Consensus Panel Recommendation for Incorporating Lipoprotein-Associated Phospholipase A2 Testing into Cardiovascular Disease Risk Assessment Guidelines

Inflammatory Markers in Cardiovascular Disease Risk Assessment of Adults at Moderate Risk 

The ATP III guidelines published in 2001 endorsed the assessment of traditional coronary artery disease (CAD) risk factors and the calculation of 10-year CAD risk using standard tables or a Framingham risk calculator for individuals with ≥2 such risk factors. For those with a 10-year CAD risk of 10%–20%, interventions were recommended to achieve low-density lipoprotein (LDL) cholesterol levels <130 mg/dL (1 mg/dL = 0.02586 mmol/L). ATP III allowed the use of inflammatory markers as an adjunct to traditional risk factor assessment to help identify which moderate-risk individuals should be reclassified as high risk, thereby justifying reduction in the LDL cholesterol goal from <130 to <100 mg/dL (Figure 1).

View Large Image Download to PowerPoint

Figure 1. Inflammatory markers incorporated into the National Cholesterol Education Project Adult Treatment Panel III (ATP III) guidelines as adjunctive to risk assessment. The ATP III guidelines incorporated the optional use of inflammatory markers in moderate-risk persons to intensify lowering of the LDL cholesterol (LDL-C) target from <130 mg/dL to <100 mg/dL (1 mg/dL = 0.02586 mmol/L). CAD = coronary artery disease; CV = cardiovascular; FRS = Framingham risk score; HDL = high-density lipoprotein; TIA = transient ischemic attack. (Adapted from Circulation.1, 2)

The AHA/CDC, in a review of inflammatory markers published in 2003, concluded that it was reasonable to measure a marker of systemic inflammation, high-sensitivity C-reactive protein (hs-CRP), to detect enhanced absolute risk in persons in whom multiple risk factor scoring projects a 10-year CAD risk of 10%–20%. Since the publication of the AHA/CDC scientific statement, a substantial body of peer-reviewed studies has highlighted Lp-PLA2 as an important cardiovascular risk marker. Lp-PLA2 is a lipoprotein-associated, macrophage-secreted enzyme that perpetuates plaque inflammation and whose elevated levels predict a 40%–400% (averaging about 100%) increased risk of myocardial infarction (MI) and stroke in population studies fully adjusted for other CVD risk factors.5 Elevated Lp-PLA2 and hs-CRP in combination reproducibly identify low-, intermediate-, and high- (relative risk >4-fold for CAD and >10-fold for stroke) risk patients in moderate-risk populations.6 The panel endorses the independent value of Lp-PLA2 as well as its additive value to hs-CRP in assessing MI risk in moderate-risk populations.6, 7, 8

Opportunities for stroke primary prevention are commonly missed because there is no AHA/American Stroke Association (ASA)–sanctioned algorithm for stroke risk assessment. Determining patients at high risk for stroke is difficult because total and LDL cholesterol do not predict stroke. A Framingham-based stroke risk calculator was proposed in 1991, but it has not been endorsed by the national associations or medical societies.9 Although the 2006 primary stroke prevention AHA/ASA guidelines recommend that stroke risk be assessed, they also comment directly on such “calculators”: “Although stroke risk–assessment tools exist, the complexities of the interactions of risk factors and the effects of certain risk factors stratified by age, gender, race-ethnicity, and geography are incompletely captured by any available global risk-assessment tool.”10 The panel recommends testing Lp-PLA2 to help identify moderate-risk individuals who may be at high risk of stroke for whom more intensive lifestyle and pharmacotherapies are indicated to achieve LDL cholesterol levels <100 mg/dL and reduce events.11, 12, 13 The panel endorses further assessment of the value of Lp-PLA2 in contemporary stroke risk assessment metrics and study of the relation among more aggressive blood pressure control, Lp-PLA2 levels, and transient ischemic attack/stroke incidence.

