HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Clearfield, M. B. Search for Related Content PubMed PubMed Citation Articles by Clearfield, M. B.

From the University of North Texas Health Science Center at Fort Worth—Texas College of Osteopathic Medicine (UNTHSC).

Address correspondence to Michael B. Clearfield, DO, Department of Internal Medicine, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX 76107-2553. E-mail: mclearfi{at}hsc.unt.edu

Recent research has focused on the use of high-sensitivity C-reactive protein (hs-CRP), a marker of inflammation, in the detection of patients at increased risk for cardiovascular disease. Several prospective studies have demonstrated that hs-CRP is an independent predictor of future risk for cardiovascular events among healthy individuals, as well as among patients with acute coronary syndromes. In addition, because half of all cardiovascular events occur in persons with low to average levels of low-density lipoprotein cholesterol, hs-CRP may aid in identifying patients at high risk for a first cardiovascular event who might otherwise be missed by lipid screening alone. Thus, hs-CRP is a potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. The Centers for Disease Control and Prevention and the American Heart Association have therefore proposed joint guidelines for the use of hs-CRP in determining cardiovascular disease risk. The author reviews numerous studies examining the prognostic value of hs-CRP and outlines ongoing efforts to assess the effect of statin therapy in healthy individuals with low levels of low-density lipoprotein cholesterol and high levels of hs-CRP.

	Methods

Top Methods Review of Studies Examining... Using hs-CRP Values for... Relationship Between Statin... JUPITER May Answer Remaining... Conclusions References

 
I searched the United State's National Library of Medicine's MEDLINE database for all relevant English-language studies and clinical trials of C-reactive protein published between January 1990 and February 2005. The following Medical Subject Heading terms and keywords were used: randomized, controlled clinical trials, clinical trials, or cohort studies and (+) C-reactive protein, and (+) coronary disease or cardiovascular diseases. These terms were then combined with the following terms: acute coronary syndromes, drug effects, endothelial cells, hydroxymethylglutaryl CoA reductase inhibitors, inflammation, LDL cholesterol, lipoproteins, metabolic syndrome, myocardial infarction, risk factors, and type 2 diabetes mellitus.

	Review of Studies Examining Prognostic Value of hs-CRP

Top Methods Review of Studies Examining... Using hs-CRP Values for... Relationship Between Statin... JUPITER May Answer Remaining... Conclusions References

 
Atherosclerosis, Inflammation, and C-Reactive Protein
Research over the past decade has led to the current understanding of atherosclerosis as an inflammatory disease that occurs in response to endothelial dysfunction.^2,6 The earliest identifiable lesion is the fatty streak, an inflammatory lesion that consists of monocyte-derived macrophages (foam cells) and T lymphocytes.^2,6 As a fatty streak progresses to an intermediate and advanced lesion, it forms a fibrous plaque—a process that involves a complex interaction between the endothelium, inflammatory cytokines, and numerous blood elements.⁶

C-reactive protein, an acute-phase reactant synthesized in the liver in response to the cytokine interleukin-6, is also a factor in the development of atherosclerotic plaque. Although CRP was initially believed to be only a marker of vascular inflammation, recent research indicates that it also plays an active role in atherogenesis.^7,8 It is detectable in the early stages of plaque development and is believed to be involved throughout the atherogenic process, facilitating everything from the initial recruitment of leukocytes to the arterial wall to the eventual rupture of the plaque.⁸

Calabro et al⁹ have proposed that the smooth muscle cells of the human coronary arteries may also produce CRP as a local response to inflammatory cytokines. They further noted that this locally produced CRP may participate in the atherogenic process.⁹ In addition, Khreiss et al¹⁰ have suggested that loss of the pentameric symmetry of CRP can result in a modified or monomeric CRP, which may be the major CRP promoter of the proinflammatory response in the coronary arteries.

The recent standardization of the hs-CRP assay allows acceptable precision down to and below 0.3 mg per liter. It is within these lower, previously "normal" ranges, that hs-CRP levels seem to have predictive abilities for coronary heart disease (CHD) events.³

C-Reactive Protein as an Independent Risk Factor
A number of large, prospective epidemiologic studies have indicated that hs-CRP is a strong independent predictor of future cardiovascular events, including myocardial infarction, ischemic stroke, peripheral vascular disease, and sudden cardiac death among individuals without known CVD.^5,11

The association between elevated hs-CRP levels and future CHD events has generally been consistent among these studies: subjects in the top quartile of hs-CRP levels have a 2 to 3 times greater relative risk of a future coronary event than do those in the bottom quartile.⁸ For example, in a cohort of 1086 apparently healthy middle-aged men in the dataset of the Physicians' Health Study, subjects with baseline levels of hs-CRP that were in the highest quartile had a twofold increase in risk of ischemic stroke or peripheral vascular disease (P=.02) and a threefold increase in risk of myocardial infarction (P<.001), relative to subjects in the lowest quartile.¹² These effects were independent of other cardiovascular risk factors, including lipid levels and tobacco use.¹²

