Pending Policies - Medicine

Measurement of Phospholipase A2 in the Assessment of Cardiovascular Risk


Effective Date:04-15-2018



Measurement of lipoprotein-associated phospholipase A2 (Lp-PLA2) and secretory type II phospholipase A2 (sPLA2-IIA) are considered experimental, investigational and/or unproven in the assessment of cardiovascular risk for all indications.


Low-density lipoproteins (LDLs) have been identified as major atherogenic lipoproteins and have long been identified by the National Cholesterol Education Project as the primary target of cholesterol-lowering therapy. LDL particles consist of a surface coat composed of phospholipids, free cholesterol, and apolipoproteins surrounding an inner lipid core composed of cholesterol ester and triglycerides. Traditional lipid risk factors such as low-density lipoprotein cholesterol (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 (CAD) occur in subjects with “normal” levels of total and LDL-C. Although treatment for elevated coronary disease risk with statins targets cholesterol levels, selection for treatment involves estimation of future CAD risk using well-validated prediction models that use additional variables.

Lipoprotein-associated phospholipase A2 (Lp-PLA2), also known as platelet-activating factor acetylhydrolase, is an enzyme that hydrolyzes phospholipids and is primarily associated with LDLs. Accumulating evidence has suggested that Lp-PLA2 is a biomarker of CAD and may have a proinflammatory role in the progression of atherosclerosis. Recognition that atherosclerosis represents, in part, an inflammatory process has created considerable interest in measurement of proinflammatory factors as part of cardiovascular disease risk assessment.

Interest in Lp-PLA2 as a possibly causal risk factor for CAD has generated development and testing of Lp-PLA2 inhibitors as a new class of drugs to reduce risk of CAD. However, clinical trials of Lp-PLA2 inhibitors have not shown significant reductions in CAD end points.1-3 Furthermore, assessment of Lp-PLA2 levels has not been used in the selection or management of subjects in the clinical trials.

Secretory type II phospholipase A2 (sPLA2-IIA) is a member of the sPLA2 family that has recently been associated with cardiovascular disease in humans. It is suggested that sPLA2-IIA may have a causal role in the initiation, progression, and/or rupture of atherosclerotic plaque.

Regulatory Status

In December 2014, the PLAC® Test (diaDexus, San Francisco, CA), a quantitative enzyme assay, was cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process for lipoprotein-associated phospholipase A2 activity. It was considered substantially equivalent to a previous version of the PLAC® Test (diaDexus), which was cleared for marketing by FDA in July 2003. FDA product code: NOE.

The AccuCardia™ Test System for measurement of secretory type II phospholipase A2 (sPLA2-IIA) has not been FDA approved for clinical use in the United States.


This policy was developed June 2005 and updated periodically with literature reviews through March 2017. Following is a summary of the key literature to date.

A large body of literature has accumulated on the utility of risk factors in the prediction of future cardiac events. The evidence reviewed for this policy statement consists of large, prospective cohort studies that have evaluated the association of lipoprotein-associated phospholipase A2 (Lp-PLA2) with cardiovascular outcomes. A smaller amount of literature is available on the utility of Lp-PLA2 as a treatment target.

The National Cholesterol Education Program (NCEP) ATP-III guidelines (1) document notes that to determine their clinical significance, the emerging risk factors should be evaluated against the following criteria to determine their clinical significance:

Significant predictive power that is independent of other major risk factors.

A relatively high prevalence in the population (justifying routine measurement in risk assessment).

Laboratory or clinical measurement must be widely available, well standardized, and inexpensive, have accepted population reference values, and be relatively stable biologically.

Preferable, but not necessarily, modification of the risk factor in clinical trials will have shown reduction in risk.

A 2002 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment summarized the steps necessary to determine utility of a novel cardiac risk factor. (46) Three steps were required:

Standardization of the 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 […] independently contributes to risk assessment compared with established risk factors.

Determination of how the novel risk assessment will be used in the management of the patient, compared with standard methods of assessing risk, and whether any subsequent changes in patient management result in an improvement in patient outcome.

Analytic Validity

According to the FDA’s Summary of Safety and Effectiveness for the diaDexus’ lipoprotein-associated phospholipase A2 (Lp-PLA2) assay, the intra-assay precision for the assay was 7% coefficient of variability (CV), and the inter-assay precision was 9% CV, with a detection limit of 1.2 ng/ml Reference intervals for the Lp-PLA2 assay were calculated from samples for 251 apparently healthy males and 174 apparently healthy females aged 40 to 70 years; the reference interval calculated from the samples (central 90%) was determined to be 120 to 342 ng/mL for females and 131 to 376 ng/mL for males. (3) the FDA concluded that the assay demonstrated acceptable analytical performance.

