RE: New test for heart disease

[Guest guest]

Hi All, Both C-reactive protein and low-density lipoprotein (LDL)

cholesterol levels are elevated in persons at risk for cardiovascular

events. Because of its critical importance in atherogenesis, LDL is the

focus of current guidelines for the determination of the risk of

cardiovascular disease. C-reactive protein is a marker of inflammation that

has been shown in several prospective, nested case–control studies to be

associated with an increased risk of myocardial infarction, stroke, sudden

death from cardiac causes, and peripheral arterial disease.

The attached new PDF-available paper and an associated one draw important

distinction, I believe. It seems to me that the data in the paper suggest

that the C-reactive protein level is a stronger predictor of cardiovascular

events than the LDL, and I am about to get the data for C-reactive protein

twice soon for the first time. My LDL is quite low (48 mg/dl as of a few

days ago).

Cheers, Al.

From: Francesca Skelton <fskelton@e...>

Date: Thu Nov 14, 2002 1:01 pm

Subject: New test for heart disease

http://www.washingtonpost.com/wp-dyn/articles/A51456-2002Nov13.html

Alan Pater, Ph.D.; Faculty of Medicine; Memorial University; St. 's, NL

A1B 3V6 Canada; Tel. No.: (709) 777-6488; Fax No.: (709) 777-7010; email:

apater@...

The New England Journal of Medicine 347 (20):1557-1565 Nov 14, 2002

Comparison of C-Reactive Protein and Low-Density Lipoprotein Cholesterol Levels

in the Prediction of First Cardiovascular Events

M. Ridker, Nader Rifai, Lynda Rose, E. Buring, and R. Cook.

ABSTRACT

Background Both C-reactive protein and low-density lipoprotein (LDL) cholesterol

levels are elevated in persons at risk for cardiovascular events. However,

population-based data directly comparing these two biologic markers are not

available.

Methods C-reactive protein and LDL cholesterol were measured at base line in

27,939 apparently

healthy American women, who were then followed

for a mean of eight years for the occurrence of myocardial infarction, ischemic

stroke,

coronary revascularization, or death from cardiovascular causes. We assessed

the value of these two measurements in predicting the risk of cardiovascular

events in the study population.

Results Although C-reactive protein and LDL cholesterol were minimally

correlated (r=0.08),

base-line levels of each had a strong linear

relation with the incidence of cardiovascular

events. After adjustment for age, smoking

status, the presence or absence of diabetes

mellitus, categorical levels of blood pressure,

and use or nonuse of hormone-replacement

therapy, the relative risks of first

cardiovascular events according to increasing

quintiles of C-reactive protein, as compared

with the women in the lowest quintile, were

1.4, 1.6, 2.0, and 2.3 (P<0.001), whereas the

corresponding relative risks in increasing

quintiles of LDL cholesterol, as compared with

the lowest, were 0.9, 1.1, 1.3, and 1.5

(P<0.001). Similar effects were observed in

separate analyses of each component of the

composite end point and among users and

nonusers of hormone-replacement therapy.

Overall, 77 percent of all events occurred

among women with LDL cholesterol levels below

160 mg per deciliter (4.14 mmol per liter), and

46 percent occurred among those with LDL

cholesterol levels below 130 mg per deciliter

(3.36 mmol per liter). By contrast, because C-reactive protein and LDL

cholesterol measurements tended to identify different high-risk groups,

screening for both biologic markers provided better prognostic information

than screening for either alone. Independent effects were also observed for

C-reactive protein in analyses adjusted for all components of the

Framingham risk score.

Conclusions These data suggest that the C-reactive protein level is a

stronger predictor of cardiovascular events than the LDL cholesterol level

and that it adds prognostic information to that conveyed by the Framingham

risk score.

Because of its critical importance in atherogenesis, low-density

lipoprotein (LDL) cholesterol is the focus of current guidelines for the

determination of the risk of cardiovascular disease.1 However,

atherothrombosis often occurs in the absence of hyperlipidemia, and recent

consensus panels assembled by the National Heart, Lung, and Blood Institute

and the Centers for Disease Control and Prevention have concluded that

population-based data on other risk factors are urgently needed.2,3

Among the biologic markers considered by those panels, there was particular

interest in C-reactive protein, a marker of inflammation that has been

shown in several prospective, nested case–control studies to be associated

with an increased risk of myocardial infarction,4,5,6,7,8,9

stroke,4,6,10,11 sudden death from cardiac causes,12 and peripheral

arterial disease.13 Although the results of these studies are highly

consistent, limitations inherent in the design of nested case–control

studies make it difficult to assess the relative merit of C-reactive

protein. In particular, population-based cutoff points for C-reactive

protein remain uncertain, and reliable data describing

receiver-operating-characteristic curves for C-reactive protein have not

been available. Moreover, there are insufficient data from prospective

cohort studies directly comparing the predictive value of C-reactive

protein with that of LDL cholesterol.

