Background Both C-reactive protein and low-density lipoprotein(LDL) cholesterol levels are elevated in persons at risk forcardiovascular events. However, population-based data directlycomparing these two biologic markers are not available.
Methods C-reactive protein and LDL cholesterol were measuredat base line in 27,939 apparently healthy American women, whowere then followed for a mean of eight years for the occurrenceof myocardial infarction, ischemic stroke, coronary revascularization,or death from cardiovascular causes. We assessed the value ofthese two measurements in predicting the risk of cardiovascularevents in the study population.
Results Although C-reactive protein and LDL cholesterol wereminimally correlated (r=0.08), base-line levels of each hada strong linear relation with the incidence of cardiovascularevents. After adjustment for age, smoking status, the presenceor absence of diabetes mellitus, categorical levels of bloodpressure, and use or nonuse of hormone-replacement therapy,the relative risks of first cardiovascular events accordingto increasing quintiles of C-reactive protein, as compared withthe women in the lowest quintile, were 1.4, 1.6, 2.0, and 2.3(P<0.001), whereas the corresponding relative risks in increasingquintiles of LDL cholesterol, as compared with the lowest, were0.9, 1.1, 1.3, and 1.5 (P<0.001). Similar effects were observedin separate analyses of each component of the composite endpoint and among users and nonusers of hormone-replacement therapy.Overall, 77 percent of all events occurred among women withLDL cholesterol levels below 160 mg per deciliter (4.14 mmolper liter), and 46 percent occurred among those with LDL cholesterollevels below 130 mg per deciliter (3.36 mmol per liter). Bycontrast, because C-reactive protein and LDL cholesterol measurementstended to identify different high-risk groups, screening forboth biologic markers provided better prognostic informationthan screening for either alone. Independent effects were alsoobserved for C-reactive protein in analyses adjusted for allcomponents of the Framingham risk score.
Conclusions These data suggest that the C-reactive protein levelis a stronger predictor of cardiovascular events than the LDLcholesterol level and that it adds prognostic information tothat conveyed by the Framingham risk score.
Because of its critical importance in atherogenesis, low-densitylipoprotein (LDL) cholesterol is the focus of current guidelinesfor the determination of the risk of cardiovascular disease.1However, 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 Controland Prevention have concluded that population-based data onother risk factors are urgently needed.2,3
Among the biologic markers considered by those panels, therewas particular interest in C-reactive protein, a marker of inflammationthat has been shown in several prospective, nested case–controlstudies to be associated with an increased risk of myocardialinfarction,4,5,6,7,8,9 stroke,4,6,10,11 sudden death from cardiaccauses,12 and peripheral arterial disease.13 Although the resultsof these studies are highly consistent, limitations inherentin the design of nested case–control studies make it difficultto assess the relative merit of C-reactive protein. In particular,population-based cutoff points for C-reactive protein remainuncertain, and reliable data describing receiver-operating-characteristiccurves for C-reactive protein have not been available. Moreover,there are insufficient data from prospective cohort studiesdirectly comparing the predictive value of C-reactive proteinwith that of LDL cholesterol.
In a previous hypothesis-generating report limited to 122 womenin whom cardiovascular disease developed (case patients) and244 controls who were participants in the Women's Health Study,we observed that several markers of inflammation, includingC-reactive protein, had prognostic value for the detection offirst vascular events over a three-year period.6 However, therelatively small number of events and the short follow-up limitthe reliability of those data. Furthermore, because of the matched-pairscase–control study design, we were unable to define generalpopulation-based cutoff points or to evaluate directly characteristicsof C-reactive protein used as a diagnostic test.
To overcome these limitations, we measured C-reactive proteinand LDL cholesterol in all 27,939 participants in the Women'sHealth Study who provided usable base-line blood samples; thesewomen had been followed for a mean of eight years. Using thesedata, we were able to calculate survival curves associated withC-reactive protein levels, to compare the predictive value ofC-reactive protein and LDL cholesterol directly in a large,representative population sample, and to define the populationdistribution of C-reactive protein levels. We also determinedthe predictive value of each biologic marker among users andnonusers of hormone-replacement therapy; this is a clinicallyrelevant issue, since hormone-replacement therapy affects levelsof both C-reactive protein and LDL cholesterol.14,15,16 Finally,we evaluated whether C-reactive protein provided prognosticinformation on risk after adjustment for all components of theFramingham risk score.
