BlueCross and BlueShield of Montana Medical Policy/Codes
Apolipoprotein E Genotype or Phenotype Testing in the Risk Assessment and Management of Cardiovascular Disease
Chapter: Medicine: Tests
Current Effective Date: October 25, 2013
Original Effective Date: October 25, 2013
Publish Date: October 25, 2013
Description

Apolipoprotein E (apo E) is the primary apolipoprotein found in VLDLs and chylomicrons. Apo E is the primary binding protein for LDL receptors in the liver and is thought to play an important role in lipid metabolism. The apo E gene is polymorphic, consisting of 3 alleles (e2, e3, and e4) that code for 3 protein isoforms, known as E2, E3, and E4, which differ from one another by one amino acid. These molecules mediate lipid metabolism through their different interactions with the LDL receptors. The genotype of apo E alleles can be assessed by gene amplification techniques, or the apo E phenotype can be assessed by measuring plasma levels of apo E.

It has been proposed that various apo E genotypes are more atherogenic than others and that apo E measurement may provide information on risk of coronary artery disease (CAD) above traditional risk factor measurement. It has also been proposed that the apo E genotype may be useful in the selection of specific components of lipid-lowering therapy, such as drug selection. In the major lipid-lowering intervention trials, including trials of statin therapy, there is considerable variability in response to therapy that cannot be explained by factors such as compliance. Apo E genotype may be one factor that determines an individual’s degree of response to interventions such as statin therapy.

Policy

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Investigational

Blue Cross and Blue Shield of Montana (BCBSMT) considers determination of the apolipoprotein E (apo E) genotype or phenotype in the risk assessment and management of cardiovascular disease experimental, investigational and unproven.

Rationale

This policy was developed in 2013 with searches of scientific literature through January 2013. This section of the current policy has been substantially revised. The following is a summary of the key literature to date.

Apo E as a Predictor of Cardiovascular Disease

A large body of research has established a correlation between lipid levels and the underlying apo E genotype. For example, in population studies, the presence of an apo e2 allele is associated with the lowest cholesterol levels and the apo e4 allele is associated with the highest levels. (1)

Numerous studies have focused on the relationship between genotype and physiologic markers of atherosclerotic disease. A number of small- to medium-sized cross-sectional and case-control studies have correlated apo E with surrogate outcomes such as cholesterol levels, markers of inflammation, or carotid intima-media thickness. (2-7) These studies have generally shown a relationship between apo E and these surrogate outcomes. Other studies have suggested that carriers of apo e4 are more likely to develop signs of atherosclerosis independent of total and LDL-cholesterol levels. (8-11)

Some larger observational studies have correlated apo E genotype with clinical disease. The Atherosclerosis Risk in Communities (ARIC) study followed up 12,000 middle-aged individuals free of coronary artery disease (CAD) at baseline for 10 years. (12) This study reported that the e3/2 genotype was associated with carotid artery atherosclerosis after controlling for other atherosclerotic risk factors. Volcik et al. reported that apo E polymorphisms were associated with LDL levels and carotid intima-media thickness but were not predictive of incident CAD. (13)

A meta-analysis published by Bennet and colleagues (14) summarized the evidence from 147 studies on the association of apo E genotypes with lipid levels and cardiac risk. Eighty-two studies included data on the association of apo E with lipid levels, and 121 studies reported the association with clinical outcomes. The authors estimated that patients with the apo e2 allele had LDL levels that were approximately 31% less compared to patients with the apo e4 allele. When compared to patients with the apo e3 allele, patients with apo e2 had an approximately 20% decreased risk for coronary events (OR: 0.80; 95% CI: 0.70–0.90). Patients with the apo e4 had an estimated 6% higher risk of coronary events that was of marginal statistical significance (OR: 1.06; 95% CI: 0.99–1.13).

