Connecting the Role of C-Reactive Protein and Statins in Cardiovascular Disease

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1 Clin. Cardiol. Vol. 26 (Suppl. III), III-39 III-44 (2003) Connecting the Role of C-Reactive Protein and Statins in Cardiovascular Disease PAUL M. RIDKER, M.D., M.P.H., FACC Center for Cardiovascular Disease Prevention, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts, USA Summary: The observation that almost half of all myocardial infarctions and strokes occur in persons without elevated levels of low-density lipoprotein cholesterol has prompted the study of factors other than hyperlipidemia that contribute to the development of atherosclerosis. A growing body of evidence indicates that plays a substantial role in plaque progression and rupture. Research interest has increasingly focused on bio of as a means of predicting more accurately which patients are at high risk for cardiovascular disease (CVD). Clinical studies indicate that C- reactive protein (CRP), a marker of systemic, independently predicts cardiovascular risk in healthy persons as well as in persons with established CVD and those with acute ischemia. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, have been shown to reduce levels of CRP through mechanisms independent of their effects on lipid levels. Initial clinical studies also suggest that CRP levels may have utility in the targeting of statin therapy, particularly in primary prevention. These results need direct testing in large, prospective clinical trials to determine whether statin therapy will benefit persons without overt hyperlipidemia but with evidence of systemic. Confirmation of these preliminary findings, if incorporated into evidence-based guidelines, may profoundly change the approach to diagnosis and treatment of CVD. Key words: bio, C-reactive protein, high-density lipoprotein cholesterol, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition, hyperlipidemia, low-density lipoprotein cholesterol, myocardial infarction, statin Introduction Almost half of all myocardial infarctions (MIs) and strokes occur in apparently healthy persons who have normal or nearnormal cholesterol levels. 1, 2 Thus, although aggressive reduction of low-density lipoprotein cholesterol (LDL-C) in accordance with the National Cholesterol Education Program (NCEP) guidelines is warranted, 3 the approach to primary and secondary prevention of cardiovascular events must encompass other risk factors as well. A growing body of laboratory and clinical evidence has implicated a chronic inflammatory process as an important contributor to the development of atherosclerosis. 4 As a result of this new understanding, researchers have been evaluating strategies for expanding the routine screening approach to include bio of that predict acute cardiovascular events independent of lipid levels. Research has also focused on the indications for the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, which appear to attenuate the risk associated with in addition to reducing LDL-C levels. 3, 5 Despite their proven efficacy in primary and secondary prevention, 6 8 these agents remain underutilized in several settings. This is particularly true in primary prevention, in which the number of patients who need to be treated to prevent one clinical event is relatively large. Low-density lipoprotein screening alone has not been found effective in determining statin efficacy. Ideally, with development of routine screening tools that identify patients at high risk, including those with elevated of systemic, statin therapy can be better integrated into a targeted, cost-effective approach to primary prevention of cardiovascular events. Address for reprints: Paul M. Ridker, M.D., M.P.H., FACC Director, Center for Cardiovascular Disease Prevention Brigham and Women s Hospital 75 Francis Street, Building Tower 3C Boston, MA 02115, USA pridker@partners.org Markers of Inflammation and Risk of Cardiovascular Events A variety of bio have been proved to predict risk of future cardiovascular events. These include interleukin 6 (IL- 6), a pleiotropic cytokine; 9 P selectin, a cell adhesion molecule involved in the tethering and rolling of platelets and mononuclear cells through the vascular system; 10 the soluble intercellular adhesion molecule ICAM-1, a protein that mediates the ad-

