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MP 2.04.21 Lipoprotein(a) Enzyme Immunoassay in the Management of Cardiovascular Disease

 

Medical Policy    
Section
Medicine
Original Policy Date
5/31/01
Last Review Status/Date
Reviewed with literature search/4:2009
Issue
4:2009
  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) (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 coronary artery disease 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

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

 


 

Policy Guidelines

There is a specific CPT code for this test:

83695: Lipoprotein (a)

 


 

Benefit Application

BlueCard/National Account Issues

Determination of lipoprotein(a) (lp[a]) may be included as a component of a comprehensive cardiovascular risk assessment offered by reference laboratories. Comprehensive risk assessment may include evaluation of small low-density lipoproteins, subclassification of high-density lipoproteins, evaluation of apolipoprotein E genotype or phenotype, total plasma homocysteine, apolipoprotein B, and high-sensitivity C-reactive protein. (These components are addressed separately in policy Nos. 2.04.12 and 2.04.202.04.25.)

 


 

Rationale

Numerous prospective cohort studies and nested case-control studies 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 Lipid Research Clinics (LRC) Coronary Prevention Primary Trial, one of the first large-scale, randomized, controlled trials 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. (1) As part of the Framingham offspring study, (2) lp(a) levels were measured in 2,191 asymptomatic men between the ages of 20 and 54 years. 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 (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. (3) 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 (4) 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 (5) 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. Bennet et al. (6) evaluated lp(a) in a nested case-control study from the Reykjavik Study in 18,569 men without a prior history of MI. The odds ratio (OR) for coronary heart disease, controlling for age, gender, and year of recruitment, was 1.61 for patients in the top third of lp(a) levels compared with patients in the bottom third (95% CI: 1.41–1.84).
Zakai and co-workers (7) 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. 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. (8) The authors found that the distribution of lp(a) levels between the groups was identical. The European Concerted Action on Thrombosis (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. (9) 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.Several meta-analyses have also examined the relationship between lp(a) levels and cardiovascular risk. The most recent of these was reported by Bennet et al. (6), which 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 OR 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.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. (3,10-12) 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 (relative risk [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).
A meta-analysis summarized evidence from observational studies on the relationship between lp(a) and stroke. (13) Five prospective cohort studies and 23 case-control studies were included in this meta-analysis. 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).Evaluation of lp(a) as a risk factor is complicated by the different methodologies for measurement, the lack of a standardized assay (14), and the complex interplay of various lipid cardiovascular risk factors. For example, further studies have suggested that elevated lp(a) levels markedly affect the cardiovascular risk associated with other lipid parameters. The Quebec Cardiovascular Study (15) evaluated the ability of lp(a) levels and other lipid parameters to predict subsequent CAD events in a prospective cohort study of 2,155 men followed up for 5 years. While elevated lp(a) was not found to be an independent risk factor for ischemic heart disease, the risk associated with a moderately increased LDL was further increased by the simultaneous presence of increased lp(a) levels.

There also may be a relationship between lp(a) as a cardiovascular risk factor and hormone status in women. Suk Danik et al. (16) 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).

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. (17, 18)Lipoprotein(a) has been identified as an “emerging risk factor” in the Adult Treatment Panel (ATP) III report of the National Cholesterol Education Program. (19) However, improved risk prediction does not by itself result in better health outcomes. (20) To improve outcomes, clinicians must have the tools to translate this information into clinical practice, which requires guidelines that incorporate emerging risk factors into existing risk prediction models and that have been demonstrated to classify patients into risk categories with greater accuracy. Predictive models also need to be accompanied by treatment guidelines that target interventions toward patients who will get the most benefit.Such tools for linking lp(a) to clinical decision-making, both in risk assessment and treatment response, are currently not available. The ATP III practice guidelines continue to tie clinical decision-making to conventional lipid measures, such as total cholesterol, LDL-C, and HDL-C. As a result, there is a lack of recommendations from this body regarding how the additional information from lp(a) levels might be used in clinical practice.In 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 to prompt reconsideration of the policy statement, which remains unchanged.

 

References:

 

  1. 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.
  2. Bostom AG, Cupples LA, Jenner JL et al.Elevated plasma lipoprotein(a) and coronary artery disease in men aged 55 years and younger. A prospective study. JAMA 1996; 276(7):544-8.
  3. 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 subfractions: the Atherosclerosis Risk in Communities (ARIC) study. Circulation 2001; 104(10):1108-13.
  4. Kamstrup PR, Benn M, Tybaerg-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.
  5. 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.
  6. Bennet A, Di Angelantonio E, Erqou S et al. Lipoprotein(a) levels and risk of future coronary heart disease. Arch Intern Med 2008; 168(6):598-608.
  7. 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.
  8. Ridker PM, Hennekens CH, Stampfer MJ. A prospective study of lipoprotein(a) and the risk of myocardial infarction. JAMA 1993; 270(18):2195-9.
  9. 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.
  10. Suk Danik J, Rifai N, Buring JE et al. Lipoprotein(a), measured with an assay independent of apolipoprotein(a) isoform size, and risk of future cardiovascular events among initially healthy women. JAMA 2006; 296(11):1363-70.
  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. Smolders B, Lemmens R, Thijs V. Lipoprotein (a) and stroke: a meta-analysis of observational studies. Stroke 2007; 38(6):1959-66.
  14. Berglund L, Anuurad E. Role of lipoprotein(a) in cardiovascular disease. J Am Coll Cardiol 2008; 52(2):132-4.
  15. Cantin B, Gagnon F, Moorjani S et al. Is lipoprotein(a) an independent risk factor for ischemic heart disease in men? The Quebec Cardiovascular Study. J Am Coll Cardiol 1998; 31(3):519-25.
  16. 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.
  17. 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.
  18.  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.
  19. Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285(19):2486-97.
  20. 2002 TEC Assessments; Tab 23 (Special Report).

 

Codes

Number

Description

CPT  83695  Lipoprotein (a) (new code effective 1/1/06) 
ICD-9 Procedure     
ICD-9 Diagnosis  250  Diabetes, code range 
  272  Disorders of lipid metabolism, code range 
  410–414  Ischemic heart disease code range 
  440  Atherosclerosis, code range 
  443  Peripheral vascular disease, code range 
  V12.5  Personal history of disease of the circulatory system 
  V17.3-17.4  Family history of ischemic heart disease or other cardiovascular disease, respectively 
HCPCS     
Type of Service  Pathology/Laboratory 
Place of Service  Outpatient 

 


 

Index

Cardiovascular Risk Assessment, Lipoprotein (a)
Lipoprotein(a)

 


 

Policy History

Date Action Reason
05/31/01 Add to Medicine section New policy
04/29/03 Replace policy Policy updated; policy statement unchanged, references added
11/9/04 Replace policy Policy updated with literature review; policy statement unchanged, reference numbers 10 and 11 added
08/17/05 Replace policy Policy updated with literature review; policy statement unchanged
12/14/05 Replace policy – coding update only CPT coding and benefit application section updated. New code specific to this test added
02/15/07 Replace policy Policy updated with literature review; no change in policy statement. Reference numbers 12-14 added
04/09/08 Replace policy  Policy updated with literature review; no change in policy statement. Reference numbers 15-18 added
04/24/09 Replace policy  Policy extensively revised with literature search; previous updates condensed. References condensed and reordered; reference numbers 6, 14, and 16 added. No change to policy statement