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The conclusions indicated that LDL-C, HDL-C, triglycerides (TG) and Lp(a), without additional apolipoproteins or lipid subfractions, were substantial predictors of CHD. Unlike other apolipoprotein evaluation, Lp(a) was found to have independently risk prediction significance. The clinical value of the Lp(a) needs to be judged against the cost of the test, what treatment plan would be initiated based on the Lp(a) measurement, and whether the Lp(a) measurement adds significant predictive value when included with the other lipid measurements (Sharrett, 2001).
Lipoprotein-associated phospholipase A2 (Lp-PLA2) An expert consensus panel (Davidson, 2008), evaluated how Lp- PLA2 might be used for determining CVD risk and concluded that testing is not recommended for the general population or for persons who are at low risk. The panel defined a simplified approach to determining criteria for testing of persons who are at least moderate-risk for CHD and
includes the following individuals:
- any age with two major risk factors
- age greater than or equal to 65 years with one major risk factor
- cigarette smoking
- fasting blood glucose greater than or equal to 100 mg/dl
- metabolic syndrome Lp-PLA2 levels greater than 200 mg/dl warrants risk reclassification and reduction of LDL levels. The authors suggest annual testing for individuals with levels greater than 200 mg/dl. The evidence reviewed by the panel lends some support to further stratify risk in select individuals and there is some evidence in the published medical literature that statin drugs and fibrates may reduce Lp-PLA2 levels. It is not presently known whether lowering Lp-PLA2 levels will decrease the incidence of CHD or stroke and improve clinical health outcomes. Treatment for elevated Lp-PLA2 is targeted at lowering LDL levels.
Corsetti et al. (2006) performed a factor analysis on blood markers and lipoprotein-associated phospholipase A2 (LpPLA2) for 766 patients of the Thrombogenic Factors and Recurrent Coronary Events (THROMBO) postinfarction study.
Their multivariable analysis concluded Lp-PLA2 is related to both hypercholesterolemia and high triglyceride-low HDL dyslipidemia in their study population.
Koenig et al. (2006) determined plasma concentrations and activity of Lp-PLA2 in 1051 patients aged 30 to 70 years old Cardiovascular Disease Risk Tests - Commercial Medical Management Guideline who had coronary heart disease and were followed for four years. In multivariable analyses, Lp-PLA2 mass and activity were strongly associated with cardiovascular events after controlling for traditional risk factors. They concluded that increased levels of Lp-PLA2 predicts future cardiovascular events in patients who already exhibit heart disease.
May et al. (2006) investigated Lp-PLA2 as an independent predictor of angiographic diagnosis of coronary artery disease and coronary death. Lp-PLA2 and C-reactive protein were measured in 1493 consecutive patients enrolled in the registry of the Intermountain Heart Collaborative Study. All patients underwent coronary angiography for coronary artery disease and were followed for 6.7 years for cardiovascular events. Lp-PLA2 was confirmed to predict the risk of coronary artery disease related death, but not all-cause death.
The Rotterdam study (Oei, 2005) is a population-based follow-up study of 7983 subjects 55 years of age. The authors performed a case-cohort study, including 308 coronary heart disease cases, 110 ischemic stroke cases, and a random sample of 1820 subjects. Compared with the first quartile of Lp-PLA2 activity, multivariate-adjusted hazard ratios for coronary heart disease for the second, third, and fourth quartiles were 1.39, 1.99, and 1.97, respectively. Corresponding multivariate-adjusted hazard ratios for ischemic stroke were 1.08, 1.58, and 1.97. The relation between Lp-PLA2 and coronary heart disease was present in both subjects with non-HDL cholesterol levels below the median and those with non-HDL cholesterol levels above the median. The authors concluded that Lp-PLA2 activity is an independent predictor of coronary heart disease and ischemic stroke in the general population.
Ballantyne et al. (2005) assessed Lp-PLA2 and C-reactive protein (CRP) levels to examine their relation to ischemic stroke in a prospective case-cohort study of 12,762 middle-aged men and women in the ARIC study. After exclusion of subjects with missing information, the final sample size for the analysis was 960. Both Lp-PLA2 and CRP levels were associated with ischemic stroke after adjustment for age, sex, and race. Hazard ratios were 2.23 for the highest vs the lowest tertile of Lp-PLA2 and 2.70 for CRP level higher than 3 vs lower than 1 mg/L.