Clinical Validity

Lp-PLA2 as a predictor of cardiovascular disease

Results of numerous, large-scale observational studies have examined whether Lp-PLA2 is an independent risk factor for cardiovascular disease. Some of these observational studies have been evaluated in systematic reviews and meta-analyses. A representative sample of some of the larger studies is given next.

Systematic Reviews of the Association Between Lp-PLA2 and CAD

Several systematic reviews and meta-analyses have summarized the association between Lp-PLA2 and cardiovascular disease in general populations.

The Emerging Risk Factors Collaboration performed a patient-level meta-analysis of the association of novel lipid risk factors with cardiovascular risk.(4) Records from 37 prospective cohort studies enrolling 165,544 participants were combined to predict cardiovascular risk over a median follow-up of 10.4 years. The authors examined the independent association of markers with cardiovascular risk and the ability to reclassify risk into clinically relevant categories. For Lp-PLA2, there were 11 studies enrolling 32,075 participants that measured this factor. Overall, Lp-PLA2 was an independent risk factor for cardiovascular events with a hazard ratio (HR) of 1.12 (95% confidence interval [CI], 1.09 to 1.21) for each 1 SD increase in Lp-PLA2 activity. There was no significant improvement in risk reclassification following the addition of Lp-PLA2 to the reclassification model, with a net reclassification improvement of 0.21 (-0.45 to 0.86). The net reclassification improvement crossing 0.0 indicates that the addition of Lp-PLA2 to the model may result in either improvement or worsening of reclassification.

A number of systematic reviews have been published that summarize the observational studies on the association of Lp-PLA2 and CV disease. (5-7) For example, Garza et al. (5) reviewed 14 observational studies enrolling 20,549 patients. This study reported the predictive ability of Lp-PLA2 levels for CV disease after adjustment for traditional cardiac risk factors. The combined odds ratio (OR) for an elevated Lp-PLA2 was reported as 1.60 (95% CI, 1.36 to 1.89) for the development of future cardiac events. A patient-level meta-analysis (6) evaluated the association between Lp-PLA2 levels, coronary artery disease (CAD), stroke, and mortality. A total of 79,036 participants from 32 prospective studies were included in this report. There were significant associations found between Lp-PLA2 and all 3 outcome measures. For every 1 standard deviation (SD) increase in Lp-PLA2 levels, the risk ratio (RR) adjusted for conventional risk factors was 1.10 (95% CI, 1.04 to 1.17) for CAD, 1.08 (95% CI, 0.97 to 1.20) for stroke, and 1.16 (95% CI, 1.09 to 1.24) for vascular death. There was also a significant association found between Lp-PLA2 levels and nonvascular deaths (RR=1.10; 95% CI, 1.04 to 1.17). The authors estimated that this strength of association was similar to that seen for non-high-density lipoprotein (HDL) cholesterol and systolic blood pressure.

Association Between Lp-PLA2 and CAD in General Population Samples

Some of the representative cohort and case-control studies evaluating the association between Lp-PLA2 and cardiovascular outcomes are described next.

The West of Scotland Coronary Prevention Study (WOSCOPS) was a 5-year, case control trial evaluating 6595 men with elevated cholesterol levels and no history of a heart attack. (8) Researchers looked at a smaller population of this study to determine if inflammatory markers such as Lp-PLA2 and high sensitivity C-reactive protein (hsCRP) were correlated with coronary heart disease (CHD) events. The 580 men who went on to have a myocardial infarction (MI) or revascularization were compared with 1160 age- and smoking-matched men who did not have an event. The results showed that those with the highest levels of Lp-PLA2 had twice the risk of an event compared with those with the lowest levels, even after adjustment for traditional risk factors and other inflammatory mediators.