The Honolulu Heart Program analyzed frozen serum samples to assess the relationship of hs-CRP to the development of myocardial infarction in clinically healthy men over a follow-up period of 20 years.¹³ Overall, hs-CRP levels in this study were associated with coronary events that occurred as many as 15 years later. As early as five years into follow-up, the risk of myocardial infarction grew with increasing hs-CRP levels (P=.009).¹³ At 10 to 15 years into follow-up, the relative odds of myocardial infarction in the highest hs-CRP quartile were 2.1 times that of the lowest quartile, after adjustment for such risk factors as total cholesterol, hypertension, and type 2 diabetes mellitus (P=.016). The strongest correlation between hs-CRP and risk of myocardial infarction occurred in those men without other risk factors.¹³

Levels of hs-CRP have also been associated with CVD events in women. In the primary prevention Women's Health Study, 122 initially healthy postmenopausal women who subsequently suffered a first cardiovascular event were paired with 244 controls matched for age and tobacco use who remained CVD event-free over a three-year follow-up period.¹⁴ Women with the highest baseline hs-CRP levels had 5 times greater risk of suffering a vascular event (relative risk [RR], 4.8; 95% confidence interval [CI], 2.3-10.1; P<.001) and 7 times the risk of myocardial infarction or stroke (RR, 7.3; 95% CI, 2.7-19.9; P<.001) than did control subjects.¹⁴ A more recent analysis from the Women's Health Study reported that in 15,632 women, hs-CRP added prognostic information beyond that noted by standard lipid measurements—even after adjusting for age, blood pressure, smoking, diabetes mellitus, and obesity.¹⁵

Nested case-control analyses of 121,700 women in the Nurses' Health Study and 51,529 men in the Health Professionals Follow-up Study recently supported the results of the Women's Health Study, finding that hs-CRP is a predictor of CHD that is independent of other cardiovascular risk factors.¹⁶

In contrast to the results of these and many other trials, a nested sample of 157 subjects from the Rotterdam Study in 2003 raised concerns about whether hs-CRP adds predictive value to traditional risk factors.¹⁷ This concern was raised again in 2004 by a cohort study of the Reykjavik trial that questioned the usefulness of CRP over more established risk markers. In this study, 2459 patients diagnosed with CHD after enrollment were matched with 3969 controls who did not have a CHD event.¹⁸ After adjustments for smoking status and other established CHD risk factors, patients whose baseline hs-CRP levels were in the top tertile (cutoff value=2.0 mg/L) had an odds ratio for CHD of 1.45 (95% CI, 1.25-1.68) compared with those in the bottom tertile (cutoff value=0.78 mg/L).¹⁸

The Reykjavik investigators concluded that hs-CRP added only marginally to the predictive value of established risk factors.¹⁸ However, the adjusted odds ratio of 1.45 for elevated hs-CRP in this study should be considered in the context of other odds ratios reported in the same group of patients: 1.87 for individuals who were current smokers versus those who had never smoked, and 1.50 for individuals with elevated systolic blood pressure versus those with normal blood pressure.¹⁸ Because the increased risk associated with elevated hs-CRP was comparable to that of well-established CVD risk factors, this study confirmed the value of hs-CRP as a strong, independent predictor of future heart disease.¹⁸

Providing additional support for the predictive value of hs-CRP, the Cardiovascular Health Study evaluated protein levels in an elderly population without a history of vascular disease.¹⁹ In this study of 3971 men and women aged 65 years or older, a single instance of elevated hs-CRP levels was associated with an increased 10-year risk of CHD beyond traditional risk factors, especially in moderate high-risk men and in high-risk women.

C-Reactive Protein With Established Coronary Heart Disease
Elevated hs-CRP has been shown to be a strong predictor of future cardiovascular risk in patients with established CHD, with or without a previous myocardial infarction. In the Scandinavian Simvastatin Survival Study, elevated hs-CRP levels predicted mortality in patients with stable ischemic heart disease.²⁰ Patients in the highest quartile for hs-CRP levels had the highest risk of death, compared with those in the first through third quartiles (odds ratio=2.51; 95% CI, 1.3-4.8).²⁰ Furthermore, Blake and Ridker⁷ have shown that elevated hs-CRP can predict risk of cardiovascular events (including death, acute myocardial infarction, and need for revascularization procedures) in patients with acute coronary syndromes (ACS).

View larger version (20K): [in this window] [in a new window]   Figure 1. High-sensitivity C-reactive protein adds prognostic information on vascular risk at all levels of the Framingham Risk Score (left) and all levels of low-density lipoprotein (LDL) cholesterol (right). (Adapted from Ridker PM, for the 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 [review].Circulation. 2003;108[19]:2292-2297.)

