High-sensitivity C-reactive Protein Assay Research Articles

Evaluation of the high-sensitivity, full-range Olympus CRP OSR6199 application on the Olympus AU640®

Implementation of high-sensitivity C-reactive protein (hs-CRP) assays as a routine laboratory parameter may be necessary. A single CRP method giving reliable results for the whole concentration range (0.1-160 mg/L) is the most practical solution for a laboratory. The aim of this study was to assess the Olympus CRP full-range immunoturbidimetric assay on an Olympus AU640 biochemistry analyser. CRP was determined in a population of patients simultaneously with the Randox CRP immunoturbidimetric assay and two immunonephelometric assays, the Dade Behring and Beckman Coulter CRP, on BN 100 and Immage systems, respectively. Analytical performance, including precision and linearity, was excellent. The correlation coefficient for linear regression was r(2)=0.998, indicating that the assay method exhibited good linearity in the working range 0-160 mg/L. The intra- and inter-assay CVs for the Olympus CRP method were <3.6% over a wide range of CRP concentrations. Linear regression analysis indicated excellent agreement between CRP values for all patients, with correlation coefficients of r(2)>0.996, 0.993 and 0.989 for the Randox, Dade Behring and Beckman methods, respectively. Bland-Altman analyses demonstrated the excellent concordance of the CRP methods for patient samples. This study demonstrates that the new full-range Olympus method can be applied to measure CRP as a marker of inflammation and of cardiovascular risk.

Genetic Variation Is Associated With C-Reactive Protein Levels in the Third National Health and Nutrition Examination Survey

Increased serum C-reactive protein (CRP) is an independent risk factor for cardiovascular disease. Previous studies have suggested that genetic variation within the CRP gene is associated with serum CRP. We genotyped CRP genetic variants in 7159 individuals from the Third National Health and Nutrition Examination Survey (NHANES III). NHANES III is American population-based sample linked to hundreds of phenotypes, including CRP; however, the CRP assay used in this survey is not a high-sensitivity CRP assay, and 65% of participants (n=4679) had CRP measurements at or below the level of detection. Despite these limitations, we identified specific CRP single-nucleotide polymorphisms (SNPs) and haplotypes associated with serum CRP levels in the general population. Two variants were associated with increased levels of serum CRP: SNP rs3093058 (in linkage disequilibrium with a CRP promoter SNP rs3093062) in the non-Hispanic black sample and the triallelic promoter SNP rs3091244 in the non-Hispanic black and Mexican American samples. Two other SNPs were associated with decreased levels of serum CRP in either the non-Hispanic black (rs1205 and rs2808630) or Mexican American (rs1205) samples. Three haplotypes inferred from 7 SNPs (ATTGCGA, TTAGCGA, and AAAGAGA) were associated (P < or = 0.01) with increased levels of serum CRP in the non-Hispanic black sample; 2 haplotypes (ATTGCGA and AAAGCGA) were associated (P < 0.05) with increased levels in the Mexican American sample; and 1 haplotype (AAAGCGA) was associated (P < 0.03) with increased levels in the non-Hispanic white sample. Post hoc analysis suggests that the AA genotype of the triallelic SNP rs3091244, after adjustment for covariates, was associated with prevalent coronary heart disease in the non-Hispanic white population sample. Genetic variation within CRP is associated with serum CRP levels in the general population and may be associated with prevalent coronary heart disease.

Point: High-Sensitivity C-Reactive Protein and Cardiac C-Reactive Protein Assays: Is There a Need to Differentiate?

Recent evidence has shown that inflammation plays a pivotal role in the inception and progression of atherosclerosis, and population studies have demonstrated a strong and independent association between baseline concentrations of inflammatory biomarkers and future coronary events. Because the majority of individuals who develop coronary events are not in a high-risk group according to the Framingham risk assessment of traditional risk factors for coronary heart disease (CHD),2 and because one half of those who suffer myocardial infarctions have normal lipid values, measurement of inflammatory markers has been suggested as an adjunct to lipid testing to better identify individuals at increased risk (1). Of the inflammatory markers evaluated by a CDC and American Heart Association (AHA) Panel in 2002(2)(3), only C-reactive protein (CRP) met the analytical requirements for outpatient clinical use and, therefore, has been studied intensely over the past decade. More than 25 prospective epidemiologic studies have shown that CRP is a strong and independent predictor of future myocardial infarction, ischemic stroke, peripheral arterial disease, and sudden cardiac death in apparently healthy men and women (4). Furthermore, 9 studies to date have demonstrated that CRP provides additional prognostic value to the Framingham Risk Score(4). Guidelines regarding the potential usefulness of CRP in primary and secondary prevention settings have been issued by the CDC and AHA(2). Physicians have become accustomed to use of the “high-sensitivity CRP (hsCRP)” terminology when considering measurement of CRP for vascular disease risk stratification, as opposed to the use of standard CRP assays that monitor infections and other inflammatory conditions. To assess CHD risk, CRP must …

Counterpoint: Food and Drug Administration Guidance for C-Reactive Protein Assays: Matching Claims with Performance Data