While these studies suggest that Lp-PLA2 is an independent risk factor for CHD, there is a lack of agreement on how this information would be used in clinical decision-making. The key outcome of risk assessment for coronary heart disease (CHD) or ischemic stroke prediction is an improvement in health outcomes, i.e., reduced morbidity and mortality.
Improved risk prediction does not by itself result in improved health outcomes. At the present time, measurements of LpPLA2 are not a component of the guidelines developed by the National Cholesterol Education Program Adult Treatment Panel III. While studies have suggested that statin drugs and fibrates may reduce levels of Lp-PLA2, it is not known whether such drug therapy in patients not already considered candidates based on other well established risk factors will ultimately decrease the incidence of coronary heart disease or ischemic stroke.
Professional Societies/Government Organizations American College of Cardiology (ACC) The 34th Bethesda Conference Report states that in general, the available data indicate that abnormal values on atherosclerosis imaging have been associated with a three-fold or greater risk of a future CHD event. Although the supporting data for ankle-brachial index (ABI) and intima-media thickness (IMT) most clearly show an independent prognostic impact of the test results, these technologies are also most static, with little room for further technical development. None of the available noninvasive measurements for atherosclerosis have demonstrated an impact on coronary heart disease management or outcomes (ACC, 2003).
American Diabetes Association and the American College of Cardiology Foundation (ADA/ACCF) The presence of so-called subclinical vascular disease may be determined by measuring coronary calcification, carotid intima media thickness or the ankle-brachial index. Patients with documented subclinical atherosclerosis are at increased risk for cardiovascular disease and may be considered candidates for more aggressive therapy. Whether such tests improve prediction or clinical decision making in patients with diabetes or cardiometabolic risk (CMR) is unclear.
Cardiovascular Disease Risk Tests - Commercial Medical Management Guideline The clinical utility of routine measurement of lipoprotein (a) is unclear, although more aggressive control of other lipoprotein parameters may be warranted in those with high concentrations of Lp(a) (Brunzell, 2008).
American Heart Association (AHA)/American Stroke Association Stroke Council (ASA) The AHA/ASA issued a guideline on primary prevention of ischemic stroke in 2006. The guideline states that no definitive recommendations about Lp(a) or Lp-PLA2 modification can be made because of a lack of outcome studies demonstrating a clinical benefit of reducing blood levels of Lp(a) or Lp-PLA2 (Goldstein, 2006).
American Heart Association According to a 1998 scientific statement by the American Heart Association (AHA) Task Force on Risk Reduction regarding primary prevention of CHD, the preponderance of evidence suggests that Lp(a) is another lipid risk factor, like LDL-C and HDL-C, although it is not considered a major risk factor. The report stated, however, that two conditions are necessary before measurements of Lp(a) can be used routinely in risk prediction: 1) establishment of a stronger link between Lp(a) and atherogenesis, and 2) greater availability of accurate and inexpensive measurements. Thus, the current Framingham risk scoring does not take into account Lp(a) as a risk factor. The executive summary of "Beyond Secondary Prevention: Identifying the High-Risk Patient for Primary Prevention," the fifth in a series of prevention conferences sponsored by the AHA, classified Lp(a) as one of several conditional risk factors. These are ones that have been correlated with CHD risk but whose "quantitative relation to major coronary events" needs to be "defined in large prospective trials." (Greenland, 2000) American Institute of Ultrasound in Medicine (AIUM) There is insufficient evidence in the peer-reviewed medical literature establishing the value of carotid artery screening using ultrasound in asymptomatic patients without clinical risk factors. Therefore, the AIUM states that, at this time, the use of ultrasound in carotid artery screening in these patients has no proven clinical benefit (AIUM, 2003).
National Heart, Lung and Blood Institute (NHLBI) NHLBI's Third Report of the National Cholesterol Education Program (NCEP) states that the extent of carotid atherosclerosis correlates positively with the severity of coronary atherosclerosis. Furthermore, recent studies show that severity of intimal medial thickness (IMT) independently correlates with risk for major coronary events. Thus, measurement of carotid IMT theoretically could be used as an adjunct in CHD risk assessment. For instance, the finding of an elevated carotid IMT (e.g., percentile for age and sex) could elevate a person with multiple risk factors to a higher risk category. However, its expense, lack of availability, and difficulties with standardization preclude a current recommendation for its use in routine risk assessment for the purpose of modifying intensity of LDL-lowering therapy.