2 III-40 Clin. Cardiol. Vol. 26 (Suppl. III) April 2003 hesion and transmigration of leukocytes; 11 and soluble CD40 ligand, which is enhanced in the setting of atherothrombosis. 12 For many of these inflammatory bio, predictive value has been demonstrated in healthy men and women and in the setting of acute coronary ischemia. However, these experimental results have been difficult to translate into clinical practice for a variety of reasons. One is the perception that levels of of vary too widely over time to allow accurate prediction of risk. 13 Another reason is the difficulty in ascertaining the relative accuracy of each marker, since few prospective studies have measured them all in the same cohort of patients. Likewise, few studies have evaluated whether these of significantly increase the predictive value of lipid screening. Finally, clinical application of these findings has been limited because standardized, commercial assays for most of are not yet available. In contrast, a comparatively well studied biomarker that may be suitable for clinical use is C-reactive protein (CRP), a marker of systemic produced in the liver largely in response to IL-6 stimulation. C-reactive protein is, in itself, a critical component of the acute-phase response as well as a major component of the innate immune response. It is a pentraxin that plays a role in monocyte recruitment into the arterial wall, effects complement activation and colocalization, induces expression of cellular adhesion molecules, mediates LDL uptake by macrophages, and has an impact on MCP-1 production. Recently, the availability of a reliable high-sensitivity assay for CRP (hs-crp) in standard clinical laboratories has facilitated development of a risk-stratification approach correlating CRP level with the likelihood of a cardiovascular event (Table I). 5 The Predictive Value of C-Reactive Protein For any biomarker to be used routinely in clinical practice, it must meet several criteria, including the ability to predict risk independent of other screening tools and to improve the accuracy of risk prediction when used in conjunction with standard measures of risk. In the case of CRP, these issues have been addressed in several large prospective clinical studies that demonstrate that baseline CRP level is a strong independent predictor of the risk of MI, stroke, peripheral arterial disease, and TABLE I Population distribution of high-sensitivity C-reactive protein in apparently healthy men and women Tertile CRP range (mg/l) Risk estimate 1 <1 Low Average 3 >3 High Data from Ref. No. 5. Abbreviation: CRP = C-reactive protein. vascular death among persons with no known history of cardiovascular disease , 22a For example, results of the Physicians Health Study strongly suggest a biologic interaction that confers the highest level of risk among those who have both hyperlipidemia and a heightened inflammatory response. 15, 23 In that study, high baseline levels of CRP, total cholesterol (TC), and ratio of high-density lipoprotein cholesterol (HDL-C) to TC (TC:HDL-C ratio) were each associated with significantly increased risks of overt cardiovascular disease (p < for each). The men in the quartile with the highest baseline levels of CRP had three times the risk of MI and two times the risk of ischemic stroke as those in the lowest quartile. This risk increase was greater than that associated with increasing levels of LDL-C. The risks remained stable over a long period of time and were independent of other lipid- and non-lipid-related risk factors. In multivariate analyses, models incorporating CRP and lipid parameters provided an improved method for predicting risk than did models using lipids alone (Fig. 1). 23 In the subsequent Women s Health Study, CRP was one of 12 bio whose predictive value was assessed in 28,263 postmenopausal women who were followed for a mean of 3 years. 13, 17, 22a The strongest univariate predictor of risk was hs-crp, which conferred a relative risk of 4.4 in those with the highest baseline levels. Other significantly associated with heightened risk included serum amyloid A, sicam-1, IL-6, homocysteine, TC, LDL-C, apolipoprotein B-100, HDL-C, and the TC:HDL-C ratio. The levels of hs- CRP and serum amyloid A were significant predictors of risk, even in the subgroup of women whose LDL-C levels were < 130 mg/dl, the target for primary prevention established by the NCEP. 3 In the multivariate analysis, the only plasma that independently predicted risk were hs-crp and the TC:HDL-C ratio. A model for calculating risk that incorporated of plus lipid levels was significantly more accurate than models based on lipid levels alone (p < 0.001). In long-term follow-up of this cohort, CRP was found to predict vascular risk at all levels of LDL cholesterol, even after adjustment for traditional risk factors. 22a Moreover, screening for CRP in addition to LDL was found to greatly Relative risk High Medium Low Total cholesterol:hdl-c ratio High Medium Low hs-crp FIG. 1 Multivariate analyses incorporating high-sensitivity C-reactive protein (hs-crp) and total cholesterol to predict relative risk of cardiovascular events. HDL-C = high-density lipoprotein cholesterol. Adapted from Ref. No. 23.