Methods
Study Design
The Women's Health Study is an ongoing evaluation of aspirinand vitamin E for the primary prevention of cardiovascular eventsamong women 45 years of age or older. Participants were enrolledbetween November 1992 and July 1995, at which time they providedinformation regarding demographic, behavioral, and lifestylefactors. All participants were followed for the occurrence offirst cardiovascular events, including nonfatal myocardial infarction,nonfatal ischemic stroke, coronary revascularization procedures,and death from cardiovascular causes. The occurrence of myocardialinfarction was considered confirmed if symptoms met the criteriaof the World Health Organization and if the event was associatedwith abnormal levels of cardiac enzymes or diagnostic electrocardiographiccriteria. Stroke was confirmed if the participant had new neurologicdeficits that persisted for more than 24 hours. Computed tomographicscans or magnetic resonance images were available for the greatmajority of events and were used to distinguish hemorrhagicfrom ischemic events. The performance of either percutaneouscoronary revascularization or coronary-artery bypass surgerywas confirmed by a review of hospital records. Deaths from cardiovascularcauses were confirmed by review of autopsy reports, death certificates,medical records, and information obtained from family members.
Before randomization, blood samples were collected in tubescontaining EDTA from 28,345 study participants and stored inliquid nitrogen until the time of analysis. Samples were thentransferred to a core laboratory facility, where they were assayedfor C-reactive protein with a validated, high-sensitivity assay(Denka Seiken) and for LDL cholesterol with a direct-measurementassay (Roche Diagnostics). This laboratory is certified forthe measurement of lipids and is a core facility for ongoingstandardization programs regarding the measurement of C-reactiveprotein. Of the samples received, 27,939 could be evaluatedand were assayed for C-reactive protein and LDL cholesterol.
Statistical Analysis
Because hormone-replacement therapy affects levels of C-reactiveprotein and LDL cholesterol, we first established population-baseddistributions for each analyte among the 15,745 women who werenot taking hormone-replacement therapy at study entry —a method consistent with the guidelines of the Department ofHealth and Human Services for lipid standardization.17 We thendivided these population data into increasing quintiles withrespect to C-reactive protein and LDL cholesterol and constructedKaplan–Meier curves for event-free survival. The relativerisks of new cardiovascular events were computed for quintiles2 through 5, as compared with the lowest quintile, in both crudeCox proportional-hazards models and models adjusted for riskfactors. Stratified analyses were used to address the predictivevalue of LDL cholesterol and C-reactive protein among usersand nonusers of hormone-replacement therapy at base line. Toevaluate whether different cutoff points might affect the riskestimates for users of hormone-replacement therapy, we repeatedthe analysis among users with cutoff points for C-reactive proteinand LDL cholesterol defined by the values in the 12,139 womenwho were using hormone-replacement therapy at base line. The55 women for whom hormone-replacement status was unknown wereexcluded from the stratified analyses.
To estimate the discriminative value of predictive models, wecalculated the C statistic on the basis of the minimal follow-uptime of six years for both C-reactive protein and LDL cholesterolin crude and risk-factor–adjusted models. This statisticis analogous to the area under the receiver-operating-characteristiccurve.18 To compute the C statistic, we compared each woman'sstatus with respect to cardiovascular disease (present or absent)at six years with the predicted six-year probability of event-freesurvival, estimated from the Cox proportional-hazards model.Subjects whose data were censored before six years of follow-up(less than 1 percent) were excluded from this calculation.
We tested for trend across the quintiles of C-reactive proteinor LDL cholesterol by entering a single ordinal term for thequintile in the Cox regression model. In addition, we testedfor deviation from linearity by comparing models containingquintile indicators with those containing a linear term in alikelihood-ratio test with 3 degrees of freedom. We also testedthe additional prognostic contribution of quintiles of C-reactiveprotein or LDL cholesterol to models containing the other variablewith a likelihood-ratio test with 4 degrees of freedom.
To evaluate joint effects, we repeated the analyses after classifyingall study participants in one of four groups on the basis ofwhether their C-reactive protein and LDL cholesterol levelswere above or below the respective study medians. Finally, usingthese data, we assessed whether C-reactive protein had independentpredictive value after simultaneous adjustment for all componentsof the Framingham risk score19 (including age, smoking status,categorical levels of blood pressure, presence or absence ofdiabetes mellitus, and high-density lipoprotein and LDL cholesterollevels) and whether C-reactive protein contributed informationon risk beyond that conveyed by the 10-year risk calculatedwith the Framingham risk score and beyond the risk associatedwith LDL cholesterol, as defined by current guidelines.1 AllP values are two-tailed, and 95 percent confidence intervalswere calculated.