Even so, if carried out under proper conditions, carotid IMT could be used to identify persons at higher risk than that revealed by the major risk factors alone.
The NCEP acknowledged that apolipoprotein B is a potential marker for all atherogenic lipoproteins, but did not conclude there was sufficient clinical evidence to justify replacing the LDL as the preferred target of therapy.
The NCEP did not find strong evidence to support lipoprotein (a) testing but accepts it as an option for selected persons.
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is not addressed in these guidelines (NHLBI, 2002).
Additional Product Information HDI/PulseWave CR-2000 (HDI, Inc.) - available in the United States for research purposes only CVProfilor® DO-2020 (HDI, Inc.) CVProfilor® MD-3000 (HDI, Inc.) - not available in the United States Additional Search Terms Cardiovascular Disease Risk Tests - Commercial Medical Management Guideline carotid sonography, contour wave analysis, intimal, Lp (a), profile screening, pulse contour analysis, pulse wave analysis, waveform profiling References and Resources Resources American College of Cardiology (ACC). Can atherosclerosis imaging techniques improve the detection of patients at risk for ischemic heart disease? Proceedings of the 34th Bethesda Conference. Bethesda, Maryland, USA. October 7, 2002. J Am Coll Cardiol. 2003 Jun 4;41(11):1856-1917.
American Institute of Ultrasound in Medicine (AIUM). Official Statement on Carotid Screening in the Asymptomatic Patient. June 2003.
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;165:2479-2484.
Brohall, G, Oden, A, and Fagerberg, B. Carotid artery intima-media thickness in patients with Type 2 diabetes mellitus and impaired glucose tolerance: a systematic review. Diabet Med. 2006;23(6):609-616.
Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care.
Cohn JN, Duprez DA, Grandits GA. Arterial elasticity as part of a comprehensive assessment of cardiovascular risk and drug treatment. Hypertension. 2005 Jul;46(1):217-20.
Corsetti JP, Rainwater DL, Moss AJ, et al. High lipoprotein-associated phospholipase A2 is a risk factor for recurrent coronary events in postinfarction patients. Clin Chem. 2006;52(7):1331-8.
Davidson MH, Corson MA, Alberts MJ, et al. Consensus panel recommendation for incorporating lipoprotein-associated phospholipase A2 testing into cardiovascular disease risk assessment guidelines. Am J Cardiol. 2008 Jun 16;101(12A):51F-57F.
Duprez DA, Cohn JN. Arterial stiffness as a risk factor for coronary atherosclerosis. Curr Atheroscler Rep. 2007 Aug;9(2):139-44.
Duprez, D. A., Kaiser, D. R., Whitwam, W., et al. Determinants of radial artery pulse wave analysis in asymptomatic individuals. Am J Hypertens. 2004;17(8):647-53.
ECRI. Custom Hotline Response. CVProfilor for Measuring Arterial Elasticity for Cardiovascular Disease. December
ECRI. Custom Hotline Response. Carotid Intima-media Thickness for Assessment of Coronary Artery Disease Risk.
Espeland, MA, O'Leary, DH, Terry, JG, et al. Carotid intimal-media thickness as a surrogate for cardiovascular disease events in trials of HMG-CoA reductase inhibitors. Curr Control Trials Cardiovasc Med. 2005;6(1):3.
Cardiovascular Disease Risk Tests - Commercial Medical Management Guideline Folsom, AR, Kronmal, RA, Detrano, RC, O'Leary, DH, Bild, DE, Bluemke, DA, Budoff, MJ, Liu, K, Shea, S, Szklo, M, Tracy, RP, Watson, KE, and Burke, GL. Coronary artery calcification compared with carotid intima-media thickness in the prediction of cardiovascular disease incidence: the Multi-Ethnic Study of Atherosclerosis (MESA). Arch Intern Med.
Foody JM, Milberg JA, Robinson K, et al. Homocysteine and lipoprotein (a) interact to increase CAD risk in young men and women. Arterioscler Thromb Vasc Biol. 2000;20:493-499.
Goldstein LB, Adams R, Alberts MJ, et al. Primary prevention of ischemic stroke: A guideline from the American Heart Association/American Stroke Association Stroke Council. Stroke. 2006;37(6):1583-1633.