The Atherosclerosis Risk in Communities (ARIC) study (9) evaluated the various risk markers and their association with increased risk in a large, diverse population of more than 12,000 people. At enrollment in the study, patients were free of CHD and were followed up for the development of the disease for the next 9 years. The case-cohort component of the study examined 2 inflammatory markers, Lp-PLA2 and hsCRP, in a subset of 608 cases and 740 controls. The results showed that elevated levels of Lp-PLA2 are higher in incident CHD cases. In people with nonelevated low-density lipoprotein (LDL) levels (<130 mg/dL), Lp-PLA2 levels were independently associated with CHD, even after adjustment for traditional risk factors and CRP. Koenig et al. (10) reported similar results in a study of 934 apparently healthy men aged 45 to 64 who were followed up between 1984 and 1998. During this period, 97 men experienced a coronary event. Elevated levels of Lp-PLA2 appeared to be predictive of future coronary events in middle-aged men with moderately elevated total cholesterol, independent of CRP.

Ballantyne et al. (11) studied Lp-PLA2 in the 12,762 apparently healthy subjects participating in the ARIC study. Mean levels of both Lp-PLA2 and CRP were higher in the 194 stroke cases; the authors concluded that Lp-PLA2 levels may provide complementary information beyond traditional risk factors in identifying those at risk for ischemic stroke. As part of the PEACE study, (12) Lp-PLA2 levels were measured in 3766 patients with stable CAD followed up for a median of 4.8 years. After adjustment for other baseline risk factors, patients in the highest quartile of Lp-PLA2 were 1.4 times more likely (95% CI, 1.17 to 1.70; p<0.001) to experience an adverse cardiovascular outcome compared with patients in the lowest quartile. Winkler et al. (13) studied 3232 consecutive patients referred for coronary angiography and reported that Lp-PLA2 levels were an independent predictor of cardiac mortality (HR=2.0; 95% CI, 1.4 to 3.1; p<0.001) after adjusting for established risk factors, including CRP and N-terminal b-natriuretic peptide. Persson et al. (14) evaluated the relationship between Lp-PLA2 and the metabolic syndrome in 4480 nondiabetic patients without a history of CAD. Both Lp-PLA2 (RR=1.54; 95% CI, 1.07 to 2.24) and the metabolic syndrome (RR=1.42; 95% CI, 1.06 to 1.90) were significant predictors of a first cardiac event. The combination of both elevated Lp-PLA2 and metabolic syndrome conferred a further increase in risk (RR=1.97; 95% CI, 1.34 to 2.90).

The Rancho Bernardo Study (15) enrolled 1077 community-dwelling elderly people without known heart disease and followed-up patients a mean of 16 years for the development of heart disease. Lp-PLA2 was an independent predictor of cardiac events, with a RR for patients in the second, third, and fourth quartiles of 1.66, 1.80, and 1.89, respectively, compared with the first quartile.

Another study evaluated the discriminatory ability of Lp-PLA2 for incident CHD in 421 cases and 800 controls from the Nurses’ Health Study.(16) Lp-PLA2 was a significant predictor of CHD after adjustment for traditional risk factors with a RR of 1.75 (95% CI, 1.09 to 2.84). It also added significantly to the discriminatory ability, as judged by an increase in the area under the curve from 0.720 without Lp-PLA2 to 0.733 with Lp-PLA2, and improved the net reclassification improvement index for discriminating between patients with and without CHD (p=0.004).

Other studies have correlated Lp-PLA2 levels with different parameters of CVD disease. Multiple publications have reported that Lp-PLA2 levels are associated with characteristics of “vulnerable atherosclerotic plaques,” both in the coronary (17) and in the carotid arteries (18). Subsequent publications also found an association between Lp-PLA2 levels and plaque rupture (19) and fibrous cap thickness in patients with acute coronary syndrome.(20) Muller et al. reported that Lp-PLA2 levels are associated with low fractional flow reserve on cardiac catheterization in 197 patients with stable CAD. (21) Tehrani et al. evaluated the association between Lp-PLA2 levels and the protective effect of high-density lipoprotein-cholesterol (HDL-C) on incident CHD among 3888 adults with known cardiovascular disease. (22) Among patients with the highest tertile of Lp-PLA2, the relationship between HDL-C and incident CHD was attenuated, although there was no consistent association of higher levels of Lp-PLA2 with CHD risk across HDL-C categories. Recent studies have shown associations between Lp-PLA2 and cardiovascular events in a nonwhite multiethnic population, (42) in the severity of angiographically defined CAD in a Chinese sample, (43) and in subclinical atherosclerosis in young adults. (44)

Some studies have shown that the association between Lp-PLA2 and CAD diminishes or disappears after adjustment for other risk factors. For example, Allison et al. (23) studied 508 patients with peripheral vascular disease followed for an average of 6.7 years. While there was a modest univariate association of Lp-PLA2 with cardiovascular events, this association disappeared after adjustment for established risk factors. In the Rotterdam Coronary Calcification Study, (24) similar results were reported. This population-based study followed 520 patients for 7 years and evaluated the association between Lp-PLA2 and coronary calcification by electron beam computed tomography scan. The unadjusted OR for each SD increase in Lp-PLA2 was 1.6 (95% CI, 1.1 to 2.4); however, this association became nonsignificant after controlling for lipid levels.