In a previous hypothesis-generating report limited to 122 women in whom

cardiovascular disease developed (case patients) and 244 controls who were

participants in the Women's Health Study, we observed that several markers

of inflammation, including C-reactive protein, had prognostic value for the

detection of first vascular events over a three-year period.6 However, the

relatively small number of events and the short follow-up limit the

reliability of those data. Furthermore, because of the matched-pairs

case–control study design, we were unable to define general

population-based cutoff points or to evaluate directly characteristics of

C-reactive protein used as a diagnostic test.

To overcome these limitations, we measured C-reactive protein and LDL

cholesterol in all 27,939 participants in the Women's Health Study who

provided usable base-line blood samples; these women had been followed for

a mean of eight years. Using these data, we were able to calculate survival

curves associated with C-reactive protein levels, to compare the predictive

value of C-reactive protein and LDL cholesterol directly in a large,

representative population sample, and to define the population distribution

of C-reactive protein levels. We also determined the predictive value of

each biologic marker among users and nonusers of hormone-replacement

therapy; this is a clinically relevant issue, since hormone-replacement

therapy affects levels of both C-reactive protein and LDL

cholesterol.14,15,16 Finally, we evaluated whether C-reactive protein

provided prognostic information on risk after adjustment for all components

of the Framingham risk score.

Methods

Study Design

The Women's Health Study is an ongoing evaluation of aspirin and vitamin E

for the primary prevention of cardiovascular events among women 45 years of

age or older. Participants were enrolled between November 1992 and July

1995, at which time they provided information regarding demographic,

behavioral, and lifestyle factors. All participants were followed for the

occurrence of first cardiovascular events, including nonfatal myocardial

infarction, nonfatal ischemic stroke, coronary revascularization

procedures, and death from cardiovascular causes. ..... Stroke was confirmed

if the participant had new neurologic

deficits that persisted for more than 24 hours. Computed tomographic scans

or magnetic resonance images were available for the great majority of

events and were used to distinguish hemorrhagic from ischemic events. ..........

........standardization programs regarding the measurement of C-reactive protein.

Of the samples received, 27,939 could be evaluated and were assayed for

C-reactive protein and LDL cholesterol.

Statistical Analysis

Because hormone-replacement therapy affects levels of C-reactive protein

and LDL cholesterol, we first established population-based distributions

for each analyte among the 15,745 women who were not taking

hormone-replacement therapy at study entry ....... We then divided these

opulation data into increasing

quintiles with respect to C-reactive protein and LDL cholesterol and

constructed Kaplan–Meier curves for event-free survival. The relative risks

of new cardiovascular events were computed for quintiles 2 through 5, as

compared with the lowest quintile......... predictive value .......

among users and nonusers of hormone-replacement therapy at base line. ....

independent predictive value after simultaneous

adjustment for all components of the Framingham risk score19 (including

age, smoking status, categorical levels of blood pressure, presence or

absence of diabetes mellitus, and high-density lipoprotein and LDL

cholesterol levels) and whether C-reactive protein contributed information

on risk beyond that conveyed by the 10-year risk calculated with the

Framingham risk score and beyond the risk associated with LDL cholesterol......

Results

Base-Line Characteristics

The mean age of the 27,939 women at base line was 54.7 years. Forty-four

percent were current users of hormone-replacement therapy, 25 percent had

hypertension, 12 percent were current smokers, and 2.5 percent had diabetes

mellitus. The mean body-mass index (the weight in kilograms divided by the

square of the height in meters) was 25.9.

Distribution of C-Reactive Protein and LDL Cholesterol Levels

Table 1 presents data on the distribution of C-reactive protein and LDL

cholesterol values among the 15,745 women who were not using

hormone-replacement therapy at the time of blood collection. These

distributions are very similar to those reported for men and women in

previous U.S. and European studies. On the basis of this sample, the cutoff

points for quintiles of C-reactive protein were less than or equal to 0.49,

more than 0.49 to 1.08, more than 1.08 to 2.09, more than 2.09 to 4.19, and

more than 4.19 mg per liter.

View this table: Table 1. Distribution of C-Reactive Protein and LDL

[in this window] Cholesterol Levels among 15,745 Study Participants

[in a new window] Who Were Not Taking Hormone-Replacement Therapy at

the Time of the Base-Line Blood Collection.

Event-free Survival

The probability of event-free survival for all study participants is

presented in Figure 1 according to base-line quintiles of C-reactive

protein and LDL cholesterol. Table 2 presents crude relative risks of a

first cardiovascular event according to increasing quintiles of base-line

C-reactive protein and LDL cholesterol, along with relative risks adjusted

for age and other risk factors. For both C-reactive protein and LDL

cholesterol, strong linear risk gradients were observed. After adjustment

for age, smoking status, the presence or absence of diabetes, blood

pressure, and use or nonuse of hormone-replacement therapy, the

multivariable relative risks of a first cardiovascular event for women in

increasing quintiles of C-reactive protein were 1.0 (the first quintile was

the reference category), 1.4, 1.6, 2.0, and 2.3 (P<0.001), whereas the

relative risks associated with increasing quintiles of LDL cholesterol were

1.0 (the first quintile was the reference category), 0.9, 1.1, 1.3, and 1.5

(P<0.001). No significant deviations from linearity in the log relative

risks were detected in either model. The apparent superiority of C-reactive

protein over LDL cholesterol in terms of the prediction of risk was

observed in similar analyses of the individual components of the composite

end point (coronary heart disease, stroke, and death from cardiovascular

causes) (Figure 2).