C-Reactive Protein, Diabetes Mellitus, and the Metabolic Syndrome
Recent evidence suggests that hs-CRP plays a major role in the physiologic processes associated with the metabolic syndrome.⁵ High levels of hs-CRP have been shown to be an independent predictor of cardiovascular risk for all degrees of severity of the metabolic syndrome.²² Furthermore, elevated hs-CRP has been correlated with abdominal obesity in men with atherogenic dyslipidemia, an important clinical characteristic of the metabolic syndrome.²³

Several studies demonstrate that hs-CRP can be used to predict the development of type 2 diabetes mellitus. In a cohort of the Women's Health Study, the relative risk of developing diabetes among women in the highest versus lowest quartiles of hs-CRP levels was 15.7 (95% CI, 6.5-37.9).²⁴ Elevated levels of hs-CRP remained a significant predictor of diabetes risk even after adjusting for body mass index, family history of diabetes mellitus, smoking, and other factors.²⁴

Another cross-sectional trial of participants in the Women's Health Study correlated hs-CRP with insulin resistance in nondiabetic women, providing additional evidence for the association between subclinical inflammation and the risk of type 2 diabetes mellitus and CVD.²⁵ The odds ratio for having elevated fasting insulin increased with each tertile of hs-CRP. The odds ratio for the highest versus lowest tertile of hs-CRP was 4.4 (95% CI, 1.9-10.1).²⁵

View larger version (23K): [in this window] [in a new window]   Figure 2. Relative risks of first myocardial infarction among apparently healthy men associated with high (>223 mg/dL), medium (191-223 mg/dL), and low (<191 mg/dL) tertiles of total cholesterol and high (>1.69 mg/L), medium (0.72-1.69 mg/L), and low (<0.72 mg/L) tertiles of high-sensitivity C-reactive protein (CRP). Those men in the highest tertile of both total cholesterol and CRP had 5.3 times the relative risk of a first myocardial infarction than those in the lowest tertiles of total cholesterol or CRP (P=.0001). (Adapted from Ridker PM, Glynn RJ, Hennekens CH. C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation. 1998;97[20]:2007-2011.)

	Using hs-CRP Values for Risk Assessment

Top Methods Review of Studies Examining... Using hs-CRP Values for... Relationship Between Statin... JUPITER May Answer Remaining... Conclusions References

 
C-Reactive Protein Adds to Global Risk Scoring
Using traditional risk factors, clinicians can predict approximately 50% to 60% of the variation in the absolute risk of a future coronary event in individual patients.²⁸ The addition of hs-CRP to current strategies for global risk assessment, such as the Framingham Risk Score (FRS), may therefore have the potential to increase the accuracy of cardiovascular risk prediction (Figure 1). Albert et al²⁹ demonstrated that hs-CRP levels are correlated with the calculated 10-year FRS in men, as well as in women not taking hormone replacement therapy. Data from the Augsburg cohort of the Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) study also showed that hs-CRP enhances the assessment of global coronary risk as measured by the FRS, particularly in persons at intermediate risk for CHD.³⁰ In the Women's Health Study, both very low (<0.5 mg/L) and very high (>10 mg/L) levels of hs-CRP were useful for risk prediction across a full range of FRS.³¹ Women with hs-CRP levels of less than 0.5 mg per liter had the lowest risk of future cardiovascular events. Women with hs-CRP levels of greater than 20 mg per liter had a risk almost 8 times higher (crude RR, 7.6; 95% CI, 4.7-12.1) than the women at lowest risk.³¹

C-Reactive Protein Adds to Value of Lipid Profile
The addition of hs-CRP levels to standard cholesterol evaluation protocols improves clinicians' abilities to predict CVD risk.^5,1 In the Physicians' Health Study, hs-CRP added to the predictive value of lipid parameters for determining future risk of myocardial infarction.³² Men with high levels of both hs-CRP and total cholesterol had a 5.3 times greater relative risk of a future myocardial infarction (P<.001) than did men with either high total cholesterol or high hs-CRP levels alone (Figure 2).³²

Measurement of hs-CRP in the Women's Health Study added predictive value to all low-density lipoprotein cholesterol (LDL-C) cutoff points, as defined in the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines.^33,34 Furthermore, women with high hs-CRP and low LDL-C levels had a higher absolute risk of a future CVD event than did women with low hs-CRP and high LDL-C levels, despite the fact that high LDL-C is traditionally targeted for aggressive intervention in primary prevention (Figure 3).^33,34 Levels of LDL-C and hs-CRP were minimally correlated in the study (r=0.08), suggesting that each level predicted risk in different groups.³³

View larger version (15K): [in this window] [in a new window]   Figure 3. Event-free survival among women with high-sensitivity C-reactive protein (CRP) and low-density lipoprotein (LDL) cholesterol levels above or below the population median values. (Reprinted from Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347:1557-1565. Copyright © 2002 Massachusetts Medical Society. All rights reserved.)

Guidelines for Use of hs-CRP in Risk Assessment
In January 2003, joint guidelines from the Centers for Disease Control and Prevention (CDC) and the American Heart Association (AHA) named hs-CRP as the inflammatory marker of choice to assess cardiovascular risk.³ The guidelines support the use of hs-CRP in primary prevention and set cutoff points according to relative risk categories: low risk (<1.0 mg/L), average risk (1.0-3.0 mg/L), and high risk (>3.0 mg/L).³ These cutoff points approximate the tertiles of hs-CRP observed in the adult population.