Association of Lp-PLA2 and CAD in Specific Populations

Some studies have specifically evaluated Lp-PLA2 as a risk factor in the diabetic population. For example, Saremi et al. (25) performed a substudy of the Veterans Affairs Diabetes trial examining risk factors that predicted the progression of coronary artery calcification over an average of 4.6 years of follow-up. Lp-PLA2 mass was 1 of 2 significant independent predictors that remained (p=0.01) after adjustment for standard risk factors. Hatoum et al. (26) evaluated Lp-PLA2 as a risk factor for incident CHD in 1517 diabetic patients enrolled in the Health Profession Follow-Up Study. After adjustment for standard risk factors, the RR for incident CHD for the upper quartile of Lp-PLA2 activity compared with the lower quartile was 1.39 (95% CI, 1.01 to 1.90; p=0.03).

Association Between Lp-PLA2 and CAD in Patients Receiving CAD Preventive Drugs

Interventional studies involving Lp-PLA2 suggest that the level of Lp-PLA2 is modifiable by antihyperlipidemic drugs (e.g., statins, fibrates, and niacin). An ad hoc study of the PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis In Myocardial Infarction) trial,(27) in which Lp-PLA2 levels were measured at baseline (n=3648) and at 30 days (n=3265) and patients were followed up for a mean of 24 months for death, MI, unstable angina, revascularization, or stroke suggested that patients randomized to atorvastatin 80 mg/d, but not pravastatin 40 mg/d, experienced a 20% reduction of Lp-PLA2 levels at 30 days, independent of other cardiac risk factors. The 30-day, Lp-PLA2 level was independently associated with an increased risk of CVD events. Another ad hoc study from the DIACOR (Diabetes and Combined Lipid Therapy Regimen) trial(28) demonstrated improved Lp-PLA2 levels (overall 16.8% reduction) compared with baseline, with no difference found between treatment groups among the 300 patients with diabetes and mixed dyslipidemias randomized to either fenofibrate 160 mg/d, simvastatin 20 mg/d, or both, for 12 weeks.

Rosenson randomized 55 hyperlipidemic subjects with metabolic syndrome to fenofibrate or placebo. (29) Fenofibrate treatment was associated with a 13% reduction in Lp-PLA2 mass compared with placebo. Saougos et al. studied the effect of 3 lipid-lowering agents, rosuvastatin, ezetimibe, and fenofibrate, on Lp- PLA2 levels. (30) All 3 agents significantly lowered Lp-PLA2 levels; fenofibrate also selectively increased HDL-associated Lp-PLA2 levels.

At least 2 clinical trials have examined the change in Lp-PLA2 levels in patients treated with statins versus placebo and evaluated whether the utility of Lp-PLA2 for risk stratification is modified by statin treatment. (31,32) Ridker et al. analyzed the changes in Lp-PLA2 levels among patients in the JUPITER trial, a randomized controlled trial (RCT) of 17,802 subjects randomized to rosuvastatin or placebo.(31) Among patients assigned to rosuvastatin, Lp-PLA2 mass decreased by 33.8%. In the placebo group, Lp- PLA2 levels were predictive of subsequent cardiac events, but this was not true in the rosuvastatin group. In a similar analysis of the MIRACL RCT, Ryu et al. analyzed 2587 patients treated with high-dose atorvastatin or placebo. (32) Atorvastatin reduced Lp-PLA2 levels in 2587 patients treated with high-dose atorvastatin or placebo. Atorvastatin reduced Lp-PLA2 mass by 32.1% and Lp-PLA2 activity by 29.5%. In the placebo group, Lp-PLA2 levels were predictive of adverse cardiac outcomes, but no relationship was found in the atorvastatin group. The authors estimated that treatment with statins reduced the attributable risk of death due to Lp-PLA2 by approximately 50%.

