Detecting patients with a previously unknown risk of cardiovascular disease For a more accurate assessment of cardiovascular risk

Test early.Treat right.Save lives.

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1 Young, I., Rifai, N. (2009). High-sensitivity C-reactive protein and cardiovascular disease. Clin Chem. 55, 201-2.2 Perk, J. et al. (2012). European Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 33(13), 1635-701.3 Montgomery, J.E., Brown, J.R. (2013). Vasc Health Risk Manag. 9, 37-45.4 Danesh, J. et al. (2000). Lipoprotein(a) and coronary heart disease. Circulation 102, 1082-5.5 Erqou, S. et al. (2009). JAMA 302, 412–23.6 Boffa, M.B., Koschinsky, M.L. (2013). Screening for and management of elevated Lp(a). Curr Cardiol Rep. Nov;15(11), 417.7 Thompson, G.R., Seed, M. (2014). Lipoprotein(a): the underestimated cardiovascular risk factor., Heart. Apr;100(7), 534-5.8 Nestel, P.J. et al. (2013). Plasma Lipoprotein(a) Concentration Predicts Future Coronary and Cardiovascular Events in Patients With Stable Coronary Heart

Disease Arterioscler Thromb Vasc Biol. Dec;33(12), 2902-8.9 Albers, J.J. et al. (2013). Relationship of apolipoproteins A-1 and B, and lipoprotein(a) to cardiovascular outcomes: the AIM-HIGH trial (Atherothrombosis

Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes). J Am Coll Cardiol. Oct 22;62(17), 1575-9.10 Kamstrup, P.R. et al. (2013). J Am Coll Cardiol. 61(11), 1146-56.11 Kamstrup, P.R. et al. (2009). JAMA. 301(22), 2331-9.12 Nordestgaard, B.G. et al. (2010). Eur Heart J. 31(23), 2844-53.13 Ridker, P.M. et al. (2002). Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events.

N Engl J Med. 347, 1557–1565.14 Koenig, W. et al. (2004). C-reactive protein modulates risk prediction based on the Framingham Score: implications for future risk assessment: results from a

large cohort study in southern Germany. Circulation. Mar 23;109(11), 1349-53.15 Yeh, E.T., Willerson, J.T. (2003). Coming of age of C-reactive protein: using inflammation markers in cardiology. Circulation. Jan 28;107(3), 370-1.16 Wald, D.S. et al. (2002). Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 325, 1202.17 Wilson, P.W. et al. (2005). C-reactive protein and risk of cardiovascular disease in men and women from the Framingham Heart Study.

Arch Intern Med;165, 24738.18 Yousuf, O. et al. (2013). High-sensitivity C-reactive protein and cardiovascular disease: a resolute belief or an elusive link?

J Am Coll Cardiol. Jul 30;62(5), 397-408.19 Cook, N.R. et al. (2006). The effect of including C-reactive protein in cardiovascular risk prediction models for women. Ann Intern Med. Jul 4;145(1), 21-9.20 Ridker, P.M. et al. (2002). Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events.

N Engl J Med. 347, 1557–1565.21 Myers, G. et al. (2009). (NACB LMPG Committee Members). National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Emerging

Biomarkers for Primary Prevention of Cardiovascular Disease. Clinical Chemistry. 55, 378–384.22 Pearson, T.A. et al. (2003). Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare

professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation;107, 499-511.23 Koenig, W. (2013). High-sensitivity C-reactive protein and atherosclerotic disease: from improved risk prediction to risk-guided therapy.

Int J Cardiol. Oct 15;168(6), 5126-34.24 Kang, S.S. et al. (1992). Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease. Ann Rev Nutr 12, 279–298.25 Study, N. (1995). Engl J. Med. 232, 268-91.26 McCully, K.S. (2007). Homocysteine, vitamins, and vascular disease prevention. Am J Clin Nutr 86 (suppl), 1563–1568.27 Boushey, C.J. et al. (1995). A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid

intakes. JAMA. Oct 4;274(13), 1049-57.

Traditional risk factors fail to identify all individuals at risk of CVD

Cardiovascular disease (CVD) is a major health burden: a high proportion of patients are not classified correctly or even missed entirely for cardiovascular (CV) risk assessment• More than 60 % of those who develop coronary events have only

one, or even none of the traditional risk factors, and more than half have either normal or mildly increased lipid values1

• European Society of Cardiology’s (ESC) guidelines on CV risk prevention use the SCORE risk charts to estimate to 10-year risk of fatal CV disease, which takes into consideration age, smoking status, systolic blood pressure and total cholesterol2

• Additional factors can be added to help further improve overall risk assessment2

Additional biomarkers improve current CV risk assessment

The addition of Lipoprotein(a), hsCRP and Homocysteine can add new information to current risk models. This leads to a more accurate categorization of individuals at increased risk for CV disease.3

Lp(a) is a major contributor to CVD and residual risk

• Epidemiologic studies and meta-analyses have demonstrated a robust and specific association of elevated Lipoprotein (a) Lp(a) levels with an increased risk of CHD4,5

• Almost 20 % of the population possess elevated levels of Lp(a) that place them at an increased risk for CVD6

• CVD events persisted in subjects with high Lp(a) levels who’s LDL cholesterol had been lowered <1.8 mmol/L by statin therapy.7 Lp(a) has been found to be responsible for this phenomenon8

• Lp(a) predicted CV events in both the control and placebo group, suggesting that Lp(a) still contributes to residual CV risk in patients achieving target LDL-C levels with statin therapy9