Recently, Ridker and Cook³¹ suggested that the scope of hs-CRP values be extended from less than 0.5 mg per liter (very low) to greater than 10 mg per liter (very high). This extension of scope would provide clinicians with additional prognostic information on cardiovascular risk. The joint CDC-AHA guidelines state that the optimal use of hs-CRP is to help guide the evaluation and therapy for primary CHD prevention for patients at intermediate risk, as defined by NCEP ATP III (10%-20% CHD risk over 10 years).^3,34 The joint guidelines also consider measurements of hs-CRP as a possible predictor of recurrent events in patients with stable coronary disease or ACS.³

The use of hs-CRP as an adjunct to lipid screening in primary prevention is intended to improve global risk prediction in patients not clearly identified as being at high risk by cholesterol levels alone.⁵ This adjustment to the screening procedure is especially important for individuals with low LDL-C levels (<130 mg/dL) but high hs-CRP levels (>3 mg/L), an often-overlooked high-risk group. Preliminary data suggest that patients with low LDL-C and high hs-CRP levels may benefit from pharmacologic intervention, preferably with statin therapy.³

In the NCEP ATP III guidelines, hs-CRP was included among the emerging risk factors whose presence might affect clinician recommendations for therapeutic options.³⁴

	Relationship Between Statin Therapy and hs-CRP

Top Methods Review of Studies Examining... Using hs-CRP Values for... Relationship Between Statin... JUPITER May Answer Remaining... Conclusions References

 
Statins, C-Reactive Protein, and Coronary Risk
Clinical trials have shown that statins reduce patient levels of CRP by 15% to 28% as early as six weeks after treatment begins, independent of the magnitude of reduction in LDL-C levels.^35-37 Data from a posthoc analysis of the secondary prevention Cholesterol and Recurrent Events (CARE) trial suggest that risk reduction of coronary events is greatest among patients with high baseline levels of hs-CRP.³⁸ In this analysis, the risk reduction attributable to pravastatin therapy among patients with high levels of hs-CRP and another marker of inflammation, serum amyloid A (SAA), was substantially greater (54%) than in patients with lower levels of hs-CRP and SAA (25%). This finding held true even though total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglyceride levels were almost identical in the two groups.³⁸

In the primary prevention Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), a posthoc analysis found that lovastatin prevented first major acute coronary events among patients with above-median hs-CRP levels and a below-median total cholesterol-to-HDL-C ratio (P=.02).³⁷ In addition, the risk of future vascular events was as great among the patients with low LDL-C and high hs-CRP levels as it was among patients with high LDL-C levels.⁴

Several recent studies have evaluated the ability of statins to reduce hs-CRP in individuals with ACS. In the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study, atorvastatin (80 mg) significantly reduced CRP by 83%, versus 74% (P<.001) with placebo, at 16 weeks.³⁹ In the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial, which compared aggressive lipid lowering with atorvastatin (80 mg) versus moderate lipid lowering with pravastatin (40 mg), atorvastatin reduced hs-CRP and LDL-C levels 38% and 35% more, respectively, than pravastatin.⁴⁰ In addition, there was a resultant statistically significant 16% reduction (P=.005) in cardiovascular events at two years.⁴⁰

Phase Z of the A to Z trial compared two simvastatin protocols for two years.⁴¹ One group in this trial received simvastatin, 40 mg, for one month and simvastatin, 80 mg, thereafter, while the other group received placebo for four months, then simvastatin, 20 mg, thereafter.⁴¹ The differences observed between these two treatment groups were smaller in both hs-CRP (17%) and LDL-C (18%) than were the corresponding differences observed in either the MIRACL or PROVE IT-TIMI 22 trials. These small differences may explain the lower cardiovascular event reduction—11% (P=.14)— recorded in the A to Z trial.⁴¹

An important aspect of many of the recent hs-CRP studies in patients with ACS has been the observed correlation between more powerful LDL-C lowering and greater reductions in hs-CRP. This relationship was demonstrated again in the REVERSing Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study, in which atorvastatin, 80 mg, lowered LDL-C by 46.3% (versus 25.2% with pravastatin, 40 mg) and hs-CRP by 36.4% (versus 5.2% with pravastatin, 40 mg; P<.001 for both).⁴² Similarly, in the 16-week ANDROMEDA study⁴³ of 509 patients, rosuvastatin, which was approved by the US Food and Drug Administration in August 2003, was shown to lower hs-CRP levels by 34% and 40% at doses of 10 mg and 20 mg, respectively. These results compared with observed reductions of 21% and 34% with atorvastatin, 10 mg and 20 mg, respectively.⁴³

