In this presentation Dr Ridker gives an update on the role of high sensitivity C-Reactive Protein (hs-CRP) in predicting the risk of heart attack and stroke, and the role of statin therapy in modulating that risk.

CRP, a marker of inflammation, has become a widely available, inexpensive test for cardiac risk, based on the results of large epidemiologic studies.

The Physician's Health Study was the first large-scale prospective study to show that the relative risk of first myocardial infarction or stroke was directly related to hsCRP levels (1). Another large-scale prospective study in postmenopausal women did a direct comparison of several markers of inflammation and found that hs-CRP was the single highest predictor of cardiovascular events among the 12 markers studied (2). Another important observation was that prediction models incorporating both inflammatory markers and lipids were better at predicting risk than models based on lipid levels alone (2).

In a direct comparison of the predictive value of LDL-C against hs-CRP in predicting first ever cardiovascular events among 27,939 initially healthy American women, the relative predictive value of CRP was significantly stronger than LDL-C for total cardiovascular events, coronary events, ischemic stroke events and cardiovascular deaths (3). Combined LDL-C and hs-CRP measurements showed that individuals with low CRP and low LDL-C have the highest probability of CV event-free survival (3). CRP was also shown to add prognostic information at all levels of LDL-C and all levels of the Framingham Risk score (3), and to predict future vascular events in patients with the metabolic syndrome (4). It was also shown that very low or very high levels of CRP provide important prognostic information on cardiovascular risk (5).

CRP is now understood to also play a direct role in atherosclerosis (6, 7) and thrombosis (8). It was shown for the first time in 1998 that the statins, potent LDL-lowering drugs, were also able to lower CRP levels and modulate the effect of CRP on the risk of coronary events (9).

Analysis of the AFCAPS/TexCAPS Study showed that not only individuals with high LDL cholesterol but also those with low LDL-C and high CRP may benefit from statin therapy in the primary prevention of coronary events (10). A test of this hypothesis is now ongoing in a trial called JUPITER (Randomized Trial of Rosuvastatin in the Primary Prevention of Cardiovascular Events Among Individuals with Low Levels of LDL-C and Elevated levels of CRP).

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The participant will learn about the role of high sensitivity C-Reactive Protein (hs-CRP) in predicting the risk of heart attack and stroke, and the role of statin therapy in modulating that risk.

1. Paul M. Ridker, M.D., Mary Cushman, M.D., Meir J. Stampfer, M.D., Russell P. Tracy, Ph.D., and Charles H. Hennekens, M.D. Inflammation, Aspirin, and the Risk of Cardiovascular Disease in Apparently Healthy Men.
NEJM 1997;336:973-79.

2. Paul M. Ridker, M.D., Charles H. Hennekens, M.D., Julie E. Buring, Sc.D., and Nader Rifai, Ph.D. C-Reactive Protein and Other Markers of Inflammation in the Prediction of Cardiovascular Disease in Women NEJM 2000;342:836-43.

3. Paul M. Ridker, M.D., Nader Rifai, Ph.D., Lynda Rose, M.S., Julie E. Buring, Sc.D., and Nancy R. Cook, Sc.D. Comparison of C-Reactive Protein and Low-Density Lipoprotein Cholesterol Levels in the Prediction of First Cardiovascular Events NEJM 2002;347: 1557-65.

4. Paul M Ridker, MD; Julie E. Buring, ScD; Nancy R. Cook, ScD; Nader Rifai, PhD C-Reactive Protein, the Metabolic Syndrome, and Risk of Incident Cardiovascular Events Circulation 2003;107: 391-7.


5. Ridker PM, Cook N. Clinical Usefulness of Very High and Very Low Levels of C-Reactive Protein Across the Full Range of Framingham Risk Scores. Circulation. 2004 Mar 29

6. Ridker PM; JUPITER Study Group. "Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial." Circulation. 2003 Nov 11;108(19):2292-7.

7. Paul A, Ko KW, Li L, Yechoor V, McCrory MA, Szalai AJ, Chan L. C-reactive protein accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice.
Circulation. 2004 Feb 10;109(5):647-55. Epub 2004 Jan 26.

8. Danenberg HD, Szalai AJ, Swaminathan RV, Peng L, Chen Z, Seifert P, Fay WP, Simon DI, Edelman ER. Increased thrombosis after arterial injury in human C-reactive protein-transgenic mice. Circulation. 2003 Aug 5;108(5):512-5. Epub 2003 Jul 21.

9. Ridker PM, Rifai N, Pfeffer MA, Sacks FM, Moye LA, Goldman S, Flaker GC, Braunwald E. Inflammation, Pravastatin, and the Risk of Coronary Events After Myocardial Infarction in Patients With Average Cholesterol Levels Circulation. 1998 Sep 1;98(9):839-44.

10. Ridker PM, Rifai N, Clearfield M, Downs JR, Weis SE, Miles JS, Gotto AM Jr; Air Force/Texas Coronary Atherosclerosis Prevention Study Investigators. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med. 2001 Jun 28;344(26):1959-65.