[ ] Figure 1. Event-free Survival According to

Base-Line Quintiles of C-Reactive Protein and LDL

Cholesterol.

The range of values for C-reactive protein was as follows:

first quintile,

[<=]0.49 mg per liter; second quintile, >0.49 to 1.08

mg per

liter; third quintile, >1.08 to 2.09 mg per

liter; fourth quintile, >2.09 to 4.19 mg per

liter; fifth quintile, >4.19 mg per liter. For

LDL cholesterol, the values were as follows:

first quintile, [<=]97.6 mg per deciliter;

second quintile, >97.6 to 115.4 mg per

deciliter; third quintile, >115.4 to 132.2 mg

per deciliter; fourth quintile, >132.2 to 153.9

mg per deciliter; fifth quintile, >153.9 mg per

deciliter. To convert values for LDL

cholesterol to millimoles per liter, multiply

by 0.02586. Note the expanded scale on the ordinate.

Table 2. Crude, Age-Adjusted, and Risk-Factor–Adjusted Relative

Risk of a First

Cardiovascular Event According to the Quintile of

C-Reactive Protein and LDL Cholesterol at Base Line.

Figure 2. Age-Adjusted Relative Risk of Future

Cardiovascular Events, According to Base-Line

C-Reactive Protein Levels (Solid Bars) and LDL Cholesterol

Levels (Open Bars).

Predictive Models

Table 2 also presents results of the C statistic analyses (area under the

receiver-operating-characteristic curve). In models of crude rates

including the entire cohort (27,939 women), the calculated area under the

receiver-operating-characteristic curve was 0.64 for C-reactive protein and

0.60 for LDL cholesterol. In prediction models including age, smoking

status, presence or absence of diabetes, blood pressure, use or nonuse of

hormone-replacement therapy, and treatment assignment, the ability of the

model based on C-reactive protein to discriminate events from nonevents was

virtually identical to that of the model based on LDL cholesterol (C

statistic for both models, 0.81). However, the likelihood-ratio chi-square

statistic was higher for the model based on C-reactive protein than for

that based on LDL cholesterol (716.4 vs. 706.0, both with 16 df). This

statistic, a more sensitive measure of model fit than the rank-based C

statistic, suggests that the model based on C-reactive protein has better

discrimination than the model based on LDL cholesterol. In addition, in

likelihood-ratio tests of the contribution of each variable, the addition

of C-reactive protein to the model based on LDL cholesterol was stronger

(chi-square = 25.4, 4 df; P<0.001) than the addition of LDL cholesterol to

the model based on C-reactive protein (chi-square = 15.0, 4 df; P=0.005).

Effects of Hormone-Replacement Therapy

Table 3 presents stratified analyses according to the use or nonuse of

hormone-replacement therapy at base line. Among women who did not use

hormone-replacement therapy, the multivariable-adjusted relative risks of a

first cardiovascular event in increasing quintiles of C-reactive protein

were 1.0, 1.8, 1.8, 2.4, and 3.0 (P<0.001), whereas the

multivariable-adjusted relative risks in increasing quintiles of LDL

cholesterol were 1.0, 0.8, 0.9, 1.1, and 1.4 (P=0.002). Among users of

hormone-replacement therapy, risk estimates were lower for both C-reactive

protein and LDL cholesterol but remained significant in crude and

age-adjusted models. Risk estimates based on C-reactive protein among users

of hormone-replacement therapy were similar regardless of whether the

quintiles were defined by measurements in nonusers or users of

hormone-replacement therapy.

Table 3. Crude, Age-Adjusted, and Risk-Factor–Adjusted Relative Risk of

a First

Cardiovascular Event, According to the Quintile of

C-Reactive Protein and LDL Cholesterol at Base Line, among 12,139

Women Who Used Postmenopausal

Hormone-Replacement Therapy and 15,745 Women Who Did Not Use

Such Therapy.