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-replacementtherapy, 25 percent had hypertension, 12 percent were currentsmokers, and 2.5 percent had diabetes mellitus. The mean body-massindex (the weight in kilograms divided by the square of theheight in meters) was 25.9.
Distribution of C-Reactive Protein and LDL Cholesterol Levels
Table 1 presents data on the distribution of C-reactive proteinand LDL cholesterol values among the 15,745 women who were notusing hormone-replacement therapy at the time of blood collection.These distributions are very similar to those reported for menand women in previous U.S. and European studies. On the basisof this sample, the cutoff points for quintiles of C-reactiveprotein 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 than4.19 mg per liter.
Table 1. Distribution of C-Reactive Protein and LDL Cholesterol Levels among 15,745 Study Participants 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 participantsis presented in Figure 1 according to base-line quintiles ofC-reactive protein and LDL cholesterol. Table 2 presents cruderelative risks of a first cardiovascular event according toincreasing quintiles of base-line C-reactive protein and LDLcholesterol, along with relative risks adjusted for age andother risk factors. For both C-reactive protein and LDL cholesterol, strong linear risk gradients were observed.After adjustmentfor 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 eventfor women in increasing quintiles of C-reactive protein were1.0 (the first quintile was the reference category), 1.4, 1.6,2.0, and 2.3 (P<0.001), whereas the relative risks associatedwith increasing quintiles of LDL cholesterol were 1.0 (the firstquintile was the reference category), 0.9, 1.1, 1.3, and 1.5(P<0.001). No significant deviations from linearity in thelog relative risks were detected in either model. The apparentsuperiority of C-reactive protein over LDL cholesterol in termsof the prediction of risk was observed in similar analyses ofthe individual components of the composite end point (coronaryheart 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 (areaunder the receiver-operating-characteristic curve). In modelsof crude rates including the entire cohort (27,939 women), thecalculated area under the receiver-operating-characteristiccurve was 0.64 for C-reactive protein and 0.60 for LDL cholesterol.In prediction models including age, smoking status, presenceor absence of diabetes, blood pressure, use or nonuse of hormone-replacementtherapy, and treatment assignment, the ability of the modelbased on C-reactive protein to discriminate events from noneventswas virtually identical to that of the model based on LDL cholesterol(C statistic for both models, 0.81). However, the likelihood-ratiochi-square statistic was higher for the model based on C-reactiveprotein than for that based on LDL cholesterol (716.4 vs. 706.0,both with 16 df). This statistic, a more sensitive measure ofmodel fit than the rank-based C statistic, suggests that themodel based on C-reactive protein has better discriminationthan the model based on LDL cholesterol. In addition, in likelihood-ratiotests of the contribution of each variable, the addition ofC-reactive protein to the model based on LDL cholesterol wasstronger (chi-square = 25.4, 4 df; P<0.001) than the additionof 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 ornonuse of hormone-replacement therapy at base line. Among womenwho did not use hormone-replacement therapy, the multivariable-adjustedrelative risks of a first cardiovascular event in increasingquintiles of C-reactive protein were 1.0, 1.8, 1.8, 2.4, and3.0 (P<0.001), whereas the multivariable-adjusted relativerisks 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-replacementtherapy, risk estimates were lower for both C-reactive proteinand LDL cholesterol but remained significant in crude and age-adjustedmodels. Risk estimates based on C-reactive protein among usersof hormone-replacement therapy were similar regardless of whetherthe quintiles were defined by measurements in nonusers or usersof 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
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 trialswill lead to a marked reduction in the use of hormone-replacementtherapy among American women,20 we sought to increase the generalizabilityof our findings by repeating these analyses including only the15,745 women who were not using hormone-replacement therapyat base line. In this analysis, the multivariable-adjusted relativerisks were as follows: low C-reactive protein–low LDLcholesterol, 1.0 (the reference category); low C-reactive protein–highLDL cholesterol, 1.5 (95 percent confidence interval, 1.0 to2.4); high C-reactive protein–low LDL cholesterol, 1.7(95 percent confidence interval, 1.1 to 2.6); and high C-reactiveprotein–high LDL cholesterol, 2.4 (95 percent confidenceinterval, 1.6 to 3.6). The corresponding age-adjusted ratesof events per 1000 person-years were 1.2, 1.9, 3.1, and 4.5,respectively. As in the total cohort, event-free survival amongnonusers of hormone-replacement therapy was worse in the highC-reactive protein–low LDL cholesterol group than in thelow 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 additionof measurements of C-reactive protein to the Framingham riskscore and to the LDL cholesterol categories of less than 130,130 to 160, and more than 160 mg per deciliter, which are definedin current guidelines for risk detection.1 After adjustmentfor all components of the Framingham risk score,19 quintilesof C-reactive protein remained a strong, independent predictorof risk in the cohort as a whole (relative risks of future cardiovascularevents 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 shownin Figure 4, increasing levels of C-reactive protein were associatedwith increased risk of cardiovascular events at all levels ofestimated 10-year risk based on the Framingham risk score.19Similarly, increasing C-reactive protein levels were associatedwith increased risk of cardiovascular events at LDL cholesterollevels 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.