Apo E as a Predictor of Response to Therapy

Apo E has been investigated as a predictor of response to therapy by examining apo E alleles in the intervention arm(s) of lipid-lowering trials. Some data suggest that patients with an apo e4 allele may respond better to diet-modification strategies. (15, 16) Other studies have suggested that response to statin therapy may vary with apo E genotype and that the e2 allele indicates greater responsiveness to statins. (15, 17)

Chiodini et al. (18) examined differential response to statin therapy according to apo E genotype, by reanalyzing data from the GISSI study according to apo E genotype. GISSI was an RCT comparing pravastatin with placebo in 3,304 Italian patients with previous myocardial infarction (MI). Patients with the apo e4 allele treated with statins had a greater response to treatment as evidenced by lower overall mortality (1.85% vs. 5.28%, respectively, p=0.023), while there was no difference in mortality for patients who were not treated with statins (2.81% vs. 3.67%, respectively, p=0.21). This study corroborates results reported in previous studies but does not provide evidence to suggest that changes in treatment should be made as a result of apo E genotype.

For the 2009 policy update, additional published studies were identified that evaluated apo E genetic status as a predictor of response to lipid-lowering therapy. Donnelly et al. (19) reported on 1,383 patients treated with statins from the Genetics of Diabetes Audit and Research in Tayside, Scotland (Go-DARTS) database. The researchers reported on the final LDL levels and percent of patients achieving target LDL according to apo E genetic status. LDL levels following treatment were lower for patients who were homozygous for apo e2, compared to patients homozygous for apo e4 (0.6 +/- 0.5 mmol/L vs. 1.7 +/- 0.3 mmol/L, p<0.001). All patients who were homozygous for apo e2 reached their target LDL level, compared to 68% of patients homozygous for apo e4 (p<0.001).

Vossen et al. (20) evaluated response to diet and statin therapy by apo e status in 981 patients with CAD who were enrolled in a cardiac rehabilitation program. These authors reported that patients with an apo e4 allele were more responsive to both diet and statin therapy than were patients with an apo e2 allele. The overall response to treatment was more dependent on baseline LDL levels than apo e genetic status, with 30–47% of the variation in response to treatment explained by baseline LDL, compared to only 1% of the variation explained by apo E status.

Conclusions

The evidence suggests that apo E genotype may be associated with lipid levels and CAD but is probably not useful in providing additional clinically relevant information beyond established risk factors. Apo E is considered a relatively poor predictor of CAD, especially when compared to other established and emerging clinical variables and does not explain a large percent of the inter-individual variation in total cholesterol (TC) and LDL levels. Moreover, apo E has not been incorporated into standardized cardiac risk assessment models and was not identified as one of the important “emerging risk factors” in the most recent ATP III recommendations.

The evidence on response to treatment indicates that apo E genotype may be a predictor of response to statins and may allow clinicians to better gauge an individual’s chance of successful treatment, although not all studies are consistent in reporting this relationship. At present, it is unclear how this type of information will change clinical management. Dietary modifications are a universal recommendation for those with elevated cholesterol or LDL levels, and statin drugs are the overwhelmingly preferred agents for lipid-lowering therapy. It is unlikely that a clinician will choose alternative therapies, even in the presence of an apo E phenotype that indicates diminished response.

None of the available evidence provides adequate data to establish that apo E genotype or phenotype improves outcomes when used in clinical care. Thus, given the uncertain impact on clinical outcomes, this testing is considered experimental, investigational and unproven.

Coding

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps. 

ICD-9 Codes

Experimental, investigational and unproven for all diagnoses.

ICD-10 Codes

Experimental, investigational and unproven for all diagnoses.