Interactions between C-Reactive Protein and LDL Cholesterol

Of all events in the study participants, 77 percent occurred among those

with LDL cholesterol levels below 160 mg per deciliter (4.14 mmol per

liter), and 46 percent occurred among those with LDL cholesterol levels

below 130 mg per deciliter (3.36 mmol per liter). However, C-reactive

protein and LDL cholesterol levels were minimally correlated (r=0.08),

suggesting that each biologic marker was detecting a different high-risk

group. We therefore constructed survival curves after dividing the study

participants into four groups on the basis of whether they were above or

below the median C-reactive protein value (1.52 mg per liter) and the

median LDL cholesterol value (123.7 mg per deciliter [3.20 mmol per

liter]). For the entire cohort (Figure 3), the multivariable-adjusted

relative risks were as follows: low C-reactive protein–low LDL cholesterol,

1.0 (this was the reference category); low C-reactive protein–high LDL

cholesterol, 1.5 (95 percent confidence interval, 1.0 to 2.1); high

C-reactive protein–low LDL cholesterol, 1.5 (95 percent confidence

interval, 1.1 to 2.1); and high C-reactive protein–high LDL cholesterol,

2.1 (95 percent confidence interval, 1.5 to 2.8). The corresponding

age-adjusted rates of events per 1000 person-years of follow-up were 1.3,

2.0, 2.6, and 3.9, respectively.

Figure 3. Event-free Survival among Women with C-Reactive Protein (CRP) and LDL

Cholesterol

Levels above or below the Median for the Study Population.

Data are shown for the entire cohort (27,939

women) and for women who were not taking

hormone-replacement therapy at base line (15,745

women). The median values were as follows: for

C-reactive protein, 1.52 mg per liter; for LDL

cholesterol, 123.7 mg per deciliter (3.20 mmol

per liter). Note the expanded scale on the ordinate.

On the assumption that recent evidence from clinical trials will lead to a

marked reduction in the use of hormone-replacement therapy among American

women,20 we sought to increase the generalizability of our findings by

repeating these analyses including only the 15,745 women who were not using

hormone-replacement therapy at base line. In this analysis, the

multivariable-adjusted relative risks were as follows: low C-reactive

protein–low LDL cholesterol, 1.0 (the reference category); low C-reactive

protein–high LDL cholesterol, 1.5 (95 percent confidence interval, 1.0 to

2.4); high C-reactive protein–low LDL cholesterol, 1.7 (95 percent

confidence interval, 1.1 to 2.6); and high C-reactive protein–high LDL

cholesterol, 2.4 (95 percent confidence interval, 1.6 to 3.6). The

corresponding age-adjusted rates of events per 1000 person-years were 1.2,

1.9, 3.1, and 4.5, respectively. As in the total cohort, event-free

survival among nonusers of hormone-replacement therapy was worse in the

high C-reactive protein–low LDL cholesterol group than in the low

C-reactive protein–high LDL cholesterol group (Figure 3).

C-Reactive Protein, LDL Cholesterol Categories, and the Framingham Risk

Score

We performed several further analyses to evaluate the addition of

measurements of C-reactive protein to the Framingham risk score and to the

LDL cholesterol categories of less than 130, 130 to 160, and more than 160

mg per deciliter, which are defined in current guidelines for risk

detection.1 After adjustment for all components of the Framingham risk

score,19 quintiles of C-reactive protein remained a strong, independent

predictor of risk in the cohort as a whole (relative risks of future

cardiovascular events in increasing quintiles, 1.0, 1.3, 1.4, 1.7, and 1.9;

P<0.001) and among nonusers of hormone-replacement therapy (relative risks,

1.0, 1.6, 1.5, 1.8, and 2.2; P=0.001). As shown in Figure 4, increasing

levels of C-reactive protein were associated with increased risk of

cardiovascular events at all levels of estimated 10-year risk based on the

Framingham risk score.19 Similarly, increasing C-reactive protein levels

were associated with increased risk of cardiovascular events at LDL

cholesterol levels below 130, 130 to 160, and above 160 mg per deciliter (Figure

4).

Figure 4. Multivariable-Adjusted Relative Risks of Cardiovascular Disease

According to Levels of

C-Reactive Protein and the Estimated 10-Year Risk

Based on the Framingham Risk Score as Currently

Defined by the National Cholesterol Education

Program and According to Levels of C-Reactive

Protein and Categories of LDL Cholesterol.

To convert values for LDL cholesterol to millimoles per

liter, multiply by 0.02586.

Discussion

The current study suggests that C-reactive protein, a marker of systemic

inflammation, is a stronger predictor of future cardiovascular events than

LDL cholesterol. In this study, C-reactive protein was superior to LDL

cholesterol in predicting the risk of all study end points; this advantage

persisted in multivariable analyses in which we adjusted for all

traditional cardiovascular risk factors and was clear among users as well

as nonusers of hormone-replacement therapy at base line. However,

C-reactive protein and LDL cholesterol levels were minimally correlated.

Thus, the combined evaluation of both C-reactive protein and LDL

cholesterol proved to be superior as a method of risk detection to

measurement of either biologic marker alone. Finally, at all levels of

estimated 10-year risk for events according to the Framingham risk score

and at all levels of LDL cholesterol, C-reactive protein remained a strong

predictor of future cardiovascular risk.

In addition to their pathophysiological implications with regard to

inflammation and atherothrombosis,21,22,23 we believe these data have

implications for the detection and prevention of cardiovascular disease.