Although formal Framingham Risk Scoring is recommended in guidelines to determine which patients with 2 risk factors are at a <10%, 10%–20%, and >20% 10-year CAD risk, understanding of and compliance with the formal risk calculation algorithm is low. The consensus panel therefore endorses a simplified framework (Table 1), based on counting of traditional Framingham risk factors in which any patient with 2 risk factors is recommended for Lp-PLA2 testing, given that the risk is at least moderate for such individuals. In addition, patients aged ≥65 years or patients who smoke are often at moderate CVD risk, despite having a single risk factor. Lastly, the single largest diagnostic group of moderate-risk persons are those with metabolic syndrome, and it has been demonstrated that elevated Lp-PLA2 adds significantly to CVD risk in these patients.14, 15 Therefore, the panel recommends that any patient diagnosed with metabolic syndrome or a fasting blood glucose value ≥100 mg/dL (1 mg/dL = 0.0555 mmol/L)be considered at moderate risk and a candidate for Lp-PLA2 testing.

Table 1. Criteria for a simplified framework to identify patients with at least moderate risk for cardiovascular disease (CVD)⁎

	•Any age with 2 risk factors† •Age ≥65 yearsAge ≥65 years⁎ •Smoker •Fasting blood glucose level ≥100 mg/dL (1 mg/dL = 0.0555 mmol/L) •Metabolic syndrome

⁎ A patient with ≥1 of the criteria is at moderate risk for CVD. † Smoking, hypertension, family history of premature coronary artery disease, low levels of high-density lipoprotein cholesterol (<40 mg/dL for men, <50 mg/dL for women [1 mg/dL = 0.02586 mmol/L]).

Inflammatory Marker Utility in Patients with Coronary Artery Disease Risk Equivalents or Diabetes Mellitus 

The establishment of a new optional LDL cholesterol goal of <70 mg/dL in the ATP III 2004 update for individuals at very high risk2 and as a reasonable goal in the AHA/CDC guidelines for secondary prevention for patients with coronary and other atherosclerotic disease4 provides for the additional utility of inflammatory markers to identify which high-risk individuals can be reclassified as very high risk, justifying the more aggressive LDL cholesterol goal of <70 mg/dL. Many high-risk patients taking statins have a significant residual risk that is identifiable with Lp-PLA2 testing. This was recently demonstrated in >12 secondary prevention studies.16 In addition, 3 studies of patients with type 2 diabetes mellitus have shown that elevated Lp-PLA2 further increases CVD risk.17, 18, 19

Therefore, the panel recommends extending the national guidelines for inflammatory marker testing in moderate-risk patients to also include high-risk patients, including patients with CAD or CAD equivalent risk.

Guideline classification of high CVD risk has been based on the presence of symptomatic atherosclerosis or diabetes, often with clinical events. The role of emerging vascular imaging technologies to detect evolving atherosclerosis before clinical appearance remains an active area of investigation and a frontier for guidelines. A consideration of the indications for vascular imaging technologies is beyond the scope of this document. However, the panel endorses the use of Lp-PLA2 in a combinatorial fashion with an expanded set of noninvasive measures of pre/subclinical atherosclerosis (Figure 2) when available, given the incremental risk prediction demonstrated with elevated Lp-PLA2 and the detection of coronary or carotid atherosclerosis on vascular imaging.8, 20, 21, 22 Therefore, Lp-PLA2 testing would add value in an expanded pool of individuals classified as high risk, such as those with carotid stenosis >50% by ultrasound or an ankle-brachial index <0.9. Also, the AHA guidelines for prevention of cardiovascular disease in women expanded the high CVD risk category to include patients with chronic kidney disease.23 Because elevated Lp-PLA2 is independent of glomerular filtration rate in patients with chronic kidney disease24 and adds to the CVD risk associated with measures of renal function (eg, cystatin C, in high-risk patients),25 its use is recommended in high-risk patients with CVD and chronic kidney disease. Because hs-CRP values >2mg/L have been associated with a residual risk beyond that conferred by LDL cholesterol level alone,26 and Lp-PLA2 in combination with hs-CRP can more potently discriminate low- and high-risk patients with CVD, the panel recommends the use of the Lp-PLA2 assay in individuals with CVD risk factors and hs-CRP values >2mg/L. In patients, such as those described above with high Lp-PLA2 levels, the LDL cholesterol target should be reduced by 30 points (ie, from 130 mg/dL to 100 mg/dL for moderate-risk patients reclassified as high risk and from 100 mg/dL to 70 mg/dL for high-risk patients reclassified to very high risk (Figure 2).

