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MP 2.04.70 Genetic Testing for Lipoprotein(a) Variant(s) as a Decision Aid for Aspirin Treatment

 

Medical Policy    
Section
Medicine 
Original Policy Date
05/2011
Last Review Status/Date
Reviewed with literature search/5:2014
Issue
5:2014
  Return to Medical Policy Index

Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract. Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage. Medical technology is constantly changing, and we reserve the right to review and update our policies periodically. 


Description

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.

Background

Much epidemiologic evidence has determined that 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 LDL levels and/or hormonal status.

LPA levels are relatively stable in people over time but vary up to 1000-fold between people, presumably on a genetic basis. A single nucleotide polymorphism (SNP) in the LPA gene, LPA rs3798220, has been associated with both elevated LPA levels and an increased risk of cardiovascular disease. This polymorphism 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 CAD. It also is 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 guidelines from 2009 recommend aspirin for men between the ages of 45 and 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 and 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 about 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 antithrombotic 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.

FDA Status
The LPA-Aspirin Check® test has not been cleared or approved by the U.S. Food and Drug Administration (FDA). Thus, genotyping is offered as a laboratory-developed test. Clinical laboratories may develop and validate tests in-house (“home-brew”) and market them as a laboratory service; such tests must meet general regulatory standards of the Clinical Laboratory Improvement Act (CLIA).The laboratory offering the service must be licensed by CLIA for high-complexity testing. Berkeley HeartLab is a CLIA-certified laboratory.


Policy

 

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 to reduce risk of cardiovascular events.


Policy Guidelines

 

There is no specific CPT code for this test. The unlisted molecular pathology code would be reported 81479.

Prior to 2013, a series of molecular diagnostic codes (83890-83912) or an unlisted code such as 84999 (unlisted chemistry procedure) would likely have been used.

An example of a possible series of CPT codes for this test would be:

83891
83892 x 2
83896 x 2
83898
83903
83912 


Benefit Application
BlueCard/National Account Issues

None identified.


Rationale

 

This policy was created in May 2011 and updated periodically with literature review. The most recent update covers the period through April 11, 2014.

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 TEC Assessment (1) 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.

Literature review

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.(2) Real-time PCR is expected to be more accurate than traditional PCR, because it preserves the exquisite sensitivity of PCR, while reducing the probability of cross-contamination that can result in false positive results.(3) The main limitations to real-time PCR accuracy are human factors such as improper assay development, incorrect data analysis, or unwarranted interpretation: to ensure reliability of results, “real-time PCR primer sets must be designed and validated by stringent criteria.”(3)

No published studies were identified that evaluated the accuracy of real-time PCR testing for the specific rs3798220 allele. Test performance (analytic validity) data are unavailable at the manufacturer website.(2)

Section Summary. This limited information suggests that real-time PCR is likely to be 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 (2008) used data from the Cardiovascular Health Study, a prospective cohort study of risk factors for myocardial infarction (MI) in 4522 subjects who were 65 years or older, to examine the association of rs3798220 with MI.(4) 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 to 1.62. The rs3798220 variant was one of the independent predictors and had the highest HR (1.62; 95% confidence interval [CI], 1.09 to 2.42). The
authors calculated the false positive reporting rate for each SNP and estimated this to be 1% for rs3798220.

Clarke et al (2009) used a case-control design to examine the association of rs3798220 with CAD in 3145 case patients and 3352 controls from 4 European countries.(5) They initially examined 48,742 SNPs in 2100 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 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 case patients and 4594 controls. In these patients, 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 to 1.98).

Luke et al (2007) examined the association of SNPs with severe CAD as determined by coronary angiography.(6) These authors used patient samples from 3 case-control studies in sequence to determine the SNPs that were most strongly associated with severe CAD. Starting with more than 12,000 SNPs, the authors identified 302 SNPs associated with severe disease; after verification in the second study, 5 SNPs 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 to 6.56).

In a similar case-control design, Shiffman et al (2008) examined the association between the rs3798220 allele and MI in 3 case-control studies totaling 762 cases and 857 controls.(7) Starting from a total of 1949 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 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).

Risk associated with genetic variants of LPA in diabetic patients may be different from that in the general population. A large prospective study performed in 2011 evaluated LPA variants in 2308 patients who had diabetes.(8) There was no significant association between genetic variants and cardiovascular risk or mortality. ORs for coronary heart disease, 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 the 2 groups (p=0.006).