3 P. M. Ridker: CRP and statins in CVD III-41 improve the ability to determine high risk individuals (Fig. 2). In fact, CRP was found to significantly improve risk prediction at all levels of the Framingham Risk Score (Fig. 3). In an interesting extension of the predictive uses for hs- CRP, two large studies have evaluated it in patients with established cardiovascular disease who were scheduled to undergo invasive treatment. Lindmark et al. studied whether of such as CRP and IL-6 predicted mortality in 3,269 patients with unstable coronary artery disease who were randomly assigned to early invasive or medical treatment. 24 For patients in whom neither CRP nor IL-6 was elevated, mortality at 6 and 12 months was similar regardless of whether an invasive or medical strategy was used. However, for those with high levels of of, mortality was significantly lower with the invasive strategy than with a medically Probability of cardiac event-free survival Low CRP low LDL Low CRP high LDL High CRP low LDL High CRP high LDL Years of follow-up FIG. 2 Cardiovascular event-free survival according to baseline levels of C-reactive protein (CRP) and low-density lipoprotein (LDL). Adapted from reference 22a. treated group. These findings may affect treatment choices, particularly in settings for which catheterization and aggressive treatment are not readily available. Results of a related study by Chew et al. demonstrated that the worst outcomes from elective percutaneous coronary revascularization occur in patients with a heightened inflammatory response. 25 Inflammation as detected by C-reactive protein may also explain much of the link between atherothrombosis and diabetes. By way of example, in recent large-scale prospective data, levels of CRP were shown to be a potent predictor of outcome even among patients already diagnosed with the metabolic syndrome 25a (Fig. 4), data which corroborate evidence that CRP levels in healthy individuals also predict the onset of type II diabetes. 25b Anti-inflammatory Effects of Statin Therapy The benefits of statin therapy for reducing the risk of cardiovascular events are primarily attributed to their well-described potency in reducing LDL-C; 3 however, it has also been hypothesized that statins may improve plaque stability via immunologic effects. 26 If this hypothesis is correct, it may help explain some of the paradoxes associated with statin therapy. First, in clinical studies, the magnitude of benefit derived from statin therapy has been larger than that predicted on the basis of the effects on LDL-C reduction alone. Second, in studies such as the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) and the Register of Information and Knowledge About Swedish Heart Intensive Care Admissions (RIKS-HIA) studies, the benefit on mortality begins very early and seems to predate the efficacy that would be predicted from LDL reduction alone. 27, 28 Third, patients undergoing statin therapy appear to have a better prognosis than those who are not taking these agents, even when LDL-C lev Relative risk multivariable relative risk C-reactive protein (mg/l) < > Framingham estimate of 10-year risk (%) FIG. 3 C-reactive protein (CRP) predicts risk of first vascular events at all levels of the Framingham Risk Score. Data adapted from reference 22a. CVD event-free survival probability Years of follow-up CRP < 1.0 mg/l CRP mg/l CRP 3.0 mg/l FIG. 4 Cardiovascular event-free survival according to baseline C-reactive protein (CRP) levels among individuals already defined as having the metabolic syndrome. Adapted from reference 25a.