Lowering hs-CRP With Statins to Reduce Coronary Risk
In a recent analysis of 2924 patients presenting with stable or unstable angina or acute myocardial infarction requiring hospitalization and coronary artery catheterization, patients with significant coronary artery disease (coronary artery stenosis 70% in 1 or more coronary arteries) were stratified by baseline hs-CRP levels and observed for an average of 2.4 years to determine the effect of hs-CRP on timing and degree of benefit of statin therapy.⁴⁴ Patients with baseline hs-CRP levels greater or equal to 12 mg per liter who were prescribed statin therapy at hospital discharge derived both a larger and significantly earlier (within two months) survival benefit from statins than did patients with hs-CRP levels less than 12 mg per liter. In those patients in the highest tertile of baseline hs-CRP (>17 mg/L), statin therapy conferred benefit as early as one week, compared with approximately two years in patients with baseline hs-CRP levels in the lowest tertile (<12 mg/L).⁴⁴ In another retrospective analysis of patients presenting with ACS, Saab et al⁴⁵ noted that patients treated with statins within 24 hours of presentation had a lower incidence of death, stroke, reinfarction, and heart failure than those whose statin therapy was delayed more than 24 hours.

In the statin studies of patients with ACS discussed in this review, lower levels of both LDL-C and hs-CRP were achieved in the more aggressively treated groups. Some investigators have speculated—though they have not yet confirmed—that the lowering of hs-CRP will confer additional benefits in decreasing cardiovascular events beyond that seen with LDL-C lowering alone.⁴² In fact, in a re-analysis of the PROVE IT-TIMI 22 trial, patients who achieved the dual target of LDL-C levels less than 70 mg per deciliter and hs-CRP levels less than 1 mg per liter achieved the largest event reduction.⁴⁶ Moreover, patients who achieved an LDL-C level less than 70 mg per deciliter but whose hs-CRP level remained greater than 2 mg per liter had a similar event reduction to those whose LDL-C was greater than 70 mg per deciliter and whose hs-CRP was less than 2 mg per liter. The reduction of both hs-CRP and LDL-C below the median values was also significantly associated with slower progression rates of atherosclerosis in a re-analysis of the REVERSAL trial.⁴⁷

	JUPITER May Answer Remaining Questions

Top Methods Review of Studies Examining... Using hs-CRP Values for... Relationship Between Statin... JUPITER May Answer Remaining... Conclusions References

 
Many treatment modalities, in addition to statins, have been shown to lower hs-CRP levels. Among these are exercise, weight loss, multivitamins, fibrates, niacin, and thiazolidinediones.^3,48,49 However, none of these modalities have correlated changes in hs-CRP with CHD event reduction, as has been suggested with statins. Research has established hs-CRP as an independent marker for CHD, but whether lowering elevated levels of hs-CRP will reduce cardiovascular events has yet to be firmly established. Moreover, a number of other questions require further investigation. For example, should future guidelines for reducing cardiovascular risk include goals for hs-CRP levels that are independent of LDL-C levels? And should there be additional treatment strategies for individuals who have achieved their LDL-C goals but still exhibit elevated hs-CRP?

The Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) is the first large-scale, prospective, randomized, placebo-controlled trial specifically designed to address these questions.⁴ JUPITER, which commenced subject enrollment in February 2003, is designed to assess whether long-term, aggressive daily LDL-C-lowering therapy with rosuvastatin, 20 mg, reduces the rate of first major cardiovascular events in individuals with LDL-C levels less than 130 mg per deciliter and hs-CRP levels greater than or equal to 2 mg per liter. Rosuvastatin has previously been shown to produce greater LDL-C reductions than milligram-equivalent or higher doses of other statins.⁵⁰

Full enrollment for JUPITER is expected to include 15,000 men and women aged 55 years or older and 65 years or older, respectively. Subjects will be randomized to either rosuvastatin or placebo and will be followed for three to four years to observe the combined endpoints of cardiovascular death, stroke, myocardial infarction, hospitalization for unstable angina pectoris, or arterial revascularization.⁴ As a secondary endpoint, JUPITER will investigate whether rosuvastatin reduces the incidence of type 2 diabetes mellitus.⁴

The results of JUPITER are expected to provide crucial information on whether the risk of a first CVD event in individuals with low LDL-C levels but high hs-CRP levels can be decreased with aggressive statin therapy. Because as many as 30 million people in the United States are in this often-overlooked high-risk group,⁵¹ the results of the JUPITER study could have a dramatic effect on clinical practice in prevention of CVD.

	Conclusions

Top Methods Review of Studies Examining... Using hs-CRP Values for... Relationship Between Statin... JUPITER May Answer Remaining... Conclusions References

 
High-sensitivity C-reactive protein, a marker of inflammation, is a strong predictor of future cardiovascular events in individuals both with and without overt CVD. Recent trials have suggested that hs-CRP may assist in stratifying risk in patients presenting with coronary artery disease, particularly those with ACS. Further studies examining hs-CRP levels may help elucidate new therapeutic strategies for the secondary prevention of CVD. High-sensitivity C-reactive protein also adds prognostic information to the calculated FRS in individuals without overt coronary disease. When combined with lipid screening, hs-CRP improves global risk prediction in patients who would otherwise not be identified for primary prevention by lipid assessment alone.