The addition of Lp(a) to risk models for CVD can improve patient risk classification• With addition of Lp(a) to risk models, 39 % and 25 % of patients

with lipoprotein(a) levels >90th percentile could be reclassified for myocardial infarction (MI) events and coronary heart disease (CHD), respectively10

• Extreme Lp(a) levels substantially improve risk prediction for MI and CHD risk10,11

• The European Atherosclerosis Society Consensus Panel recommends screening for elevated lipoprotein(a) in individuals at intermediate or high CVD/CHD risk12

hsCRP is a strong predictor of cardiovascular disease

High sensitive C-reactive protein (hsCRP) has been shown to be a predictor of CVD in multiple studies• Large scale prospective studies in the US and Europe have

consistently shown the predictive value of CRP in CVD13,14

• C-reactive protein has been shown to be a better predictor of the risk of cardiovascular events than low-density lipoprotein (LDL) cholesterol13,15

• In a meta-analysis of 22 studies with an average follow-up of 12 years, the top CRP tertile showed a 58 % increased cardiac risk compared to the bottom CRP tertile16

Risk prediction models can be improved by the addition of hsCRP• The addition of hsCRP to the Framingham risk score led

to a net classification of 11.8 % and 5.6 % for CHD and CVD respectively17,18

• More than 20 % of all participants with intermediate risk could be reclassified with the addition of hsCRP19

hsCRP is a major contributor to CVD risk

C-reactive protein has been shown to be a better predictor of the risk of cardiovascular events than low-density lipoprotein (LDL) cholesterol.20

The use of hsCRP in risk prediction is recommended by various guidelines • ESC guidelines recommend that hsCRP may be measured as

part of refined risk assessment in patients with an unusual or moderate CV risk profile21

• If risk is intermediate (10 % – 20 %) and uncertainty remains as to the use of preventive therapies such as statins or Aspirin®, then hsCRP measurement might be useful for further stratification into a higher or lower risk category22

• The optional use of hsCRP to identify patients without known CVD who may be at higher absolute risk than estimated by major risk factors, specifically, those patients at intermediate risk (e.g., 10 % to 20 % risk of coronary heart disease over 10 years). Result can guide physicians in evaluation further diagnosis or treatment decisions23

Homocysteine is a strong, independent risk factor for cardiovascular disease

Numerous clinical and epidemiologic studies have established elevated blood homocysteine (HCY) as a potent independent risk factor for vascular disease24

• Subsequent observations from approximately 80 clinical and epidemiologic studies have demonstrated that hyperhomo-cysteinemia is an independent, dose-dependent risk factor for atherosclerotic vascular disease and for arterial and venous thromboembolism20

• For example, moderate-to-intermediate hyperhomocysteinemia is present in 12 – 47 % of patients with coronary, cerebral, or peripheral arterial occlusive diseases25

Homocysteine is an early risk marker for high-risk patients with proven positive patient outcome• Meta-analysis of 72 studies has demonstrated significant

associations between homocysteine and the risk of ischaemic heart disease, deep vein thrombosis, pulmonary embolism and stroke. The results of the meta-analysis provide further strong evidence for a causal relationship between elevated homocysteine and CVD264

• Modest reduction of homocysteine is predicted to lower the risk of CVD up to 25 %

Lowering homocysteine reduce the risk up to 25 % for CVD

Predicted decrease in CVD risk following reduction in blood total homocysteine concentration.26 Whiskers represent the upper and lower 95 % confidence intervals for the calculated decrease in risk.

Homocysteine provide additive prognostic information over cholesterolA 5 μmol/L increase in HCY is equivalent to approx. 20 mg/dL increase in total cholesterol levels. Numerous studies have shown that the connection between HCY levels and athero sclerosis is even stronger than the connection between atherosclerosis and cholesterol. A concentration-dependent correlation between HCY and CV risk has been established from the Framingham study.

Homocysteine as a risk factor for coronary heart diseaseBoushey, et al., performed a meta-analysis of 27 clinical studies, and summarized the odds ratio between elevated HCY and development of vascular disease. The authors found an OR of 1.6 (95 % CI, 1.4 to 1.7) for men and 1.8 (95 % CI, 1.3 to 1.9) for women for a 5-mol/L HCY increment, suggesting that about 10 % of the population’s CHD risk appears attributable to HCY.27 This stimulated clinical investigations of HCY as a risk factor for CHD and its use in clinical patient care.

HCY Lp(a)

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Test early.Treat right.Save lives.

Detecting patients with a previously unknown risk of cardiovascular disease

1 Nestel, P.J. et al. (2013). Arterioscler Thromb Vasc Biol 33(12), 2902-8. 2 Yeh, E.T., Willerson, J.T. (2003). Circulation 107, 370-2. 3 Refsum, H. et al. (1998). Annu Rev Med 49, 31-62. 4 McCully, K.S. (2007). Am J Clin Nutr 86(suppl), 1563-8. 5 Wald, D.S. et al. (2002). BMJ 325, 1202.6 Montgomery, J.E., Brown, J.R. (2013). Vasc Health Risk Manag. 9, 37-45.

Detecting patients with a previously unknown risk of cardiovascular disease

• Lp(a) levels are associated with future CV disease and CHD events1

• hsCRP levels can identify the risk of future heart attack and stroke2

• Homocysteine is a strong, independent risk factor for CV disease3-5

• Lp(a), hsCRP and HCY improve cardiovacular risk assessment allowing for better treatment decisions6