View Large Image Download to PowerPoint

Figure 2. Recommendation for use of lipoprotein-associated phospholipase A2 (Lp-PLA2) testing. The consensus panel endorses Lp-PLA2 testing in moderate-risk persons determined as having simply 2 risk factors. An Lp-PLA2 >200 ng/mL warrants reclassification of the moderate-risk patient as high cardiovascular risk and should prompt reduction of the low-density lipoprotein cholesterol (LDL-C) target from <130 mg/dL to <100 mg/dL (1 mg/dL = 0.02586 mmol/L). Similarly, patients with coronary artery disease (CAD) or CAD risk equivalents may be considered at very high risk when Lp-PLA2 is elevated, warranting reduction in the LDL-C target from <100 mg/dL to <70 mg/dL. The panel expands the definition of CAD risk equivalent from the original Adult Treatment Panel III (ATP III) definition, based on current evidence. *Suggested frequency of Lp-PLA2 testing: measure individuals with Lp-PLA2 ≤200 ng/mL annually for continued monitoring of risk classification. CV = cardiovascular; HDL = high-density lipoprotein; hs-CRP = high-sensitivity C-reactive protein. TIA = transient ischemic attack. (Adapted from Circulation.1, 2, 3)

The consensus panel has reviewed an earlier recommendation of a conservative cut point or decision value of 235 ng/mL for Lp-PLA2 mass concentration, based in part on the 50th percentile level of Lp-PLA2 in a healthy population.27 Based on a review of several recent Lp-PLA2 studies finding an apparent risk threshold for cardiovascular events at the second tertile for Lp-PLA2 elevation, we endorse lowering the cut point, so that a value >200 ng/mL would indicate that the patient is at higher risk.20, 22, 25, 28

Once a patient is correctly reclassified as high or very high CVD risk, health outcomes will be improved by lowering the LDL cholesterol treatment target. It is now well established that lowering LDL cholesterol in higher-risk patients lowers the number of CVD events, regardless of baseline LDL cholesterol levels (Figure 3).2, 4, 29, 30, 31, 32, 33

View Large Image Download to PowerPoint

Figure 3. Event rates plotted against low-density lipoprotein (LDL) cholesterol levels during statin therapy in secondary prevention studies. Once patients are determined to be at high risk for coronary artery disease (CAD), further reduction of LDL cholesterol improves health outcomes, regardless of baseline LDL cholesterol. Therefore, patients at moderate or high cardiovascular risk with elevated lipoprotein-associated phospholipase A2 will benefit from further LDL cholesterol lowering. Event rates for the HPS, CARE, and LIPID studies are for death from CAD and nonfatal myocardial infarction. Event rates for the 4S and TNT studies also include resuscitation after cardiac arrest. *For cholesterol, 1 mg/dL = 0.02586 mmol/L. 4S = Scandinavian Simvastatin Survival Study; CARE = Cholesterol and Recurrent Events; HPS = Heart Protection Study; LIPID = Long-Term Intervention with Pravastatin in Ischaemic Disease; TNT = Treating to New Targets. (Adapted with permission from N Engl J Med29; Adapted from Lancet,30, 33 and N Engl J Med.31, 32)