Although statin therapy has been shown to benefit individuals with elevated hs-CRP levels, it is not known whether aggressive statin therapy can reduce the risk of a first cardiovascular event in persons with low LDL-C but high hs-CRP. The ongoing JUPITER trial is the first major randomized, controlled trial to assess the effects of statin therapy on the risk of a first cardiovascular event in such subjects. A positive outcome in JUPITER would provide strong evidence supporting the use of statin therapy for the 25 million to 30 million Americans who fall outside the current NCEP ATP III treatment guidelines. This outcome would represent a tremendous step forward in CHD prevention.

Finally, preliminary data suggest that lowering hs-CRP levels may evolve as a separate, distinct therapeutic goal. However, additional prospective randomized trials are needed before targeted treatment to lower hs-CRP levels to a specific range can be endorsed.

	References

Top Methods Review of Studies Examining... Using hs-CRP Values for... Relationship Between Statin... JUPITER May Answer Remaining... Conclusions References

 
1. Ridker PM. Cardiology Patient Page. C-reactive protein: a simple test to help predict risk of heart attack and stroke. Circulation.2003; 108:e81 -e85. Available at: http://circ.ahajournals.org/cgi/content/full/108/12/e81. Accessed August 1, 2005.[Free Full Text]

2. Farmer JA, Torre-Amione G. Atherosclerosis and inflammation [review]. Curr Atheroscler Rep.2002; 4:92 -98.[Medline]

3. Pearson TA, Mensah GA, Hong Y, Smith SC Jr, for the Centers for Disease Control and Prevention and the American Heart Association Workshop on Markers of Inflammation and Cardiovascular Disease. CDC/AHA workshop on markers of inflammation and cardiovascular disease: application to clinical and public health practice: overview. Circulation.2004; 110:e543 -544. Available at: http://circ.ahajournals.org/cgi/content/full/110/25/e543. Accessed August 3, 2005.[Free Full Text]

4. Ridker PM, for the 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 [review].Circulation.2003; 108:2292 -2297. Available at: http://circ.ahajournals.org/cgi/content/full/108/19/2292. Accessed August 3, 2005.[Free Full Text]

5. Ridker PM. Clinical application of C-reactive protein for cardiovascular disease detection and prevention [review]. Circulation.2003; 107:363 -369. Available at: http://circ.ahajournals.org/cgi/content/full/107/3/363. Accessed August 3, 2005.[Free Full Text]

6. Ross R. Atherosclerosis: An inflammatory disease [review]. N Engl J Med.1999; 340:115 -126.[Free Full Text]

7. Blake GJ, Ridker PM. C-reactive protein and other inflammatory risk markers in acute coronary syndromes [review]. J Am Coll Cardiol. 2003; 41(4 Suppl S):37S -42S.[Abstract/Free Full Text]

8. Ridker PM, Bassuk SS, Toth PP. C-reactive protein and risk of cardiovascular disease: Evidence and clinicial application [review]. Curr Atheroscler Rep.2003; 5:341 -349.[Medline]

9. Calabro P, Willerson JT, Yeh ETH. Inflammatory cytokines stimulated C-reactive protein production by human coronary artery smooth muscle cells. Circulation.2003; 108:1930 -1932. Available at: http://circ.ahajournals.org/cgi/content/full/108/16/1930. Accessed August 3, 2005.[Abstract/Free Full Text]

10. Khreiss T, Jozsef L, Potempa LA, Filep JG. Conformational rearrangement in C-reactive protein is required for proinflammatory actions on human endothelial cells. Circulation.2004; 109:2016 -2022. Available at: http://circ.ahajournals.org/cgi/content/full/109/16/2016. Accessed August 3, 2005.[Abstract/Free Full Text]

11. Ridker PM. High-sensitivity C-reactive protein: Potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation.2001; 103:1813 -1818. Available at: http://circ.ahajournals.org/cgi/content/full/103/13/1813. Accessed August 3, 2005.[Abstract/Free Full Text]

12. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med.1997; 336:973 -979.[Abstract/Free Full Text]

13. Sakkinen P, Abbott RD, Curb JD, Rodriguez BL, Yano K, Tracy RP. C-reactive protein and myocardial infarction. J Clin Epidemiol. 2002;55:445 -451.[Medline]

14. Ridker PM, Buring JE, Shih J, Matias M, Hennekens CH. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation.1998; 98: 731-733. Available at: http://circ.ahajournals.org/cgi/content/full/98/8/731. Accessed August 3, 2005.[Abstract/Free Full Text]

15. Ridker PM, Rifai N, Bradwin G, Buring JE. Non-HDL cholesterol, apolipoproteins A-l and B100, standard lipid measures, lipid ratios, and CRP as risk factors for cardiovascular disease in women. JAMA. 2005;294:326 -333.[Abstract/Free Full Text]