Seventy-seven percent of first cardiovascular events among the 27,939 women

in this study occurred in those with LDL cholesterol levels below 160 mg

per deciliter, and 46 percent occurred in those with levels below 130 mg

per deciliter. Thus, large proportions of first cardiovascular events in

women occur at LDL cholesterol levels below the threshold values for

intervention and treatment in the current guidelines of the National

Cholesterol Education Program.1

Our data also help establish the population distribution of C-reactive

protein. That the cutoff points for the quintiles in the current population

are very close to those previously described in smaller studies from the

United States and Europe is reassuring and consistent with evidence

describing the stability and reproducibility of values obtained for

C-reactive protein with new, high-sensitivity assays.24 These data also

demonstrate that a single set of cutoff points for C-reactive protein in

women can be used regardless of their status with regard to

hormone-replacement therapy — an issue that has been of concern in previous

work.14,15,16

The current data also have implications for the targeting of preventive

therapies. We previously demonstrated in a randomized trial that statin

therapy may have clinical value for primary prevention among persons with

elevated C-reactive protein but low LDL cholesterol levels.25 According to

the survival analyses in the current study (Figure 3), women in the high

C-reactive protein–low LDL cholesterol subgroup were at higher absolute

risk than those in the low C-reactive protein–high LDL cholesterol

subgroup, yet it is only the latter group for whom aggressive prevention is

likely to be considered by most physicians. These observations suggest that

continued reliance on LDL cholesterol to predict the risk of cardiovascular

events will not lead to optimal targeting of statin therapy for primary

prevention; this suggestion is consistent with data from the Heart

Protection Study, in which LDL cholesterol levels did not predict the

efficacy of statins for secondary prevention.26 Our data thus strongly

support the need for a large-scale trial of statin therapy among persons

with low levels of LDL cholesterol but high levels of C-reactive protein.27

Unlike other markers of inflammation, C-reactive protein levels are stable

over long periods, have no diurnal variation, can be measured inexpensively

with available high-sensitivity assays, and have shown specificity in terms

of predicting the risk of cardiovascular disease.24,28,29,30 However,

despite the consistency of prospective data in diverse

cohorts,4,5,6,7,8,9,10,11,12,13,16,25,31 decisions regarding the clinical

use of C-reactive protein remain complex. To evaluate fully the clinical

usefulness of any new biologic marker requires more than a direct

comparison with LDL cholesterol or the Framingham risk score; other

factors, such as lipid subfractions, triglycerides, Lp(a) lipoprotein,

homocysteine, insulin resistance, and hypofibrinolysis, either in

combination with or in place of other traditional markers, must also be

taken into account. Furthermore, it is increasingly clear that no single

common pathway is likely to account for all cardiovascular events and that

interactions between novel biologic markers and more traditional risk

factors, such as high blood pressure, smoking, obesity, diabetes, low

levels of physical activity, and use of hormone-replacement therapy, may be

more or less important for individual patients. Thus, as our findings

indicate, new biologic and statistical approaches will be needed as

information from basic vascular biology begins the transition into clinical

practice.

References

1. Expert Panel on Detection, Evaluation, and Treatment of High Blood

Cholesterol in Adults. Executive summary of the 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). JAMA

2001;285:2486-2497.[iSI][Medline]

2. Centers for Disease Control/American Heart Association Workshop on

Inflammatory Markers and Cardiovascular Disease: application to

clinical and public health practice, Atlanta, March 14–15, 2002.

Atlanta: Centers for Disease Control and Prevention, 2002.

3. Grundy SM, D'Agostino RB Sr, Mosca L, et al. Cardiovascular risk

assessment based on US cohort studies: findings from a National Heart,

Lung, and Blood Institute workshop. Circulation

2001;104:491-496.[Full Text]

4. Ridker PM, Cushman M, Stampfer MJ, RP, Hennekens CH.

Inflammation, aspirin, and the risk of cardiovascular disease in

apparently healthy men. N Engl J Med 1997;336:973-979. [Erratum, N

Engl J Med 1997;337:356.][Abstract/Full Text]

5. RP, Lemaitre RN, Psaty BM, et al. Relationship of C-reactive

protein to risk of cardiovascular disease in the elderly: results from

the Cardiovascular Health Study and the Rural Health Promotion

Project. Arterioscler Thromb Vasc Biol

1997;17:1121-1127.[Abstract/Full Text]

6. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and

other markers of inflammation in the prediction of cardiovascular

disease in women. N Engl J Med 2000;342:836-843.[Abstract/Full Text]

7. Koenig W, Sund M, Froelich M, et al. C-reactive protein, a sensitive

marker of inflammation, predicts future risk of coronary heart disease

in initially healthy middle-aged men: results from the MONICA

(Monitoring Trends and Determinants in Cardiovascular Disease)

Augsburg Cohort Study, 1984 to 1992. Circulation

1999;99:237-242.[Abstract/Full Text]

8. Danesh J, Whincup P, M, et al. Low grade inflammation and

coronary heart disease: prospective study and updated meta-analyses.