Procedural Codes: 84999
References
  1. Hallman DM, Boerwinkle E, Saha N et al. The apolipoprotein E polymorphism: a comparison of allele frequencies and effects in nine populations. Am J Hum Genet 1991; 49(2):338-49.
  2. Koch W, Hoppmann P, Schomig A et al. Apolipoprotein E gene epsilon2/epsilon3/epsilon4 polymorphism and myocardial infarction: case-control study in a large population sample. Int J Cardiol 2008; 125(1):116-7.
  3. Kulminski AM, Ukraintseva SV, Arbeev KG et al. Health-protective and adverse effects of the apolipoprotein E epsilon2 allele in older men. J Am Geriatr Soc 2008; 56(3):478-83.
  4. Schmitz F, Mevissen V, Krantz C et al. Robust association of the APOE epsilon4 allele with premature myocardial infarction especially in patients without hypercholesterolaemia: the Aachen study. Eur J Clin Invest 2007; 37(2):106-8.
  5. Vaisi-Raygani A, Rahimi Z, Nomani H et al. The presence of apolipoprotein epsilon4 and epsilon2 alleles augments the risk of coronary artery disease in type 2 diabetic patients. Clin Biochem 2007; 40(15):1150-6.
  6. Ciftdogan DY, Coskun S, Ulman C et al. The association of apolipoprotein E polymorphism and lipid levels in children with a family history of premature coronary artery disease. J Clin Lipidol 2012; 6(1):81-7.
  7. Vasunilashorn S, Glei DA, Lan CY et al. Apolipoprotein E is associated with blood lipids and inflammation in Taiwanese older adults. Atherosclerosis 2011; 219(1):349-54.
  8. de Andrade M, Thandi I, Brown S et al. Relationship of the apolipoprotein E polymorphism with carotid artery atherosclerosis. Am J Hum Genet 1995; 56(6):1379-90.
  9. Eichner JE, Kuller LH, Orchard TJ et al. Relation of apolipoprotein E phenotype to myocardial infarction and mortality from coronary artery disease. Am J Cardiol 1993; 71(2):160-5.
  10. Wilson PW, Myers RH, Larson MG et al. Apolipoprotein E alleles, dyslipidemia, and coronary heart disease. The Framingham Offspring Study. JAMA 1994; 272(21):1666-71.
  11. Wilson PW, Schaefer EJ, Larson MG et al. Apolipoprotein E alleles and risk of coronary disease. A meta-analysis. Arterioscler Thromb Vasc Biol 1996; 16(10):1250-5.
  12. Sharrett AR, Ballantyne CM, Coady SA et al. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: The Atherosclerosis Risk in Communities (ARIC) Study. Circulation 2001; 104(10):1108-13.
  13. Volcik KA, Barkley RA, Hutchinson RG et al. Apolipoprotein E polymorphisms predict low density lipoprotein cholesterol levels and carotid artery wall thickness but not incident coronary heart disease in 12,491 ARIC study participants. Am J Epidemiol 2006; 164(4):342-8.
  14. Bennet AM, Di Angelantonio E, Ye Z et al. Association of apolipoprotein E genotypes with lipid levels and coronary risk. JAMA 2007; 298(11):1300-11.
  15. Ordovas JM, Mooser V. The APOE locus and the pharmacogenetics of lipid response. Curr Opin Lipidol 2002; 13(2):113-7.
  16. Sarkkinen E, Korhonen M, Erkkila A et al. Effect of apolipoprotein E polymorphism on serum lipid response to the separate modification of dietary fat and dietary cholesterol. Am J Clin Nutr 1998; 68(6):1215-22.
  17. Carmena R, Roederer G, Mailloux H et al. The response to lovastatin treatment in patients with heterozygous familial hypercholesterolemia is modulated by apolipoprotein E polymorphism. Metabolism 1993; 42(7):895-901.
  18. Chiodini BD, Franzosi MG, Barlera S et al. Apolipoprotein E polymorphisms influence effect of pravastatin on survival after myocardial infarction in a Mediterranean population: the GISSI-Prevenzione study. Eur Heart J 2007; 28(16):1977-83.
  19. Donnelly LA, Palmer CN, Whitley AL et al. Apolipoprotein E genotypes are associated with lipid-lowering responses to statin treatment in diabetes: a Go-DARTS study. Pharmacogenet Genomics 2008; 18(4):279-87.
  20. Vossen CY, Hoffmann MM, Hahmann H et al. Effect of APOE genotype on lipid levels in patients with coronary heart disease during a 3-week inpatient rehabilitation program. Clin Pharmacol Ther 2008; 84(2):222-7.
  21. Novel Lipid Risk Factors in Risk Assessment and Management of Cardiovascular Disease Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2012 July) Pathology/Laboratory 2.04.65.
History
October 2013  New 2013 BCBSMT medical policy.  Determination of the apolipoprotein E (apo E) genotype or phenotype in the risk assessment and management of cardiovascular disease is considered experimental, investigational and unproven.
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Apolipoprotein E Genotype or Phenotype Testing in the Risk Assessment and Management of Cardiovascular Disease