16. Pai JK, Pischon T, Ma J, Manson JE, Hankinson SE, Joshipura K, et al. Inflammatory markers and the risk of coronary heart disease in men and women. N Engl J Med.2004; 351:2599 -2610.[Abstract/Free Full Text]

17. van der Meer IM, de Maat MP, Kiliaan AJ, van der Kuip DA, Hofman A, Witteman JC. The value of C-reactive protein in cardiovascular risk prediction: the Rotterdam Study. Arch Intern Med.2003; 163:1323 -1328.[Abstract/Free Full Text]

18. Danesh J, Wheeler JG, Hirschfield GM, Eda S, Eiriksdottir G, Rumley A, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med. 2004;350:1387 -1397.[Abstract/Free Full Text]

19. Cushman M, Arnold AM, Psaty BM, Manolio TA, Kuller LH, Burke GL, Polak JF, Tracy RP. C-reactive protein and the 10-year incidence of coronary heart disease in older men and women. Circulation.2005; 112:25 -31.[Abstract/Free Full Text]

20. Crea F, Monaco C, Lanza GA, Maggi E, Ginnetti F, Cianflone D, et al. Inflammatory predictors of mortality in the Scandinavian Simvastatin Survival Study. Clin Cardiol.2002; 25:461 -466.[Medline]

21. Curb JD, Abbott RD, Rodriquez BL, Sakkinen P, Popper JS, Yano K, et al. C-reactive protein and the future risk of thromboembolic stroke in healthy men. Circulation.2003; 107:2016 -2020. Available at: http://circ.ahajournals.org/cgi/content/full/107/15/2016. Accessed August 3, 2005.[Abstract/Free Full Text]

22. Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14,719 initially healthy American women. Circulation.2003; 107:391 -397. Available at: http://circ.ahajournals.org/cgi/content/full/107/3/391. Accessed August 3, 2005.[Abstract/Free Full Text]

23. Lemieux I, Pascot A, Prud'homme D, Alméras N, Bogaty P, Nadeau A, et al. Elevated C-reactive protein: another component of the atherothrombotic profile of abdominal obesity. Arterioscler Thromb Vasc Biol. 2001;21:961 -967. Available at: http://atvb.ahajournals.org/cgi/content/full/21/6/961. Accessed August 3, 2005.[Abstract/Free Full Text]

24. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA. 2001;286:327 -334.[Abstract/Free Full Text]

25. Pradhan AD, Cook NR, Buring JE, Manson JE, Ridker PM. C-reactive protein is independently associated with fasting insulin in nondiabetic women. Arterioscler Thromb Vasc Biol.2003; 23: 650-655. Available at: http://atvb.ahajournals.org/cgi/content/full/23/4/650. Accessed August 3, 2005.[Abstract/Free Full Text]

26. Freeman DJ, Norrie J, Caslake MJ, Gaw A, Ford I, Lowe GD, et al, for the West of Scotland Coronary Prevention Study. C-reactive protein is an independent predictor of risk for the development of diabetes in the West of Scotland Coronary Prevention Study. Diabetes.2002; 51:1596 -1600. Available at: http://diabetes.diabetesjournals.org/cgi/content/full/51/5/1596. Accessed August 3, 2005.[Abstract/Free Full Text]

27. Han TS, Sattar N, Williams K, Gonzalez-Villalpando C, Lean MEJ, Haffner SM. Prospective study of C-reactive protein in relation to the development of diabetes and metabolic syndrome in the Mexico City Diabetes Study. Diabetes Care.2002; 25:2016 -2021. Available at: http://care.diabetesjournals.org/cgi/content/full/25/11/2016. Accessed August 3, 2005.[Abstract/Free Full Text]

28. Rader DJ. Inflammatory markers of coronary risk. N Engl J Med. 2000;343:1179 -1182.[Free Full Text]

29. Albert MA, Glynn RJ, Ridker PM. Plasma concentration of C-reactive protein and the calculated Framingham coronary heart disease risk score. Circulation.2003; 108:161 -165. Available at: http://circ.ahajournals.org/cgi/content/full/108/2/161. Accessed August 3, 2005.[Abstract/Free Full Text]

30. Koenig W, Lowel H, Baumert J, Meisinger C. 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.2004; 109:1349 -1353. Epub 2004 March 15. Available at: http://circ.ahajournals.org/cgi/content/full/109/11/1349. Accessed August 3, 2005.[Abstract/Free Full Text]

31. 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; 109:1955 -1959. Available at: http://circ.ahajournals.org/cgi/content/full/109/16/1955. Accessed August 3, 2005.[Abstract/Free Full Text]

32. Ridker PM, Glynn RJ, Hennekens CH. C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation.1998; 97:2007 -2011. Available at: http://circ.ahajournals.org/cgi/content/full/97/20/2007. Accessed August 3, 2005.[Abstract/Free Full Text]

33. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347:1557 -1565.[Abstract/Free Full Text]

34. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation.2002; 106:3143 -3421. Available at: http://circ.ahajournals.org/cgi/content/full/106/25/3143. Accessed August 1, 2005.[Free Full Text]

