New biochemical markers of risk of Coronary Heart Disease (CHD)

Chris PearceACS SSC

Aims and ObjectivesIntroduction – why look for new biomarkers?

Possible candidates.

hsCRP - Primary CHD. - Disadvantages.

Clinical relevance.

Traditional risk factorsLow specificity and sensitivity:

1.Coronary events occur in those with low risk lipid levels. (Ridker et al, 2002)

2.20-25% of events occur in those with only one risk factor. (Khot et al, 2003)

New biomarkers – Inflammation?

(Libby, 2004)

Candidates

(Ridker et al, 2004)

CandidateshsCRP =

High Sensitivity C-reactive Protein

(Ridker et al, 2004)

Emergence of hsCRP

(Ridker et al, 1997)

Emergence of hsCRP

(Ridker et al, 1997)

Incident myocardial infarction28, 263 women, used a

commercially available assay for hsCRP.

(Ridker et al, 2000)

27,939 women, showing CRP t0 be better than LDL.

(Ridker et al, 2002)

Clinical risk stratification tools

(Ridker and Cook, 2004)

(Cook et al, 2006)

Clinical risk stratification tools50% of

intermediate risk women re-classified.

More accurate correlation with observed disease.

(Ridker et al, 2007a)

Clinical risk stratification tools50% of

intermediate risk women re-classified.

More accurate correlation with observed disease.

(Ridker et al, 2007)

Response to statin therapy

Effects seen to be largely independent of changes in lipid concentration.

(Albert et al, 2001)

Response to statin therapy

Effects seen to be largely independent of changes in lipid concentration.

(Albert et al, 2001)

(Ridker et al, 2005)

Response to statin therapy

Future treatment

The JUPITER trial.

17,802 person with LDL cholesterol <3.36 mmol/Litre, but hsCRP over >2 mg/Litre from 26 countries.

Randomised to 20mg Rosuvastatin OD or placebo.

Enrolment completed by December 2006, with initial three year follow up.

(Ridker et al, 2007b)

Disadvantages to CRPGenetics – Is the ability to make CRP

genetically determined?

Inflammation – Can risk stratification be influenced by systemic inflammation?

Implications for practice America – 2003 CDCP/AHA publish first set of

guidance cautiously endorsing use of CRP as an adjunct to traditional risk factors.

(Pearson et al, 2003)

UK – 2007 NICE guidance on secondary prevention of MI gives no mention of CRP.

UK – 2010 NICE “Guidance on the prevention of cardiovascular disease at the population level,” expected.

http://www.nice.org.uk

ConclusionThe evidence base for CRP as a predictor of first

cardiovascular events is strong.

A response to statin therapy allows CRP to be clinically useful.

American regulatory bodies have endorsed the use of CRP.

In time, a host of inflammatory mediators may be used to calculate risk.

References Albert, M.A., Danielson, E., Rifai, N. & Ridker, P.M. (2001) Effect of statin therapy on c-

reactive protein levels. Journal of the American Medical Association 286, 64-70 Cook, N., Buring, J.E. & Ridker, P.M. (2006) The effect of including c-reactive protein in

cardiovascular risk prediction models for women. Annals of Internal Medicine 145, 21-29. Khot, U.N., Khot, M.B., Bajzer, C.T., Sapp, S.K., Ohman, E.M., Brener, S.J., Ellis, S.G.,

Lincoff, A.M. & Topol, E.J. (2003) Prevalence of conventional risk factors in patients with coronary heart disease. Journal of the American Medical Association 290, 898-904.

Libby, P. (2002) Inflammation in atherosclerosis. Nature 420, 868-874. Miller, D.T., Zee, R.Y.L., Danik, J.S., Kozlowski, P., Chasman, D.I., Lazarus, R., Cook, N.R.,

Ridker, P.M. & Kwiatkowski, D.J. (2005) Association of common crp gene variants with crp levels and cardiovascular events. Annals of Human Genetics 69, 623-638.

Pearson, T.A., Mensah, G.A., Alexander, R.W., Anderson, J.L., Cannon, R.O., Criqui, M., Fadl, Y.Y., Fortmann, S.P., Hong, Y., Myers, G.L., Rifai, N., Smith, S.C., Taubert, K., Tracy, R.P. & Vinicor, F. (2003) Markers of inflammation and cardiovascular disease. Circulation 107, 499-511.

Ridker, P.M., Brown, N.J., Vaughan, D.E., Harrison, D.G. & Mehta, J.L. (2004) Established and emerging plasma biomarkers in the prediction of first atherothrombotic events. Circulation 109, 6-19.

Ridker, P.M., Buring, J.E., Rifai, N. & Cook, N.R. (2007a) Development and validation of improved algorithms for the assessment of global cardiovascular risk in women. Journal of the American Medical Association 297, 611-619.

Ridker, P.M., Cannon, C.P., Morrow, D., Rifai, N., Rose, L.M., McCabe, C.H., Pfeffer, M.A. & Braunwald, E. (2005) C-reactive protein levels and outcomes after statin therapy. New England Journal of Medicine 352, 20-8

Ridker, P.M. & Cook, N. (2004) Clinical usefulness of very high and very low levels of c-reactive protein across the full range of framingham risk scores. Circulation 109, 1955-1959.

Ridker, P.M., Cushman, M., Stampfer, M.J., Tracy, R.P. & Hennekens, C.H. (1997) Inflammation, aspirin and the risk of cardiovascular disease in apparently healthy men. New England Journal of Medicine 336, 973-9.

Ridker, P.M., Fonseca, F.A.H., Genest, J.,Gotto, A.M., Kastelein, J.J.P., Khurmi, N.S., Koenig, W., Libby, P., Lorenzatti, A.J., Nordestgaard, B.G., Shephard, J., Willerson, J.T. & Glynn, R.J. (2007b) Baseline characteristics of participants in the JUPITER trial, a randomised placebo-controlled primary prevention trial of statin therapy among individuals with low low-density lipoprotein cholesterol and elevated high-sensitivity c-reactive protein. American Journal of Cardiology 100, 1659-1664.

Ridker, P.M., Hennekens, C.H., Buring, J.E. & Rifai, N. (2000) C-reactive protein and other markers of inflammation in the prediction of cardiovascualr disease in women. New England Journal of Medicine 342, 836-43.

Ridker P.M., Rifai, N., Rose, L., Buring, J.E. & Cook, N.R. (2002) Comparison of c-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. New England Journal of Medicine 347, 1557-65.

Sabatine, M.S., Morrow, D.A., Jablonski, K.A., Rice, M.M., Warnica, W., Domanski, M.J., Hsia, J., Gersh, B.J., Rifai, N., Ridker, P.M., Pfeffer, M.A. & Braunwald, E. (2007) Prognostic significance of the centres for disease control/american heart association high-sensitivity c-reactive protein cut points for cardiovascular and other outcomes in patients with stable coronary artery disease. Circulation 115, 1528-1536.

Tice , J.A., Browner, W., Tracy, R.P. & Cummings, S.R. (2003) The relation of c-reactive protein levels to total and cardiovascular mortality in older U.S women. American Journal of Medicine 114, 199-205.