A 2013 case-control study of 2136 cases and 1211 controls evaluated whether SNPs rs3798220 and rs10455872 were associated with an increased risk of coronary disease.(9) Genotyping of these 2 SNPs 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 increased odds of MI of 2.14 (95% CI, 1.37
to 3.33, p<0.001) and 1.45 (95% CI, 1.36 to 2.24, p<0.001) for rs3798220 and rs10455872, respectively. Two additional SNPs, rs3127599 and rs9346818, also were found to be associated with risk of MI, with ORs 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 MI or CHD event.(10) Genotyping of rs3798220, rs10455872, and LPA-KIV-2 repeats was performed by PCR. 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-KIV-2 repeat genotype, and 5% of the variation was explained by the rs3798220 genotype. Hazard ratios for rs3798220 carriers were 1.3 (95% CI, 0.8 to 2.1) for MI 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 MI 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 MI and 1.1 (95% CI, 0.5 to 2.1) for CHD compared with noncarriers.

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.(12)) 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.(13) 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).

Section Summary. 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.

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 versus placebo for primary prevention of cardiovascular events in healthy women. In 2009, 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.(14) 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 with noncarriers, and carriers had a 2-fold increased risk for subsequent cardiovascular events compared with noncarriers.

The authors reported 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 interaction of the LPA rs3798220 variant and aspirin use from the Atherosclerosis Risk in Communities (ARIC) study.(15) The ARIC study was a prospective cohort study of risk factors for CAD in 15,792 subjects. The LPA genetic substudy 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 did not reach statistical significance (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. These data are supportive, but not conclusive, of the hypothesis that carriers of the rs3798220 allele may derive greater benefit from aspirin therapy compared with 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 leads to changes in management and whether these changes in management improve outcomes.

Practice Guidelines and Position Statements
Guidelines exist that contain recommendations for testing of LPA serum levels, but no guidelines were identified with recommendations for genetic testing.(16-18)

American College of Cardiology/American Heart Association

In 2013, ACC and AHA issued conjoint guidelines on the assessment of cardiovascular risk.(19) The guidelines were based on a systematic review conducted by an expert panel appointed by the National Heart, Lung, and Blood Institute.(20) The panel noted that LPA was considered as a risk predictor, but its contribution to risk assessment “awaits further consideration at a later time.”

Summary
The LPA minor allele, rs3798220, is associated with higher levels of lipoprotein(a) (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 genetic 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 may derive greater benefit from aspirin treatment compared with noncarriers. It is unclear whether this information derived from genetic testing leads to changes in management. In particular, it cannot be determined from available evidence whether deviating from current guidelines on aspirin treatment based on LPA genetic testing improves outcomes. Therefore, measurement of the LPA rs3798220 variant as a decision aid for aspirin treatment is considered investigational.

References:

  1. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). C-Reactive Protein as a Cardiac Risk Marker (Special Report). TEC Assessments 2002; Volume 17, Tab 23.
  2. Berkeley HeartLab® LPA-AspirinCheck Web site. 2011. Available online at: http://lpa-aspirincheck.com/testprocess/processing/. Last accessed April 2011.
  3. Valasek MA, Repa JJ. The power of real-time PCR. Adv Physiol Educ 2005; 29(3):151-9.
  4. 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):173-9.
  5. 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):2518-28.
  6. 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 2007; 27(9):2030-6.
  7. 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(8):e2895.
  8. 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 2012; 33(3):325-34.
  9. 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.
  10. Kamstrup PR, Tybjaerg-Hansen A, Nordestgaard BG. Extreme lipoprotein(a) levels and improved cardiovascular risk prediction. J Am Coll Cardiol 2013; 61(11):1146-56.
  11. 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.
  12. 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.
  13. 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.
  14. 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 2009; 203(2):371-6.
  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):179-80.
  16. Cardiovascular risk reduction in atherogenic dyslipidemia: beyond LDL-C and statins: recommendations from the European Atherosclerosis Society Consensus. 2012. Available online at: http://www.eas-society.org/consensus_position_paper_initiative.asp. Last accessed March 2012.
  17. 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.
  18. 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):151-67.
  19. 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.
  20. 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:
    http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437741.48606.98/suppl/DC1. Last accessed April 2014. 

 

Codes

Number

Description

CPT

 

No specific code (See Policy Guidelines)

ICD-9-CM diagnosis

 

Investigational for all relevant diagnoses

ICD-10-CM (effective 10/1/15)   Investigational for all relevant diagnoses
ICD-10-PCS (effective 10/1/15)   Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.

 


Index

Aspirin, Genetic Testing
Lipoprotein(a), Genetic Testing
 


Policy History

Date Action Reason
05/12/11 Add to Medicine section, Pathology/Laboratory subsection New policy. 
5/10/12 Replace policy Policy updated with literature search, references 8, 11, 12 added. No change to policy statement.
05/09/13 Replace policy Policy updated with literature search through March 2013, reference 9 and 10 added. No change to policy statement.
5/22/14 Replace policy Policy updated with literature review through April 11, 2014; references 11-13 and 18-20 added; references 2 and 16 updated. No change to policy statement.