BlueCross and BlueShield of Montana Medical Policy/Codes
Lipoprotein(a) Enzyme Immunoassay in the 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

Lipoprotein (a) (lp[a]) is a lipid-rich particle similar to low-density lipoprotein (LDL). Apolipoprotein B is the major apolipoprotein associated with LDL; in lp(a), however, there is an additional apolipoprotein (a) covalently linked to the apolipoprotein B. The apolipoprotein (a) molecule is structurally similar to plasminogen, suggesting that lp(a) may contribute to the thrombotic and atherogenic basis of cardiovascular disease. Levels of lp(a) are relatively stable in individuals over time, but vary up to 1000-fold between individuals, presumably on a genetic basis. The similarity between apolipoprotein (a) and fibrinogen has stimulated intense interest in lp(a) as a link between atherosclerosis and thrombosis. In addition, approximately 20% of patients with coronary artery disease (CAD) have elevated levels of lp(a). Therefore, it has been proposed that levels of lp(a) may be an independent risk factor for coronary artery disease.

Traditional lipid risk factors such as LDL-C, while predictive on a population basis, are weaker markers of risk on an individual basis. Only a minority of subjects with elevated LDL and cholesterol levels will develop clinical disease, and up to 50% of cases of CAD occur in subjects with “normal” levels of total and LDL cholesterol. Thus there is considerable potential to improve the accuracy of current cardiovascular risk prediction models.

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.

Coverage

Measurement of lipoprotein (a) in the evaluation and management of cardiovascular disease is considered experimental, investigational and unproven.

Rationale

The following is a summary of the key literature to date.

Lipoprotein A as a Predictor of Cardiovascular Risk

Numerous prospective cohort studies and systematic reviews have evaluated lipoprotein (a) (lp[a]) as a cardiovascular risk factor. The following are representative prospective trials drawn from the extensive literature on this topic.

The Emerging Risk Factors Collaboration published a patient-level meta-analysis of 37 prospective cohort studies enrolling 154,544 individuals. (1) Risk prediction was examined for a variety of traditional and non-traditional lipid markers. For lp(a), evidence from 24 studies on 133,502 individuals reported that lp(a) was an independent risk factor for reduced cardiovascular risk, with an adjusted hazard ratio for cardiovascular events of 1.13 (95% CI: 1.09-1.18). The addition of lp(a) to traditional risk factors resulted in a small improvement in risk prediction, with an increase in the C-statistic of approximately 0.002. On reclassification analysis, there was no significant improvement in the net reclassification index (0.05%, 95% CI: -0.59 to 0.70).

A systematic review by Genser et al. (2) included 67 prospective studies on 181,683 individuals that evaluated the risk of cardiovascular disease associated with lp(a). Pooled analysis was performed on 37 studies that reported the endpoints of cardiovascular events. When grouped by design and populations, the relative risks for these studies, comparing the uppermost and lowest strata of lp(a), ranged from 1.64-2.37. The relative risk (RR) for cardiovascular events was higher in patients with previous cardiovascular disease compared to patients without previous disease. There were no significant associations found between lp(a) levels, overall mortality, or stroke.

The Lipid Research Clinics (LRC) Coronary Primary Prevention Trial, one of the first large-scale, RCTs of cholesterol-lowering therapy, measured initial lp(a) levels and reported that lp(a) was an independent risk factor for coronary artery disease (CAD) when controlled for other lipid and non-lipid risk factors. (3) As part of the Framingham offspring study, lp(a) levels were measured in 2,191 asymptomatic men between the ages of 20 and 54 years. (4) After a mean follow-up of 15 years, there were 129 coronary heart disease events, including myocardial infarction (MI), coronary insufficiency, angina, or sudden cardiac death. Comparing the lp(a) levels of these patients with the other participants, the authors concluded that elevated lp(a) was an independent risk factor for the development of premature coronary heart disease (i.e., before age 55 years). The Atherosclerosis Risk in Communities Study (ARIC) study evaluated the predictive ability of lp(a) in 12,000 middle-aged individuals free of CAD at baseline who were followed up for 10 years. (5) The lp(a) levels were significantly higher among patients who developed CAD compared with those who did not, and lp(a) levels were an independent predictor of CAD above traditional lipid measures.

Kamstrup and colleagues (6) analyzed data from the Copenhagen City Heart Study, which followed up 9,330 individuals from the Copenhagen general population over a period of 10 years. This study reported a graded increase in risk of cardiac events with increasing lp(a) levels. At extreme levels of lp(a) above the 95th percentile, the adjusted hazard ratio for MI was 3.6 (95% CI: 1.7–7.7) for women and 3.7 (95% CI: 1.7–8.0) in men. Tzoulaki and colleagues (7) reported data from the Edinburgh Artery Study, which was a population cohort study that followed up 1,592 individuals for a mean of 17 years. These authors reported that lp(a) was an independent predictor of MI, with an odds ratio of 1.49 (95% CI: 1.0–2.2) for the highest one-third versus the lowest one-third.