Section Summary: Clinical Validity

A large consistent body of evidence has established that Lp-PLA2 level is an independent predictor of CAD. Relatively few studies have examined the degree to which Lp-PLA2 improves on existing CAD prediction models in terms of clinically important magnitudes of reclassification. Levels of Lp-PLA2 decrease substantially after treatment with antilipid medications, including statins. However, in treated patients, Lp-PLA2 levels may no longer be associated with risk of CAD, and thus may not be useful as a measure of treatment response.

Clinical Utility

Although the preceding studies have shown that Lp-PLA2 is an independent risk factor for CAD, clinical utility depends on whether the use of Lp-PLA2 levels improves on existing models of CAD prediction, which then to translate into differences in treatment that improve patient outcomes. Establishing improved outcomes compared to existing prediction models could be demonstrated with clinical trials, but the expected difference in outcomes would probably be so small that the sample size of the trial would be impractically large. Decision modeling is another approach to estimating differences in patient outcomes due to improved reclassification of risk. A robust validated model using Lp-PLA2 levels to predict CAD outcomes is necessary to use the test to manage patients. No studies identified evaluated whether a testing strategy that uses Lp-PLA2 levels improves health outcomes.

Secretory type II Phospholipase A2 (sPLA2-IIA)

In a 2015 UpToDate article it was noted “ Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a macrophage-secreted enzyme that may perpetuate plaque inflammation and whose elevated levels predict a 40 to 400 percent (averaging about 100 percent) increased risk of myocardial infarction (MI) and stroke in population studies fully adjusted for other cardiovascular disease risk factors. Clinical trials with an inhibitor of Lp-PLA2 did not show improved outcomes.” In a 2015 UpToDate article (40), phospholipase A2 inhibitors were noted as therapies that have not been shown to improve outcomes in patients with coronary vascular disease (CVD). The article included information on three large randomized trials of lipoproteinase inhibitors that have shown no significant clinical benefits. In the VISTA-16 trial, 5145 patients with a recent acute coronary syndrome were randomly assigned to varespladib (a secretory PLA2 inhibitor) or placebo for 16 weeks. The trial was stopped early for futility and possible emerging harm. In the STABILITY trial, 15,828 patients with stable coronary heart disease were randomly assigned to either darapladib, a selective oral inhibitor of LP-PLA2, or placebo. During a median follow-up of 3.7 years, there was no significant difference in the rate of the primary end point (time to cardiovascular death, MI, or stroke) between darapladib and placebo (9.7 versus 10.4 percent; hazard ratio 0.94, 95% CI 0.85-1.03). The SOLID-TIMI 52 trial randomly assigned 13,026 patients within 30 days of hospitalization with and acute coronary syndrome to once-daily darapladib or placebo. After a median follow-up of 2.5 years, there was no significant difference between the two groups in the rate of the primary composite cardiovascular outcome of coronary heart disease death, MI, or urgent coronary revascularization for myocardial ischemia (16.3 versus 15.6 percent, respectively).

Mallet and colleagues noted the following in a review article regarding lipoprotein-associated and secreted phospholipases A2 (41). The authors of this review noted that most of the research on the different PLA2s remained confined to basic studies until the WOSCOPS study reported a positive association between high plasma levels of Lp-PLA2 and risk of coronary events. Since then, many studies appeared on the role of Lp-PLA2 and sPLA2-IIA in atherosclerosis at the level of biology and epidemiology. It is still unclear whether these PLA2s act as true biological effectors of cardiovascular diseases in humans and whether they have proven utility as biomarkers of disease severity. Evidence supporting the importance of PLA2s in atherosclerosis includes their localization in atherosclerotic lesions, their proximity to lipid deposits in the arterial wall, and epidemiological studies showing associations between circulating PLA2 levels and cardiovascular risk. Experiments in mice with deficiency or overexpression of various sPLA2s demonstrated a pathogenic role of these enzymes in atherosclerosis. Because more than 1 sPLA2 can be involved in various and possibly complementary or opposite pathways in atherosclerosis, the understanding of the expression, function, and regulation of each PLA2 subtype in specific tissues and disease states in different species is of particular importance. As a result, controlling the activity of complementary PLA2s may appear more favorable than inhibiting a specific enzyme for disease treatment. Continuing research aimed at understanding how Lp-PLA2 and sPLA2-IIA regulate vascular inflammation and plaque development in animal models and in humans is of the utmost importance to firmly establish and validate these emerging novel therapeutic strategies to combat atherosclerosis.