Also, in regards to patients who are already defined as very high risk based on recent acute coronary syndrome, multiple or poorly controlled/controllable risks, but for whom the LDL cholesterol target of 70 mg/dL has been achieved, there is evidence from small clinical trials that combination lipid-modifying treatments to reduce LDL cholesterol, increase high-density lipoprotein (HDL) cholesterol, and/or reduce triglycerides can be an even more effective risk reduction strategy. Large ongoing trials of combination therapies in high-risk populations (eg, the Action to Control Cardiovascular Risk in Diabetes [ACCORD] study, and the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL-C/High Triglyceride and Impact on Global Health Outcomes [AIM-HIGH] study) should demonstrate conclusively the benefit of such treatments. Very-high-risk patients already taking statins with LDL cholesterol at target but high Lp-PLA2 levels should be considered for combination lipid-modifying therapies that modify HDL cholesterol and triglycerides. This is supported by studies that identified additional incremental reductions in Lp-PLA2 levels when niacin or fish oils were added to patients already taking statins. Of note in these studies, the additional reductions in Lp-PLA2 would not have been predicted by changes in LDL cholesterol.

Conclusion 

Traditional risk factor counting, lipid measurement, and cardiac imaging do not directly assess whether a patient has rupture-prone, thin-fibrous cap plaque(s). In contrast, elevation in blood levels of Lp-PLA2 at minimum indicates that plaque inflammation and endothelial dysfunction is present and that preventive treatments should be intensified. A simplified approach to cardiovascular risk stratification is proposed that builds on the national cholesterol and inflammatory marker guidelines. Our proposed algorithm should enable a simple, rapid, and more accurate determination of who is at high or very high CVD event risk by incorporating Lp-PLA2 as an adjunct to traditional risk factors and measures of evolving atherosclerosis.

There are several advantages to this approach. First, although it is easy for busy clinicians to identify persons who have ≥2 CVD risk factors, widespread use of Framingham risk calculation tools has not been successfully implemented, even in academic medical school settings.34 Furthermore, Framingham risk scoring may underestimate risk in nonwhite populations, whereas Lp-PLA2 seems to be a consistent CVD risk predictor in studies across different ethnic populations.35 Also, there is a significant potential for less reliance on relatively expensive imaging studies or invasive testing to assess CVD risk. Although an elevated Lp-PLA2 does not indicate in which arterial bed an advanced plaque may reside, it should signal a shift in perception of atherosclerosis as a preventable, systemic disease related to inflammation, plaque rupture, and thrombosis. The remedies should therefore be primarily systemic, including intensification of lifestyle changes, as well as pharmacologic lipid-modifying therapies. Elevated Lp-PLA2 levels should remind clinicians to discuss stroke risk and prevention with their patients, and it might serve as a compliance tool. The recent findings of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial, which compared “optimal medical therapy” to percutaneous interventions plus optimal medical therapy in patients with stable CAD, demonstrated that intensification of lifestyle and lipid treatment, especially combination lipid-modifying treatment, may lead to the need for fewer invasive interventions.36

Lp-PLA2 testing is not recommended for use in low-risk populations as a screening tool, but is recommended in persons assessed to be at moderate or high CVD risk by traditional risk assessment. Based on the current state of knowledge, the consensus panel recommends that Lp-PLA2 testing be used in conjunction with this simplified model of CVD risk assessment in non–low-risk individuals to identify persons who are at increased risk for heart attack and/or stroke. These individuals, once identified as at even higher CVD risk, would then benefit from achieving more favorable lipid values through intensification of lifestyle modification and lipid-modifying therapies.

Recommended areas of future research include: (1) ongoing and future trials using a low molecular weight inhibitor of the Lp-PLA2 enzyme; (2) further evaluation of Lp-PLA2 in combination with other biomarkers (such as low HDL, high lipoprotein[a], high oxidized phospholipids, etc.) to further improve the area under the curve or c statistic and also to better reclassify moderate-risk persons; (3) evaluation of Lp-PLA2 in combination with noninvasive imaging (eg, carotid intima–media thickness, coronary calcium scoring) to better identify high- (and low-) risk patients; and (4) analyses of the cost-effectiveness of more accurate risk stratification with biomarker testing.