Zakai and co-workers (8) evaluated 13 potential biomarkers for independent predictive ability compared to established risk factors, using data from 4,510 individuals followed up for 9 years in the Cardiovascular Health Study. The lp(a) was 1 of 7 biomarkers that had incremental predictive ability above established risk factors. The adjusted hazard ratio for each standard deviation increase in lp(a) was 1.07 (95% CI: 1.0-1.12).

Some studies, however, have failed to demonstrate such a relationship. In the Physicians’ Health Study, initial lp(a) levels in the 296 participants who subsequently experienced MI were compared with lp(a) levels in matched controls who remained free from CAD. (9) The authors found that the distribution of lp(a) levels between the groups was identical. The European Concerted Action on Thrombosis and Disabilities (ECAT) study, a trial of secondary prevention, evaluated lp(a) as a risk factor for coronary events in 2,800 patients with known angina pectoris. (10) In this study, lp(a) levels were not significantly different among patients who did and did not have subsequent events, suggesting that lp(a) levels were not useful risk markers in this population.

Some researchers have hypothesized that there is a stronger relationship between lp(a) and stroke than for coronary heart disease. Similar to the situation with cardiac disease, the majority of prospective studies, but not all, have indicated that lp(a) is an independent risk factor for stroke. In 1 prospective cohort study, Rigal and co-workers (11) reported that an elevated lp(a) level was an independent predictor of ischemic stroke in men (OR: 3.55; 95% CI: 1.33–9.48) but not in women (OR: 0.42; 95% CI: 0.12–1.26). In the ARIC prospective cohort study of 14,221 participants, (12) elevated lp(a) was a significant independent predictor of stroke in African-American women (RR: 1.84; 95% CI: 1.05-3.07) and white women (RR: 2.42; 95% CI: 1.30–4.53) but not in African-American men (RR: 1.72; 95% CI: 0.86–3.48) or white men (RR: 1.18; 95% CI: 0.47–2.90).

There also may be a relationship between lp(a) as a cardiovascular risk factor and hormone status in women. Suk Danik et al. (13) reported the risk of a first cardiovascular event over a 10-year period in 27,736 women enrolled in the Women’s Health Study. After controlling for standard cardiovascular risk factors, lp(a) was an independent predictor of risk in women who were not taking hormonal replacement therapy (HR: 1.77; 95% CI: 1.36–2.30, p<0.0001). However, for women who were taking hormonal replacement therapy, lp(a) levels were not a significant independent predictor of cardiovascular risk (HR: 1.13; 95% CI: 0.84–1.53, p=0.18).

Several meta-analyses have also examined the relationship between lp(a) levels and cardiovascular risk. Bennet et al. (14) synthesized the results of 31 prospective studies with at least 1 year of follow-up and that reported data on cardiovascular death and nonfatal MI. The combined results revealed a significant positive relationship between lp(a) and cardiovascular risk, with an odds ratio for patients with lp(a) in the top-third compared to those in the bottom-third of 1.45 (95% CI: 1.32–1.58). This analysis reported a moderately high degree of heterogeneity in the included studies (I2=43%), reflecting the fact that not all studies reported a significant positive association.

Smolders et al. summarized evidence from observational studies on the relationship between lp(a) and stroke. (15) Five prospective cohort studies and 23 case-control studies were included in this meta-analysis. Results from prospective cohort studies, lp(a) added a modest amount of incremental predictive information (combined RR for the highest one-third of lp(a): 1.22; 95% CI: 1.04–1.43). From case-control studies, an elevated lp(a) level was also associated with an increased risk of stroke (combined OR 2.39; 95% CI: 1.57–3.63).

A patient-level meta-analysis of 36 prospective studies published between 1970 and 2009 included 126,634 participants. (16) Overall, the independent association of lp(a) with vascular disease was consistent across studies but modest in size. The combined risk ratio, adjusted for age, sex, and traditional lipid risk factor, was 1.13 (95% CI: 1.09–1.18) for coronary heart disease and 1.10 (95% CI: 1.02–1.18) for ischemic stroke. There was no association of lp(a) levels with mortality.

Genetic studies have examined the association of various genetic loci with lp(a) levels, and Mendelian randomization studies have examined whether lp(a) is likely to be causative for CAD. In one such study, (17) there were 3 separate loci identified for increased lp(a) levels. Genetic variants were identified at 2 of these loci that were independently associated with coronary disease (OR: 1.70; 95% CI: 1.49–1.95, and OR: 1.92; 95% CI: 1.48–2.49). This finding strongly implies that elevated lp(a) levels are causative of coronary disease, as opposed to simply being associated.