Summary of Evidence

For individuals who have a risk of cardiovascular disease (CVD) who receive lipoprotein-associated phospholipase A2 (Lp-PLA2) testing, the evidence includes studies of analytic validity and studies of the association between Lp-PLA2 and various coronary artery disease outcomes. Relevant outcomes are overall survival, disease-specific survival, and test validity. The studies have demonstrated that Lp-PLA2 levels are an independent predictor of CVD. Evidence of clinical utility is lacking. To improve outcomes, clinicians must have the tools to incorporate Lp-PLA2 test results into existing risk prediction models, and these models should demonstrate improved classification into risk categories that will improve treatment and health outcomes. Direct evidence for improved health outcomes with the use of Lp-PLA2 in clinical practice is lacking. Although Lp-PLA2 levels are associated with CVD risk, changes in patient management that would occur as a result of obtaining Lp-PLA2 levels in practice are not well-defined. The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Position Statements

American College of Cardiology and American Heart Association

The American College of Cardiology and American Heart Association published joint guidelines on the assessment of cardiovascular risk in asymptomatic patients in 2013 (45). Lipoprotein-associated phospholipase A2 (Lp-PLA2) testing was not mentioned in these guidelines, which was a change from 2010 guidelines (36). In this prior guideline, Lp-PLA2 was given a IIb recommendation for assessing cardiovascular risk in intermediate-risk asymptomatic adults.

American Association of Clinical Endocrinologists

The American Association of Clinical Endocrinologists published guidelines on the management of dyslipidemia and prevention of atherosclerosis in 2012. These guidelines made the following recommendations for Lp-PLA2 testing.

European Society of Cardiology et al.

In 2012, the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice issued guidelines on cardiovascular disease prevention. (38) These guidelines include the following statement about Lp-PLA2 testing: LpPLA2 may be measured as part of a refined risk assessment in patients at high risk of a recurrent acute atherothrombotic event (Class IIb recommendation; Level of Evidence B; weak evidence).


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.



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.


The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

0423T, 83698



ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual

Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <>.


1. National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Adult Treatment Panel III guidelines. 2001. Available online at: Last accessed May 12, 2014.

2. Aaronson KD, Eppinger MJ, Dyke DB, et al. Left ventricular assist device therapy improves utilization of donor hearts. J Am Coll Cardiol 2002; 39(8):1247-54.

3. FDA. 510(K) Summary -- diaDexus PLAC Test. 2013. Available online at: Last accessed May 22, 2014.

4. Di Angelantonio E, Gao P, Pennelis L, et al. Lipid-Related Markers and Cardiovascular Disease Prediction. JAMA 2012; 307(23):2499-506.

5. Garza CA, Montori VM, McConnell JP et al. Association between lipoprotein-associated phospholipase A2 and cardiovascular disease: a systematic review. Mayo Clin. Proc. 2007; 82(2):159-65.

6. Thompson A, Gao P, Orfei L et al. Lipoprotein-associated phospholipase A (2) and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies. Lancet 2010; 375(9725):1536-44.

7. Vittos O, Toana B, Vittos A et al. Lipoprotein-associated phospholipase A2 (Lp-PLA2): a review of its role and significance as a cardiovascular biomarker. Biomarkers 2012; 17(4):289-302.

8. Packard CJ, O'Reilly DS, Caslake MJ et al. Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease. West of Scotland Coronary Prevention Study Group. N. Engl. J. Med. 2000; 343(16):1148-55.

9. Ballantyne CM, Hoogeveen RC, Bang H et al. Lipoprotein-associated phospholipase A2, high sensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study. Circulation 2004; 109(7):837- 42.

10. Koenig W, Khuseyinova N, Lowel H et al. Lipoprotein-associated phospholipase A2 adds to risk prediction of incident coronary events by C-reactive protein in apparently healthy middle-aged men from the general population: results from the 14-year follow-up of a large cohort from southern Germany. Circulation 2004; 110(14):1903-8.

11. Ballantyne CM, Hoogeveen RC, Bang H et al. Lipoprotein-associated phospholipase A2, high sensitivity C-reactive protein, and risk for incident ischemic stroke in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study. Arch Intern Med. 2005; 165(21):2479-84.

12. Sabatine MS, Morrow DA, O'Donoghue M et al. Prognostic utility of lipoprotein-associated phospholipase A2 for cardiovascular outcomes in patients with stable coronary artery disease. Arterioscler. Thromb. Vasc. Biol. 2007; 27(11):2463-9.