35. Jialal I, Stein D, Balis D, Grundy SM, Adams-Huet B, Devaraj S. Effect of hydroxymethyl glutaryl coenzyme A reductase inhibitor therapy on high sensitive C-reactive protein levels. Circulation.2001; 103:1933 -1935. Available at: http://circ.ahajournals.org/cgi/content/full/103/15/1933. Accessed August 3, 2005.[Abstract/Free Full Text]

36. Albert MA, Danielson E, Rifai N, Ridker PM, for the PRINCE Investigators. Effect of statin therapy on C-reactive protein levels: the Pravastatin Inflammation/CRP Evaluation (PRINCE): a randomized trial and cohort study. JAMA.2001; 286:64 -70.[Abstract/Free Full Text]

37. Ridker PM, Rifai N, Clearfield M, Downs JR, Weis SE, Miles JS, et al, for the 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;344:1959 -1965. Available at: http://content.nejm.org/cgi/content/abstract/344/26/1959. Accessed August 3, 2005.[Abstract/Free Full Text]

38. Ridker PM, Rifai N, Pfeffer MA, Sacks FM, Moye LA, Goldman S, et al, for the Cholesterol and Recurrent Events (CARE) Investigators. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Circulation.1998; 98: 839-844. Available at: http://circ.ahajournals.org/cgi/content/full/98/9/839. Accessed August 3, 2005.[Abstract/Free Full Text]

39. Kinlay S, Schwartz GG, Olsson AG, Rifai N, Leslie SJ, Sasiela WJ, et al, for the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering Study Investigators. High-dose atorvastatin enhances the decline in inflammatory markers in patients with acute coronary syndromes in the MIRACL study. Circulation.2003; 108:1560 -1566. Available at: http://circ.ahajournals.org/cgi/content/full/108/13/1560. Accessed August 3, 2005.[Abstract/Free Full Text]

40. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, et al, for the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med.2004; 350:1495 -1504.[Abstract/Free Full Text]

41. de Lemos JA, Blazing MA, Wiviott SD, Lewis EF, Fox KA, White HD, et al, for the A to Z Investigators. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA.2004; 292:1307 -1316.[Abstract/Free Full Text]

42. Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA, et al, for the REVERSAL Investigators. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA.2004; 291:1071 -1080.[Abstract/Free Full Text]

43. Betteridge DJ, Gibson M, on behalf of the ANDROMEDA Investigators. Effect of rosuvastatin and atorvastatin on LDL-C and CRP levels in patients with type 2 diabetes: results of the ANDROMEDA study [abstract]. Atherosclerosis.2004; 5(Suppl 1):107 -108.[Medline]

44. Muhlestein JB, Anderson JL, Horne BD, Carlquist JF, Bair TL, Bunch TJ, et al, for the Intermountain Heart Collaborative Study Group. Early effects of statins in patients with coronary artery disease and high C-reactive protein. Am J Cardiol.2004; 94:1107 -1112.[Medline]

45. Saab FA, Eagle KA, Kline-Rogers E, Fang J, Otten R, Mukherjee D, for the Michigan Cardiovascular Outcomes Research and Reporting Program of the University of Michigan Cardiovascular Center. Comparison of outcomes in acute coronary syndrome in patients receiving statins within 24 hours of onset versus at later times. Am J Cardiol.2004; 94:1166 -1168.[Medline]

46. Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McGabe CH, et al, for the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22) Investigators. C-reactive protein levels and outcomes after statin therapy. N Engl J Med.2005; 352:20 -28.[Abstract/Free Full Text]

47. Nissen SE, Tuzcu EM, Schoenhagen P, Crowe T, Sasiela WJ, Tsai J, et al, for the REVERSAL Investigators. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med. 2005;352:29 -38.[Abstract/Free Full Text]

48. Yki-Järvinen H. Thiazolidinediones [review]. N Engl J Med. 2004;351:1106 -1118.[Free Full Text]

49. Church TS, Earnest CP, Wood KA, Kampert JB. Reduction of C-reactive protein levels through use of a multivitamin. Am J Med. 2003;115:702 -707.[Medline]

50. Jones PH, Davidson MH, Stein EA, Bays HE, McKenney JM, Miller E, et al; STELLAR Study Group. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR^* Trial). Am J Cardiol.2003; 92:152 -160.[Medline]

51. Ridker PM. Should statin therapy be considered for patients with elevated C-reactive protein? The need for a definitive clinical trial [editorial]. Eur Heart J.2001; 22:2135 -2137. Available at: http://eurheartj.oxfordjournals.org/cgi/reprint/22/23/2135. Accessed August 1, 2005.[Free Full Text]

This article has been cited by other articles:

				L. J. Moran, M. Noakes, P. M. Clifton, G. A. Wittert, D. P. Belobrajdic, and R. J. Norman C-Reactive Protein before and after Weight Loss in Overweight Women with and without Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 2944 - 2951. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Clearfield, M. B. Search for Related Content PubMed PubMed Citation Articles by Clearfield, M. B.