Determining whether the treatment of patients with elevated Lp-PLA2 in the absence of LDL cholesterol elevation to the level currently indicating lipid-modifying therapies improves clinical outcomes should also be a high priority. Development of risk algorithms for ischemic stroke, where Lp-PLA2 appears to be most robust, may be particularly helpful, especially in light of the recent Prospective Studies Collaboration findings that elevated levels of total, LDL, and non-HDL cholesterol are not useful stroke risk predictors.37 Finally, Lp-PLA2, as with hs-CRP, is lowered by lipid-modifying therapy, and low levels of Lp-PLA2 have been associated with a very low risk of cardiovascular events in both low- and high-risk populations.20, 22, 25, 28 Although the use of serial measurement of Lp-PLA2 in patients on lipid-modifying treatment to assess for plaque stabilization has not been formally studied and is not currently endorsed by this panel, this application represents a promising hypothesis to test in the future.

Author Disclosures 

The authors who contributed to this article have disclosed the following industry relationships.

Michael H. Davidson, MD, is a member of the Speakers' Bureau for Abbott Laboratories, AstraZeneca Pharmaceuticals, Daiichi-Sankyo, Inc., diaDexus, Inc., Merck & Co., Inc., Merck/Schering-Plough, Oscient Pharmaceuticals, Pfizer, Inc, and Takeda Pharmaceuticals; is a consultant for Abbott Laboratories, AstraZeneca Pharmaceuticals, Daiichi-Sankyo, Inc., diaDexus, Inc., Merck & Co., Inc., Merck/Schering-Plough, Pfizer, Inc, Roche Pharmaceuticals, sanofi aventis, and Takeda Pharmaceuticals; has received grant/research support from Abbott Laboratories, AstraZeneca Pharmaceuticals, Daiichi-Sankyo, Inc., Merck & Co., Inc., Merck/Schering-Plough, Pfizer, Inc, Roche Pharmaceuticals, and Takeda Pharmaceuticals; is on the advisory board for Abbott Laboratories, Access Health, Atherogenics, AstraZeneca Pharmaceuticals, Daiichi-Sankyo, Inc., Merck & Co., Inc., Merck/Schering-Plough, Oscient Pharmaceuticals, Pfizer, Inc, Roche Pharmaceuticals, Takeda Pharmaceuticals and is on the Board of Directors for Angiogen and Sonogene and is Chief Medical Officer of Professional Evaluation, Inc.

Marshall A. Corson, MD, is on the Speakers' Bureau for Abbott Laboratories, diaDexus, Inc., Forest Pharmaceuticals, Merck/Schering-Plough, Novartis, Oscient, and Pfizer, Inc.; his wife is an employee of diaDexus, Inc., and is a shareholder in Merck and Novartis.

Jeffrey L. Anderson, MD, has received speaker honoraria from diaDexus, Inc. who has also supported research projects with his institution.

Philip B. Gorelick, MD, is a consultant for Bayer; is on the Speakers' Bureau and is a Stroke Steering Committee member for Boehringer Ingelheim; and is a study adjudicator for Pfizer, Inc.

Peter H. Jones, MD, has received research grants from Abbott Laboratories, and AstraZeneca; and serves as a consultant for Abbott Laboratories, AstraZeneca, Pfizer Inc, and Merck/Schering-Plough.

Mark J. Alberts, MD, is a member of the Speakers' Bureau and serves as a consultant for diaDexus, Inc.

Amir Lerman, MD, has no financial arrangement or affiliation with a corporate organization or manufacturer of a product discussed in this article.

Joseph P. McConnell, PhD, has no financial arrangement or affiliation with a corporate organization or manufacturer of a product discussed in this article.

Howard S. Weintraub, MD, is on the Speakers' Bureau for Pfizer Inc, CVT, diaDexus, Inc., Novartis, Merck, and Takeda Pharmaceuticals.