13. Winkler K, Hoffmann MM, Winkelmann BR et al. Lipoprotein-associated phospholipase A2 predicts 5- year cardiac mortality independently of established risk factors and adds prognostic information in patients with low and medium high-sensitivity C-reactive protein (the Ludwigshafen risk and cardiovascular health study). Clin. Chem. 2007; 53(8):1440-7.

14. Persson M, Hedblad B, Nelson JJ et al. Elevated Lp-PLA2 levels add prognostic information to the metabolic syndrome on incidence of cardiovascular events among middle-aged nondiabetic subjects. Arterioscler. Thromb. Vasc. Biol. 2007; 27(6):1411-6.

15. Daniels LB, Laughlin GA, Sarno MJ et al. Lipoprotein-associated phospholipase A2 is an independent predictor of incident coronary heart disease in an apparently healthy older population: the Rancho Bernardo Study. J. Am. Coll. Cardiol. 2008; 51(9):913-9.

16. Hatoum IJ, Cook NR, Nelson JJ et al. Lipoprotein-associated phospholipase A2 activity improves risk discrimination of incident coronary heart disease among women. Am. Heart J. 2011; 161(3):516- 22.

17. Liu YS, Hu XB, Li HZ et al. Association of lipoprotein-associated phospholipase A (2) with characteristics of vulnerable coronary atherosclerotic plaques. Yonsei Med. J. 2011; 52(6):914- 22.

18. Sarlon-Bartoli G, Boudes A, Buffat C et al. Circulating lipoprotein-associated phospholipase A2 in high-grade carotid stenosis: a new biomarker for predicting unstable plaque. Eur. J. Vasc. Endovasc. Surg. 2012; 43(2):154-9.

19. Liu CF, Qin L, Ren JY et al. Elevated plasma lipoprotein-associated phospholipase A (2) activity is associated with plaque rupture in patients with coronary artery disease. Chin. Med. J. (Engl). 2011; 124(16):2469-73.

20. Gu X, Hou J, Yang S et al. Is lipoprotein-associated phospholipase A2 activity correlated with fibrouscap thickness and plaque volume in patients with acute coronary syndrome? Coron. Artery Dis. 2014; 25(1):10-5.

21. Muller O, Ntalianis A, Wijns W et al. Association of biomarkers of lipid modification with functional and morphological indices of coronary stenosis severity in stable coronary artery disease. Journal of cardiovascular translational research 2013; 6(4):536-44.

22. Tehrani DM, Gardin JM, Yanez D et al. Impact of inflammatory biomarkers on relation of high density lipoprotein-cholesterol with incident coronary heart disease: cardiovascular Health Study. Atherosclerosis 2013; 231(2):246-51.

23. Allison MA, Denenberg JO, Nelson JJ et al. The association between lipoprotein-associated phospholipase A2 and cardiovascular disease and total mortality in vascular medicine patients. J. Vasc. Surg. 2007; 46(3):500-6.

24. Kardys I, Oei HH, Hofman A et al. Lipoprotein-associated phospholipase A2 and coronary calcification. The Rotterdam Coronary Calcification Study. Atherosclerosis 2007; 191(2):377-83.

25. Saremi A, Moritz TE, Anderson RJ et al. Rates and determinants of coronary and abdominal aortic artery calcium progression in the Veterans Affairs Diabetes Trial (VADT). Diabetes Care 2010; 33(12):2642-7.

26. Hatoum IJ, Hu FB, Nelson JJ et al. Lipoprotein-associated phospholipase A2 activity and incident coronary heart disease among men and women with type 2 diabetes. Diabetes 2010; 59(5):1239- 43.

27. O'Donoghue M, Morrow DA, Sabatine MS et al. Lipoprotein-associated phospholipase A2 and its association with cardiovascular outcomes in patients with acute coronary syndromes in the PROVE IT-TIMI 22 (PRavastatin Or atorVastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction) trial. Circulation 2006; 113(14):1745-52.

28. Muhlestein JB, May HT, Jensen JR et al. The reduction of inflammatory biomarkers by statin, fibrate, and combination therapy among diabetic patients with mixed dyslipidemia: the DIACOR (Diabetes and Combined Lipid Therapy Regimen) study. J. Am. Coll. Cardiol. 2006; 48(2):396- 401.

29. Rosenson RS. Fenofibrate reduces lipoprotein associated phospholipase A2 mass and oxidative lipids in hypertriglyceridemic subjects with the metabolic syndrome. Am. Heart J. 2008; 155(3): 499 e9-16.

