be associated with risk of MI, with odds ratios of 1.18 (95% CI: 1.06-1.32) and 0.88 (95% CI: 0.79-0.97), respectively.
 
A Danish cohort study of 8,720 participants was followed for 10 years to determine if LPA variants or lipoprotein(a) levels increased the risk of a first-time MI or CHD event (Kamstrup, 2013). Genotyping of rs3798220, rs10455872 and LPA-KIV-2 repeat genotype was performed by PCR. The authors found that 21% of the total variation in lipoprotein(a) levels was explained by the LPA-KIV-2, that 5% of the variation was explained by rs3798220 genotype, and that 27% of the variation was explained by rs10455872 genotype. The hazard ratio for carriers of rs3798220 was 1.3 (95% CI: 0.8-2.1) for MI and 1.4 (95% CI: 1.1-1.9) for CHD compared to noncarriers. LPA rs10455872 carriers had hazard ratios of 1.3 (95% CI: 1.1-1.6) for MI and 1.1 (95% CI: 0.9-1.3) for CHD compared to noncarriers, whereas homozygous rs10455872 patients had hazard ratios of 1.2 (95% CI: 0.5-3.3) for MI and 1.1 (95% CI: 0.5-2.1) for CHD compared to noncarriers.
 
2014 Update
A literature search conducted through June 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Wang et al (2014) conducted a case-control study and did not find an association between rs3798220 genotype and MI risk in a Chinese population.(11) Cases (n=2365) were patients who had experienced a first MI, drawn from hospitals in 15 cities in China. (This was the Chinese cohort of the global INTERHEART study. Age- and sex-matched controls (n=2678) were healthy adult visitors to the hospitals and had no history of cardiovascular disease. In logistic regression analysis adjusted for age, sex, and body mass index, OR for MI in rs3798220 carriers compared with noncarriers was 1.12 (95% CI, 0.57 to 2.22; p=0.73).
 
Similarly, Anderson et al (2013) did not find an association between rs3798220 genotype and prevalent CAD in 1235 patients in the Intermountain Heart Collaborative Study Registry who underwent coronary angiography. CAD was defined as stenosis of 70% or more of coronary artery diameter, and non-CAD as stenosis less than 10% plus no history of CAD, MI, or coronary artery revascularization. By these definitions, 801 patients (65%) had CAD and 434 (35%) did not. In logistic regression analysis adjusted for age, sex, body mass index (natural log), hyperlipidemia, hypertension, diabetes, smoking history, and family history of premature CAD, OR 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 prevalent CAD; OR in rs10455872 carriers versus noncarriers was 1.77 (95% I, 1.22 to 2.57; p=0.003).
 
This information is sufficient to conclude that the genetic variant, LPA rs3798220, is an independent risk factor for cardiovascular disease. It has not been determined whether measurement of the genetic variant is superior to measurement of LPA levels as an independent risk factor for cardiovascular disease.
 
Guidelines exist that contain recommendations for testing of LPA serum levels, but no guidelines were identified with recommendations for genetic testing.
 
American College of Cardiology/American Heart Association
In 2013, ACC and AHA issued conjoint 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.”
 
2015 Update
A literature search conducted through June 2015 did not reveal any new information that would prompt a change in the coverage statement.  
 
2018 Update
A literature search was conducted through June 2018.  There was no new information identified that would prompt a change in the coverage statement.
 

CPT/HCPCS:
81479Unlisted molecular pathology procedure
84999Unlisted chemistry procedure

References: American College of Cardiology/American Heart Association.(2013) 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: http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437741.48606.98/suppl/DC1. Last accessed April 2014.

Anderson JL, Knight S, May HT et al.(2013) 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.

Anderson TJ, Gregoire J, Hegele RA et al.(2012) 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):151-67.

Berkeley HeartLab® LPA-AspirinCheck Web site. Available online at: http://lpa-aspirincheck.com/testprocess/processing/. Last accessed April 2011.

Chasman DL, Shiffman D, Zee RY et al.(2009) Polymorphism in the apolipoprotein(a) gene, plasma lipoprotein(a), cardiovascular disease, and low-dose aspirin therapy. Atherosclerosis 2009; 203(2):372-6.

Clarke R, Peden JF, Hopewell JC et al.(2009) Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med 2009; 361(26):2518-28.

Goff DC, Jr., Lloyd-Jones DM, Bennett G et al.(2013) 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.

Kamstrup PR, Tybjaerg-Hansen A, Nordestgaard BG.(2013) Extreme lipoprotein(a) levels and improved cardiovascular risk prediction. J Am Coll Cardiol 2013; 61(11):1146-56.

Koch W, Mueller JC, Schrempf M et al.(2013) 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.

Luke MM, Kane JP, Liu DM et al.(2007) A polymorphism in the protease-like domain of apolipoprotein(a) is associated with severe coronary artery disease. Thromb Vasc Biol 2007; 27(9):2030-6.

Qi Q, Workalemahu T, Zhang C et al.(2012) Genetic variants, plasma lipoprotein(a) levels, and risk of cardiovascular morbidity and mortality among two prospective cohorts of type 2 diabetes. Eur Heart J 2012; 33(3):325-34.

Shiffman D, Chasman DI, Ballantyne CM et al.(2009) Coronary heart disease risk, aspirin use, and apolipoprotein(a) 4399Met allele in the Atherosclerosis Risk in Communities (ARIC) study. Thromb Haemost 2009; 102(1):179-80.

Shiffman D, Kane JP, Louie JZ et al.(2008) Analysis of 17,576 potentially functional SNPs in three case-control studies of myocardial infarction. PLoS One 2008; 3:e2895.

Shiffman D, O’Meara ES, Bare LA et al.(2008) Association of gene variants with incident myocardial infarction in the Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 2008; 28(1):173-9.

Tsivgoulis G, Sergentanis TN, Chan A et al.(2014) Chronic cerebrospinal venous insufficiency and multiple sclerosis: a comprehensive meta-analysis of case-control studies. Ther Adv Neurol Disord 2014; 7(2):114-36.

Valasek MA, Repa JJ.(2005) The power of real-time PCR. Adv Physiol Educ 2005; 29(3):151-9.

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

Yusuf S, Hawken S, Ounpuu S et al.(2004) 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.

Zwischenberger BA, Beasley MM, Davenport DL et al.(2013) Meta-analysis of the correlation between chronic cerebrospinal venous insufficiency and multiple sclerosis. Vasc Endovascular Surg 2013; 47(8):620-4.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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