BMJ 2000;321:199-204.[Abstract/Full Text]

9. Mendall MA, Strachan DP, Butland BK, et al. C-reactive protein:

relation to total mortality, cardiovascular mortality and

cardiovascular risk factors in men. Eur Heart J

2000;21:1584-1590.[iSI][Medline]

10. Rost NS, Wolf PA, Kase CS, et al. Plasma concentration of C-reactive

protein and risk of ischemic stroke and transient ischemic attack: the

Framingham Study. Stroke 2001;32:2575-2579.[Abstract/Full Text]

11. Ford ES, Giles WH. Serum C-reactive protein and self-reported stroke:

findings from the Third National Health and Nutrition Examination

Survey. Arterioscler Thromb Vasc Biol

2000;20:1052-1056.[Abstract/Full Text]

12. Albert CM, Ma J, Rifai N, Stampfer MJ, Ridker PM. Prospective study of

C-reactive protein, homocysteine, and plasma lipid levels as

predictors of sudden cardiac death. Circulation

2002;105:2595-2599.[Abstract/Full Text]

13. Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic

atherosclerosis: a comparison of C-reactive protein, fibrinogen,

homocysteine, lipoprotein(a), and standard cholesterol screening as

predictors of peripheral arterial disease. JAMA

2001;285:2481-2485.[iSI][Medline]

14. Cushman M, Legault C, Barrett-Connor E, et al. Effect of

postmenopausal hormones on inflammation-sensitive proteins: the

Postmenopausal Estrogen/Progestin Interventions (PEPI) Study.

Circulation 1999;100:717-722.[Abstract/Full Text]

15. Ridker PM, Hennekens CH, Rifai N, Buring JE, Manson JE. Hormone

replacement therapy and increased plasma concentration of C-reactive

protein. Circulation 1999;100:713-716.[Abstract/Full Text]

16. Pradhan AD, Manson JE, Rossouw JE, et al. Inflammatory biomarkers,

hormone replacement therapy, and incident coronary heart disease:

prospective analysis from the Women's Health Initiative observational

study. JAMA 2002;288:980-987.[iSI][Medline]

17. Hainline A, Karon J, Lippel K, eds. Manual of laboratory operations,

lipid research clinics program, and lipid and lipoprotein analysis.

2nd ed. Bethesda, Md.: Department of Health and Human Services, 1982.

18. Hanley JA, McNeil BJ. The meaning and use of the area under a receiver

operating characteristic (ROC) curve. Radiology

1982;143:29-36.[Abstract]

19. PWF, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel

WB. Prediction of coronary heart disease using risk factor categories.

Circulation 1998;97:1837-1847.[Abstract/Full Text]

20. Writing Group for the Women's Health Initiative Investigators. Risks

and benefits of estrogen plus progestin in healthy postmenopausal

women: principal results from the Women's Health Initiative randomized

controlled trial. JAMA 2002;288:321-333.[iSI][Medline]

21. Ross R. Atherosclerosis -- an inflammatory disease. N Engl J Med

1999;340:115-126.[Full Text]

22. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis.

Circulation 2002;105:1135-1143.[Abstract/Full Text]

23. Buffon A, Biasucci LM, Liuzzo G, D'Onofrio G, Crea F, Maseri A.

Widespread coronary inflammation in unstable angina. N Engl J Med

2002;347:5-12.[Abstract/Full Text]

24. WL, Moulton L, Law TC, et al. Evaluation of nine automated

high-sensitivity C-reactive protein methods: implications for clinical

and epidemiological applications. Clin Chem 2001;47:418-425. [Erratum,

Clin Chem 2001;47:980.][Abstract/Full Text]

25. Ridker PM, Rifai N, Clearfield M, et al. 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.[Abstract/Full Text]

26. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection

Study of cholesterol lowering with simvastatin in 20 536 high-risk

individuals: a randomised placebo-controlled trial. Lancet

2002;360:7-22.[iSI][Medline]

27. Ridker PM. Should statin therapy be considered for patients with

elevated C-reactive protein? The need for a definitive clinical trial.

Eur Heart J 2001;22:2135-2137.[iSI][Medline]

28. Ockene IS, s CE, Rifai N, Ridker PM, G, Stanek E.

Variability and classification accuracy of serial high-sensitivity

C-reactive protein measurements in healthy adults. Clin Chem

2001;47:444-450.[Abstract/Full Text]

29. Ewart HKM, Ridker PM, Rifai N, et al. Absence of diurnal variation of

C-reactive protein levels in healthy human subjects. Clin Chem

2001;47:426-430.[Abstract/Full Text]

30. Rifai N, Buring JE, Lee IM, Manson JE, Ridker PM. Is C-reactive

protein specific for vascular disease in women? Ann Intern Med

2002;136:529-533.[iSI][Medline]

31. 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.[Abstract/Full Text]

This article has been cited by other articles:

* Mosca, L. (2002). C-Reactive Protein -- To

Screen or Not to Screen?. N Engl J Med

347: 1615-1617 C-Reactive Protein — To Screen or Not to Screen?