30. Saougos VG, Tambaki AP, Kalogirou M et al. Differential effect of hypolipidemic drugs on lipoprotein-associated phospholipase A2. Arterioscler. Thromb. Vasc. Biol. 2007; 27(10):2236-43.

31. Ridker PM, Macfadyen JG, Wolfert RL et al. Relationship of Lipoprotein-Associated Phospholipase A2 Mass and Activity with Incident Vascular Events among Primary Prevention Patients Allocated to Placebo or to Statin Therapy: An Analysis from the JUPITER Trial. Clin. Chem. 2012; 58(5):877- 86.

32. Ryu SK, Mallat Z, Benessiano J et al. Phospholipase A2 enzymes, high-dose atorvastatin, and prediction of ischemic events after acute coronary syndromes. Circulation 2012; 125(6):757-66.

33. Investigators S, White HD, Held C et al. Darapladib for preventing ischemic events in stable coronary heart disease. N. Engl. J. Med. 2014; 370(18):1702-11.

34. Mohler ER, 3rd, Ballantyne CM, Davidson MH et al. The effect of darapladib on plasma lipoprotein-associated phospholipase A2 activity and cardiovascular biomarkers in patients with stable coronary heart disease or coronary heart disease risk equivalent: the results of a multicenter, randomized, double-blind, placebo-controlled study. J. Am. Coll. Cardiol. 2008; 51(17):1632-41.

35. Serruys PW, Garcia-Garcia HM, Buszman P et al. Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque. Circulation 2008; 118(11):1172-82.

36. Greenland P, Alpert JS, Beller GA et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 2010; 56(25):e50-103.

37. Jellinger PS, Smith DA, Mehta AE et al. American association of clinical endocrinologists' guidelines for management of dyslipidemia and prevention of atherosclerosis. Endocr Pract 2012; 18 Suppl 1:1-78.

38. Members: ATF, Perk J, De Backer G et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012): The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur. Heart J. 2012; 33(13):1635-701.

39. Measurement of Lipoprotein-associated Phospholipase A2 (Lp-PLA2) in the Assessment of Cardiovascular Risk. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2015 December) 2.04.32.

40. Hennekens, C., Kaski, J., et al. Secondary prevention of cardiovascular disease. In: UpToDate, 2015, UpToDate, Waltham, MA. Accessed November 2015.

41. Mallat, Z. Lambeau, G. et al. Lipoprotein-Associated and Secreted Phospholipases A2 in Cardiovascular Disease: Roles as Biological Effectors and Biomarkers. Circulation. 2010; 122:2183-2200.

42. Garg PK, McClelland RL, Jenny NS, et al. Lipoprotein-associated phospholipase A2 and risk of incident cardiovascular disease in a multi-ethnic cohort: The multi ethnic study of atherosclerosis. Atherosclerosis. Jul 2015; b241 (1):176-182. PMID 26004387

43. Cai A, Li G, Chen J, et al. Increased serum level of Lp-PLA2 is independently associated with the severity of coronary artery diseases: a cross-sectional study of Chinese population. BMC Cardiovasc Disord. 2015; b15:14. PMID 25879827

44. Celik O, Ozturk D, Akin F, et al. Evaluation of lipoprotein-associated phosholipase A2 and plaque burden/composition in young adults. Coron Artery Dis. May 2015; 26(3):266-271. PMID 25647459

45. 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. Circulation. Jun 24 2014; 129(25 Suppl 2):S49-73. PMID 24222018

46. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Special Report: C-Reactive Protein as a Cardiac Risk Marker. TEC Assessment. 2002; 17:Tab 23.

Policy History:

4/15/2018 Reviewed. No changes.
6/1/2017 Document updated with literature review. Coverage unchanged.
4/15/2016 Reviewed. No changes.
1/1/2016 Document updated with literature review. Coverage changed to add the following: Secretory type II phospholipase A2 (sPLA2-IIA) is considered experimental, investigational and/or unproven in the assessment of cardiovascular risk for all indications. In addition, title changed from Measurement of Lipoprotein-associated Phospholipase A2 (Lp-PLA2) in the Assessment of Cardiovascular Risk. CPT/HCPCS code(s) updated.
4/1/2015 Document updated with literature review. Coverage unchanged.
2/1/2012 Document updated with literature review. Coverage unchanged.
9/1/2009 Revised/updated entire document. No change in coverage. Coverage position remains experimental, investigational, and unproven.
3/15/2007 Revised/updated entire document
6/1/2005 New medical document

Archived Document(s):

Back to Top