Lipoprotein A as Treatment Target

There is a lack of evidence to determine whether lp(a) can be used as a target of treatment. Several randomized studies of lipid-lowering therapy have included measurements of lp(a) as an intermediate outcome measurement. While these studies have demonstrated that lp(a) levels are reduced in patients receiving statin therapy, the data are inadequate to demonstrate how this laboratory test can be used to improve patient management. (18, 19)

Summary

A large amount of epidemiologic evidence has determined that lp(a) is an independent risk factor for cardiovascular disease. The overall degree of risk associated with lp(a) levels appears to be modest, and the degree of risk may be mediated by other factors such as LDL levels and/or hormonal status. There is considerable uncertainty regarding the clinical utility of measuring lp(a), specifically how knowledge of lp(a) levels can be used in clinical care of patients who are being evaluated for lipid disorders. There is scant evidence on the use of lp(a) as a treatment target for patients with hyperlipidemia. The available evidence is insufficient related to impact on clinical outcomes; testing for lp(a) 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 diagnosis codes.

ICD-10 Codes

Experimental, investigational and unproven for all diagnosis codes.

Procedural Codes: 83695
References
  1. Di Angelantonio E GP, Pennells L, et al. Lipid-Related Markers and Cardiovascular Disease Prevention. JAMA 2012; 307(23):2499-506.
  2. Genser B, Dias KC, Siekmeier R et al. Lipoprotein (a) and risk of cardiovascular disease--a systematic review and meta-analysis of prospective studies. Clin Lab 2011; 57(3-4):143-56.
  3. Schaefer EJ, Lamon-Fava S, Jenner JL et al. Lipoprotein(a) levels and risk of coronary heart disease in men. The Lipid Research Clinics Coronary Primary Prevention Trial. JAMA 1994; 271(13):999-1003.
  4. Bostom AG, Cupples LA, Jenner JL et al. Elevated plasma lipoprotein(a) and coronary heart disease in men aged 55 years and younger. A prospective study. JAMA 1996; 276(7):544-8.
  5. 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.
  6. Kamstrup PR, Benn M, Tybjaerg-Hansen A et al. Extreme lipoprotein(a) levels and risk of myocardial infarction in the general population: the Copenhagen City Heart Study. Circulation 2008; 117(2):176-84.
  7. Tzoulaki I, Murray GD, Lee AJ et al. Relative value of inflammatory, hemostatic, and rheological factors for incident myocardial infarction and stroke: the Edinburgh Artery Study. Circulation 2007; 115(16):2119-27.
  8. Zakai NA, Katz R, Jenny NS et al. Inflammation and hemostasis biomarkers and cardiovascular risk in the elderly: the Cardiovascular Health Study. J Thromb Haemost 2007; 5(6):1128-35.
  9. Ridker PM, Hennekens CH, Stampfer MJ. A prospective study of lipoprotein(a) and the risk of myocardial infarction. JAMA 1993; 270(18):2195-9.
  10. Bolibar I, von Eckardstein A, Assmann G et al. Short-term prognostic value of lipid measurements in patients with angina pectoris. The ECAT Angina Pectoris Study Group: European Concerted Action on Thrombosis and Disabilities. Thromb Haemost 2000; 84(6):955-60.
  11. Rigal M, Ruidavets JB, Viguier A et al. Lipoprotein (a) and risk of ischemic stroke in young adults. J Neurol Sci 2007; 252(1):39-44
  12. Ohira T, Schreiner PJ, Morrisett JD et al. Lipoprotein(a) and incident ischemic stroke: the Atherosclerosis Risk in Communities (ARIC) study. Stroke 2006; 37(6):1407-12.
  13. Suk Danik J, Rifai N, Buring JE et al. Lipoprotein(a), hormone replacement therapy, and risk of future cardiovascular events. J Am Coll Cardiol 2008; 52(2):124-31.
  14. Bennet A, Di Angelantonio E, Erqou S et al. Lipoprotein(a) levels and risk of future coronary heart disease: large-scale prospective data. Arch Intern Med 2008; 168(6):598-608.
  15. Smolders B, Lemmens R, Thijs V. Lipoprotein (a) and stroke: a meta-analysis of observational studies. Stroke 2007; 38(6):1959-66.
  16. Erqou S, Kaptoge S, Perry PL et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 2009; 302(4):412-23.
  17. 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.
  18. Bays HE, Dujovne CA, McGovern ME et al. Comparison of once-daily, niacin extended-release/lovastatin with standard doses of atorvastatin and simvastatin (the ADvicor Versus Other Cholesterol-Modulating Agents Trial Evaluation [ADVOCATE]). Am J Cardiol 2003; 91(6):667-72.
  19. Van Wissen S, Smilde TJ, Trip MD et al. Long term statin treatment reduces lipoprotein(a) concentrations in heterozygous familial hypercholesterolaemia. Heart 2003; 89(8):893-6.
  20. 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.  Measurement of lipoprotein (a) in the evaluation and management of cardiovascular disease is considered experimental, investigational and unproven. 
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Lipoprotein(a) Enzyme Immunoassay in the Management of Cardiovascular Disease