C-Reactive Protein — To Screen or Not to Screen?

Prediction is very difficult, especially about the future.

— Niels Bohr

More than 20 years ago, 246 risk factors for coronary heart disease (CHD)

had already been identified, and the number continues to grow.1 Advances in

genomics and proteomics will provide even more candidate markers to

consider for routine assessment in practice. Risk stratification is important

because information about the probability of a cardiovascular event in the

future can help target therapy and resources to those most likely to benefit.

Of the several hundred known correlates of CHD, only a handful have had

the staying power to be recommended for routine screening. The question of

which new risk factors, if any, should be added to conventional risk

assessment with regard to CHD is important for clinicians and policymakers,

especially because the disease continues to be a major public health problem.

The impetus to pursue new predictors of CHD arises from the discovery that

traditional risk factors do not fully account for the occurrence of disease. For

example, only about half of patients with CHD have hypercholesterolemia.2

This finding may indicate that average levels of cholesterol in the population

are not normal from a pathobiologic perspective, but it also underscores the

multifactorial pathogenesis of CHD.

Important advances in understanding the pathophysiology of atherosclerosis have

been made in recent years, and

inflammatory mechanisms are now believed to play a central part in the origins

and complications of CHD.3

C-reactive protein is an acute-phase reactant that markedly increases during an

inflammatory response. C-reactive

protein levels have been helpful for decades in monitoring many diseases. A new

use for this old test has gained

momentum in recent years as a result of observations that minor elevations of

C-reactive protein are predictive of

cardiovascular events in patients with CHD.4 High-sensitivity tests for

C-reactive protein now make possible the

measurement of C-reactive protein levels within the normal range.5 C-reactive

protein not only may be a marker

of low-grade chronic systemic inflammation but also may be directly involved in

atherosclerosis; it can amplify the

inflammatory response through complement activation, tissue damage, and

activation of endothelial cells.6 The

possibility that the high-sensitivity assay for C-reactive protein may enhance

our prognostic and therapeutic

capabilities is of considerable interest, but its value has not been fully

established.

In this issue of the Journal, Ridker et al. add to the growing body of evidence

that C-reactive protein is an

independent predictor of cardiovascular disease.7 The authors previously used

data from the Women's Health

Study to conduct a small case–control analysis with three years of follow-up.

The results showed that C-reactive

protein levels predicted the risk of cardiovascular disease.8 The current study,

which extends the previous results,

includes data from the entire study cohort of nearly 28,000 women with data on

base-line levels of C-reactive

protein, who were followed for a mean of eight years, and uses a composite

cardiovascular end point.

The crude data showed that C-reactive protein levels predicted subsequent

cardiovascular disease more strongly

than did the levels of low-density lipoprotein (LDL) cholesterol. When adjusted

for a variety of traditional risk

factors, C-reactive protein and LDL cholesterol were equivalent in their ability

to discriminate women who later

had an event from those who did not, on the basis of the area under the

receiver-operating-characteristic curve,

but C-reactive protein was found to be a better predictor when a likelihood test

was performed. Statistical

significance can be inflated with large sample sizes, of course, whereas the

clinical importance of a difference may

be minimal. This fact should be taken into consideration as statistics are

translated into clinical strategy. In the

study by Ridker et al., the association between C-reactive protein and

cardiovascular disease was independent of

traditional risk factors, but no information is provided from a formal test to

determine whether there was added

value over the information provided by the global Framingham risk score. The

data lend support to the

inflammatory hypothesis of the pathogenesis of coronary heart disease and also

raise a number of important issues

about statistical predictors of coronary heart disease and their clinical

relevance. The findings of Ridker et al. from

this study of healthy women are consistent with published reports in diverse

populations.9 These data raise the

question of whether it is time to begin more widespread assessment of C-reactive

protein.

In 1968, and Jungner outlined criteria for screening programs and

suggested that if there is no generally

accepted treatment, it is premature to embark on routine screening.10 The

landscape of prevention has changed

dramatically since that time, and there is growing recognition that levels of

one risk factor can modify treatment

plans aimed at ameliorating another risk factor. A more contemporary set of

questions to consider before

implementing routine screening for newly identified risk factors is shown in

Table 1. The answers to many of the

questions remain unknown with respect to C-reactive protein.

Table 1. Ten Questions to Consider before Screening for Novel Risk Factors in

Clinical Practice.

C-reactive protein has been associated with mortality from all causes in the

elderly, suggesting that it is a

nonspecific marker of clinical outcomes.11 Moreover, multiple markers of

inflammation have been identified

(although most have not been as extensively studied as C-reactive protein), and

in the future, inflammatory

markers more specific to the progression of atherosclerosis may be identified.