4 III-42 Clin. Cardiol. Vol. 26 (Suppl. III) April 2003 els for both groups are comparable. Fourth, statins reduce ambulatory ischemia and symptomatic angina, benefits that are not traditionally associated with reduction in LDL-C alone. Finally, statins reduce the risk of a first thromboembolic stroke, although LDL-C is not a potent risk factor for stroke. Results of several large, prospective clinical trials indicate that statin therapy consistently and rapidly reduces CRP levels through mechanisms that are independent of the effects on LDL-C. 6, In the Cholesterol and Recurrent Events (CARE) study, for example, median CRP levels decreased significantly among those randomly allocated to pravastatin therapy (p = 0.004). 29 Similarly, in the prospective, randomized, double-blind Pravastatin Inflammation/CRP Evaluation (PRINCE) trial, which involved over 2,800 patients, median CRP levels were 16.9% lower (p < 0.01) at 24 weeks in pravastatin but did not change in the placebo group. 30 The CRP-lowering effect was seen consistently irrespective of gender, age, smoking history, weight, or presence of diabetes. Similar results have been obtained in studies of atorvastatin, lovastatin, cerivastatin, and simvastatin, indicating that the anti-inflammatory response is a class effect shared by all statins. 6, 7, 30, 32, 33 In both the CARE trial of secondary prevention and in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) trial of primary prevention, the relative clinical efficacy of statin therapy was greater among those with elevated levels of CRP. In the CARE trial, the subgroup with the highest risk of reinfarction was placebo who had elevated CRP and serum amyloid A levels. 34 In contrast, patients with evidence of who received pravastatin had a risk similar to that seen in patients who did not have elevated of (Fig. 5). A similar effect in primary prevention was also observed in the AFCAPS/TexCAPS study, which was undertaken to determine whether the benefits of statin therapy can be extended to Relative risk Statin without p Trend = Placebo without Statin Placebo Statin with Placebo with Fig. 5 In the CARE trial, placebo who had elevated C- reactive protein (CRP) and serum amyloid A levels had the highest risk of reinfarction, whereas patients with evidence of who received pravastatin had a risk similar to that seen in patients who had no elevated. Reprinted from Ref. No. 34 with permission. persons with average TC and LDL-C levels but below-average HDL-C. 7, 31 With regard to CRP, AFCAPS/TexCAPS participants were placed into one of four categories, according to whether their LDL-C and CRP levels were above or below the median (> 149 mg/dl and < 1.6 mg/l, respectively). As with other trials of statin therapy, a 30 to 35% risk reduction was seen in lovastatin. Assessment of outcome according to CRP at baseline and 1-year follow-up confirmed that CRP is a strong independent predictor of future vascular risk, after adjusting for all parameters in the Framingham risk score. Lovastatin therapy reduced the CRP level by 14.8% (p < 0.001). There was no relation between the CRP levels and LDL-C, HDL-C, or triglyceride levels, which indicates that inflammatory response cannot be predicted on the basis of lipid levels. Most important, however, patients with elevated CRP levels but low LDL levels achieved a relative risk reduction with statin therapy almost identical to that observed among those with overt hyperlipidemia. In fact, for patients without hyperlipidemia but with elevated CRP levels, the number needed to treat to prevent one vascular event was 43, a value almost identical to that for patients with hyperlipidemia regardless of CRP level (number needed to treat = 47) (Table II). Conclusion Data concerning the predictive value of CRP are exceptionally consistent. Within the past 7 years, clinical studies have shown that CRP levels provide a strong global measure of cardiovascular risk independent of LDL-C levels. While recent data clearly demonstrate that CRP is a stronger risk factor than LDL cholesterol 22a, it is important to emphasize that CRP levels should not be used as a replacement for cholesterol screening. Instead, risk-prediction algorithms using CRP evaluation must be considered as an adjunct to measures of hyperlipidemia to determine risk. Development of this strategy has been facilitated by the recent availability of inexpensive commercial assays for hs-crp, which have demonstrated variability and classification accuracy similar to that of chol- TABLE II Rates of coronary events, relative risk, and numbers needed to treat according to baseline low-density lipoprotein cholesterol and C-reactive protein levels Rate of acute coronary events Study group Statin Placebo RR NNT Low LDL-C/low CRP Low LDL-C/high CRP High LDL-C/low CRP High LDL-C/high CRP Adapted from Ref. No. 31. Abbreviations: CRP = C-reactive protein, LDL-C = low-density lipoprotein cholesterol, NNT = numbers needed to treat, RR = relative risk.

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