In addition to their pathophysiological implications with regardto inflammation and atherothrombosis,21,22,23 we believe thesedata have implications for the detection and prevention of cardiovasculardisease. Seventy-seven percent of first cardiovascular eventsamong the 27,939 women in this study occurred in those withLDL cholesterol levels below 160 mg per deciliter, and 46 percentoccurred in those with levels below 130 mg per deciliter. Thus,large proportions of first cardiovascular events in women occurat LDL cholesterol levels below the threshold values for interventionand treatment in the current guidelines of the National CholesterolEducation Program.1
Our data also help establish the population distribution ofC-reactive protein. That the cutoff points for the quintilesin the current population are very close to those previouslydescribed in smaller studies from the United States and Europeis reassuring and consistent with evidence describing the stabilityand reproducibility of values obtained for C-reactive proteinwith new, high-sensitivity assays.24 These data also demonstratethat a single set of cutoff points for C-reactive protein inwomen can be used regardless of their status with regard tohormone-replacement therapy — an issue that has been ofconcern in previous work.14,15,16
Unlike other markers of inflammation, C-reactive protein levelsare stable over long periods, have no diurnal variation, canbe measured inexpensively with available high-sensitivity assays,and have shown specificity in terms of predicting the risk ofcardiovascular disease.24,28,29,30 However, despite the consistencyof prospective data in diverse cohorts,4,5,6,7,8,9,10,11,12,13,16,25,31decisions regarding the clinical use of C-reactive protein remaincomplex. To evaluate fully the clinical usefulness of any newbiologic marker requires more than a direct comparison withLDL cholesterol or the Framingham risk score; other factors,such as lipid subfractions, triglycerides, Lp(a) lipoprotein,homocysteine, insulin resistance, and hypofibrinolysis, eitherin combination with or in place of other traditional markers,must also be taken into account. Furthermore, it is increasinglyclear that no single common pathway is likely to account forall cardiovascular events and that interactions between novelbiologic markers and more traditional risk factors, such ashigh blood pressure, smoking, obesity, diabetes, low levelsof 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 approacheswill be needed as information from basic vascular biology beginsthe transition into clinical practice.
Supported by grants (HL-43851, HL-63293, and HL-58755) fromthe National Heart, Lung, and Blood Institute, Bethesda, Md.;by the Doris Duke Charitable Foundation, New York; and by theLeducq Foundation, Paris.
Dr. Ridker is named as a coinventor on patents filed by Brighamand Women's Hospital that relate to the use of inflammatorybiologic markers in cardiovascular disease.
Source Information
From the Center for Cardiovascular Disease Prevention and the Divisions of Preventive Medicine (P.M.R., L.R., J.E.B., N.R.C.) and Cardiology (P.M.R.), Brigham and Women's Hospital and Harvard Medical School; and the Department of Laboratory Medicine, Children's Hospital and Harvard Medical School (N.R.) — all in Boston.
Address reprint requests to Dr. Ridker at the Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, 900 Commonwealth Ave. East, Boston, MA 02215, or at pridker{at}partners.org.
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Perreault, L., Ma, Y., Dagogo-Jack, S., Horton, E., Marrero, D., Crandall, J., Barrett-Connor, E., for the Diabetes Prevention Program,
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Lund, S. S, Tarnow, L., Stehouwer, C. D A, Schalkwijk, C. G, Teerlink, T., Gram, J., Winther, K., Frandsen, M., Smidt, U. M, Pedersen, O., Parving, H.-H., Vaag, A. A
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Previous
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, 
