Towards better screening of CV risk

1. Towards better screening of CV risk Paul Ridker MD Associate Professor of Medicine Division of Preventive Medicine and Cardiovascular Diseases Harvard Medical School Boston, MA

2. CRP vs hs-CRP High-sensitivityC-reactive protein tests • Standard CRPtests • designed to detect clinical information • cannot predict cardiovascular event rates • hs-CRP tests • can detect C-reactive protein levels far below the lower sensitivity limits of standard clinical assay • can predict cardiovascular event rates

3. Plaques Determining vulnerability Factors affecting the propensity of plaques to rupture • lipids • the inflammatory process • the inflammation itself Atherogenesis and atherothrombosis are as much inflammatory disorders as lipid disorders. Ross R. N Engl J Med 1999;340(2):115-126

4. The clinical picture Markers of inflammation Half of all individuals that have MI or stroke do not have abnormalities of lipid function. For specific markers of inflammation, hs-CRP turns out to be the most clinically useful in determining who is truly at risk for future heart attacks and stroke in currently healthy populations of men and women.

5. Women's Health Study Enhancing screening forcardiovascular disease NIH-funded study • large-scale prospective cohort • designed to determine a variety of issues in women's health, including the fundamental determinants of cardiovascular events Ridker PM, et al. NEngl J Med 2000; 342(12): 836-843

6. Physicians’ Health Study CRP levels and risk of MI or stroke study of healthy middle-aged men experimental assay for hs-CRP used Results the higher the level of C-reactive protein, the higher the risk of having either a myocardial infarction or a stroke Ridker PM, et al. Circulation 1998;97(20):2007-2011

7. Women's Health Study Markers measured 12 different putative markers of risk were simultaneously measured in the same baseline blood sample using a commercial assay. hs-CRP serum amyloid A ICAM 1 interleukin-6 total cholesterol LDL cholesterol HDL cholesterol apolipoprotein A-I apolipoprotein B-100 Lp(a) ratio of total cholesterol to HDL homocysteine Ridker PM, et al. N Engl J Med 2000; 342(12): 836-843

8. Women's Health Study Results for otherwise healthy women The single strongest predictor of future risk of heart attack and stroke was hs-CRP, not lipid level. Women with the higher levels of the hs-CRP were at nearly 4.5 times increased risk of having a future heart attack or stroke. LDL cholesterol levels only had a predictive value of about 2.2 (this marker is potentially better than lipid screening). Homocysteine and Lp(a) values were marginal at best. Homocysteine was a significant predictor of risk but much less predictive than the inflammatory markers. Ridker PM, et al. N Engl J Med 2000; 342(12): 836-843

9. Women's Health Study Additive effects of CRP hs-CRP greatly increases the predictive value of standard lipid screening. With lipid and the inflammatory process data, predicting future vascular events is much more accurate. Ridker PM, et al. N Engl J Med 2000; 342(12): 836-843

10. Women's Health Study CRP and normal lipid levels Subgroup Only women with LDL cholesterol of 130 mg/dL(3.37 mmol/L) or less were included. hs-CRP levels and risk hs-CRP levels were associated with a 4-fold increase in risk. Low levels of cholesterol may not mean low risk if there is an enhanced propensity to inflammatory response. Women with a propensity to plaque rupture may be a high-risk subgroup. Ridker PM, et al. N Engl J Med 2000; 342(12): 836-843

11. CARE trial Statins and CRP levels The CARE trial (Cholesterol and Recurrent Events) showed that people randomly allocated to pravastatin therapy had significantly lower CRP levels than those allocated to placebo. The magnitude of risk reduction associated with pravastatin was greatest among those who had the inflammatory response. Research is being done to determine if the combination of lipid screening and hs-CRP testing will identify truly high-risk patients who will benefit from statin therapy. Ridker PM, et al. Circulation 1999 20;100(3):230-235

12. CARE trial High CRP levels are never good People with low lipid levels and low CRP levels were the lowest-risk group. People with high lipid levels and high CRP level were the highest-risk group. Still at high risk • people with low CRP levels but high lipid levels • people with high CRP levels but low lipid levels Ridker PM, et al. Circulation 1999 20;100(3):230-235

13. NHANES data CRP in younger people hs-CRP testing is limited to people who might otherwise be screened for cholesterol. NHANES research group Population studies found fairly broad ranges of CRP levels, even in younger patients. This suggests that the inflammatory process may well be present in our teens and 20s. This is not surprising, because we know that atherosclerosis is a chronic lifelong disease and the inflammatory process is predicting events 8, 10, 12 years down the road. Ford ES, et al. Arterioscler Thromb Vasc Biol 2000;20(4):1052-1056

14. Physicians’ Health Study Differentiating inflammations CRP is a very nonspecific marker of inflammation. Infections and trauma drive CRP levels up well into the clinical range. But, hs-CRP testing detects very low-grade levels in healthy patients. Still, in clinical practice, CRP levels should be measured 2 to 3 weeks after an acute infection. Ridker PM, et al. Circulation 2000;101:1767

15. Physicians’ Health Study CRP and obesity CRP is elevated in obese patients. Body Mass Index and obesity are determinants of CRP levels. But hs-CRP is predictive among lean and heavy individuals. Meditation through the pro-inflammatory response may be one of the mechanisms that make obesity so destructive in terms of vascular function. Ridker PM, et al. Circulation 2000;101:1767

16. CRP levels Mediator or marker? CRP is likely a downstream marker of a much more sophisticated process, with no direct vascular effects. There may be a systemic, low-grade inflammatory response. There may be a population distribution, where some people have more inflammatory response, some less. The inflammatory response in our 50s and 60s may lead to increased vulnerability of plaques. 

17. Women's Health Study Markers associated with increased risk • ICAM-1, one of the adhesion molecules involved in the adhesion and transmigration of macrophages and monocytes across the endothelium • interleukin-6, one of the primary drivers of CRP production • serum amyloid A, another hepatically derived acute-phase reactant Ridker PM, et al. N Engl J Med 2000; 342(12): 836-843

18. Women's Health Study CRP: probably a marker Because other markers and/or upstream modulators predict risk, CRP is probably a marker. The single strongest clinical predictor is the hs-CRP, likely because it gives a downstream overview of the whole process. Measuring IL-6 or ICAM 1 is difficult in a clinical setting. Advantages of hs-CRP • it is a very hardy protein • there is very little degradation • it can be handled like a typical outpatient analyte • it is very stable • it is easy to measure   Ridker PM, et al. N Engl J Med 2000; 342(12): 836-843

19. Unstable angina Attilio Maseri's Italian group Liuzzo G, et al. N Engl J Med 1994; 331(7):417-424 Acute coronary syndromes TIMI investigators Morrow DA, et al. J Am Coll Cardiol 1998; 31(7):1460-1465 European studies from the FRISC investigators Toss H, et al. Circulation 1997; 96(12):4204-4210 Ongoing research Data for hs-CRP

20. Potential uses The future of hs-CRP These inflammatory markers might be used as a method of targeting therapy or as a method of providing entire new avenues of therapy. If this inflammatory response is profoundly involved in the acute coronary syndromes and in changing that plaque from stable to unstable, we might have an impact on the inflammatory component as well as the thrombotic component in clinical trials.