C-reactive protein is correlated with

central adiposity and insulin resistance.12 The association of C-reactive

protein with metabolic risk factors may

account for some of its predictive value and does not clarify treatment

strategies. Primary- and

secondary-prevention trials have shown that treatment with statins reduces

levels of C-reactive protein and rates

of cardiovascular disease, with the beneficial effects of treatment greatest

among those with elevated base-line

levels of C-reactive protein.13,14 These data are promising, but they come from

a post hoc analysis and need to be

confirmed in prospective trials. Several other pharmacotherapies have been shown

to reduce levels of C-reactive

protein, but data on a possible correlation between a reduction in inflammation

and a reduction in clinical events

are limited.6

Is there a downside to beginning widespread screening for C-reactive protein

before definitive data become

available? Historically, beta carotene provides an example. Plasma levels of

carotenoids are predictive of coronary

heart disease and are also a marker of other risk factors.15 Substantial data

from basic-science and epidemiologic

studies lent support to the oxidation hypothesis of coronary heart disease, yet

in randomized trials, beta carotene

therapy did not prove beneficial and was, surprisingly, associated with an

elevated risk of cancer.15 Even if the

inflammation hypothesis proves to be correct, the cost effectiveness of altering

management on the basis of the

results of screening for C-reactive protein needs to be determined.

Evidence supports an association of higher levels of C-reactive protein with an

increased risk of cardiovascular

disease, but the predictive power of this association is markedly diminished

when adjusted for other risk factors.

Any clinical significance of the added value of C-reactive protein over

conventional markers of coronary heart

disease is debatable. The relative contributions of C-reactive protein as a

marker, a causative agent, or a

consequence of coronary heart disease are unclear. This uncertainty does not

preclude C-reactive protein from

playing an important part in prognostication and the tailoring of therapy;

however, whether its value will be

confirmed in randomized trials is unknown. Such research will provide vital

information to confirm or refute the

inflammatory hypothesis of atherosclerosis. Before these data become available,

it may be premature to adopt

widespread assessment of C-reactive protein. In the interim, it is prudent to

focus effort and resources on

screening for and treatment of major conventional risk factors, levels of which

are suboptimal worldwide.

Scientists and policymakers should develop a systematic approach to testing and

adopting screening guidelines for

emerging risk factors. A major criterion in the process of developing

evidence-based screening guidelines should

be that routine assessment of a new biologic marker has been demonstrated to

enhance patient care and reduce

the burden of cardiovascular disease.

References

1.Hopkins PN, RR. A survey of 246 suggested coronary risk factors.

Atherosclerosis

1981;40:1-52.[iSI][Medline]

2.EUROASPIRE: a European Society of Cardiology survey of secondary prevention

of coronary heart

disease: principal results. Eur Heart J 1997;18:1569-1582. [Erratum, Eur

Heart J

1998;19:356-7.][iSI][Medline]

3.Ross R. Atherosclerosis -- an inflammatory disease. N Engl J Med

1999;340:115-126.[Full Text]

4.Haverkate F, SG, Pyke SDM, Gallimore JR, Pepys MB. Production of

C-reactive protein and

risk of coronary events in stable and unstable angina. Lancet

1997;349:462-466.[iSI][Medline]

5.Rifai N, RP, Ridker PM. Clinical efficacy of an automated

high-sensitivity C-reactive protein assay.

Clin Chem 1999;45:2136-2141.[Abstract/Full Text]

6.Bhatt DL, Topol EJ. Need to test the arterial inflammation hypothesis.

Circulation

2002;106:136-140.[Full Text]

7.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/Full Text]

8.Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other

markers of inflammation in

the prediction of cardiovascular disease in women. N Engl J Med

2000;342:836-843.[Abstract/Full Text]

9.Danesh J, Whincup P, M, et al. Low grade inflammation and coronary

heart disease: prospective

study and updated meta-analyses. BMJ 2000;321:199-204.[Abstract/Full Text]

10. JMG, Jungner F. Principles and practice of screening for disease.

Public health papers no. 34.

Geneva: World Health Organization, 1968.

11. TB, Ferrucci L, RP, et al. Associations of elevated

interleukin-6 and C-reactive protein levels

with mortality in the elderly. Am J Med 1999;106:506-512.[iSI][Medline]

12.Chambers JC, Eda S, Bassett P, et al. C-reactive protein, insulin

resistance, central obesity, and coronary

heart disease in Indian Asians from the United Kingdom compared with

European Whites. Circulation

2001;104:145-150.[Abstract/Full Text]

13.Ridker PM, Rifai N, Clearfield M, et al. 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.[Abstract/Full Text]

14.Ridker PM, Rifai N, Pfeffer MA, et al. Inflammation, pravastatin, and the

risk of coronary events after

myocardial infarction in patients with average cholesterol levels.

Circulation

1998;98:839-844.[Abstract/Full Text]

15.The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The

effect of vitamin E and beta

carotene on the incidence of lung cancer and other cancers in male smokers.

N Engl J Med

1994;330:1029-1035.[Abstract/Full Text]