Dr. Rifai and coauthors seem to have misunderstood the guidance proffered by the US Food and Drug Administration (FDA)1 and the laboratory safety tip addressing the issue of matching claims with performance data for C-reactive protein (CRP) assays. The FDA believes that different claims for CRP require very different data sets and different performance criteria to support differing intended uses. FDA premarket guidance proposals are written to benefit companies and FDA reviewers regarding recommendations for studies that support premarket submissions for medical devices in the United States. They are not meant to be clinical practice guidelines; however, FDA guidelines are meant to be based on sound science, committed to truth in labeling, and intended to help to ensure the safety and effectiveness of medical devices for the promotion of public health. The driving force behind FDA premarket assay reviews is based on the indications for use of a given assay. For regulatory purposes, the distinction between CRP assays, high-sensitivity (hs)CRP assays, and cardiac (c)CRP assays lies with the Indications for Use. In the Guidance for Industry and FDA Staff: Criteria for Assessment of C-Reactive Protein (CRP), High Sensitivity …

High sensitivity C-reactive protein in asthma

Asthma is characterised by chronic inflammation of the airways, but the relevance of high-sensitivity assays for C-reactive protein (hs-CRP), which are known to be a sensitive marker of low-grade systemic inflammation, has not been fully studied in asthma. The objective was to examine serum hs-CRP levels in patients with asthma and their relationship to clinical characteristics and degree of airway inflammation. Serum hs-CRP levels were cross-sectionally examined in steroid-naive (n = 22) and steroid-inhaling (n = 23) adult patients with asthma and healthy controls (n = 14). All were nonsmokers. Serum hs-CRP levels were significantly increased in steroid-naive patients (mean+/-sd 1.33+/-1.48 mg.L(-1)) compared with controls (0.21+/-0.30 mg.L(-1)), but not in patients on inhaled corticosteroid. Among steroid-naive patients, serum hs-CRP levels significantly negatively correlated with indices of pulmonary function (forced expiratory volume in one second/forced vital capacity and forced mid-expiratory flow) and positively with sputum eosinophil count. Among patients on inhaled corticosteroid, hs-CRP levels did not correlate with any indices. In conclusion, an increase in serum C-reactive protein levels measured by high-sensitivity assays may be associated with airflow obstruction and airway inflammation, and may serve as a surrogate marker of airway inflammation in asthma.

Plasma C-reactive protein concentration is not affected by isocaloric dietary fat reduction

Objective There is a strong correlation between plasma C-reactive protein (CRP) concentration and risk of cardiovascular death. Low-fat diets have been recommended for maintenance of cardiovascular health, and it is known that a low-fat diet associated with weight loss lowers CRP concentration. However, it remains unclear whether dietary fat has an effect independent from weight change on markers of inflammation. Methods Sixteen overweight subjects who were 46 ± 14 y old were placed on a weight-maintaining baseline diet consisting of 35% fat, 45% carbohydrate, and 20% energy as protein. After 2 wk, subjects were switched to an isocaloric low-fat diet consisting of 15% fat, 65% carbohydrate, and 20% protein for another 2 wk. For the final 12 wk of the study, subjects consumed the same 15% fat diet ad libitum. At the end of each diet phase, CRP was measured by a high-sensitivity CRP assay. Results The weight of subjects remained stable during the first 4 wk of isocaloric diets. Plasma CRP concentrations after 2 wk on the weight-maintaining 35% fat diet and 2 wk on the isocaloric 15% fat diet were not significantly different (median ± interquartile range 1.42 ± 3.30 and 1.59 ± 3.29 mg/L, respectively). Three months of ad libitum low-fat diet consumption resulted in a 4.1 ± 0.7 kg weight loss associated with a decrease in CRP concentration to 1.17 ± 2.03 mg/L ( P = 0.03). Conclusion Loss of body weight decreases CRP concentration, but a decrease in dietary fat without a concurrent change in body weight does not affect CRP concentration in overweight healthy subjects.

Human Anti–Tumor Necrosis Factor Monoclonal Antibody (Adalimumab) in Crohn’s Disease: the CLASSIC-I Trial

Tumor necrosis factor blockade has been shown to be an effective treatment strategy in Crohn's disease (CD). Adalimumab is a human immunoglobulin G1 (IgG(1)) monoclonal antibody targeting tumor necrosis factor (TNF). A randomized, double-blind, placebo-controlled, dose-ranging trial was performed to evaluate the efficacy of adalimumab induction therapy in patients with CD. A total of 299 patients with moderate to severe CD naive to anti-TNF therapy were randomized to receive subcutaneous injections at weeks 0 and 2 with adalimumab 40 mg/20 mg, 80 mg/40 mg, or 160 mg/80 mg or placebo. The primary endpoint was demonstration of a significant difference in the rates of remission at week 4 (defined as a Crohn's Disease Activity Index score <150 points) among the 80 mg/40 mg, 160 mg/80 mg, and placebo groups. The rates of remission at week 4 in the adalimumab 40 mg/20 mg, 80 mg/40 mg, and 160 mg/80 mg groups were 18% (P = .36), 24% (P = .06), and 36% (P = .001), respectively, and 12% in the placebo group. Adverse events occurred at similar frequencies in all 4 treatment groups except injection site reactions, which were more common in adalimumab-treated patients. Adalimumab was superior to placebo for induction of remission in patients with moderate to severe Crohn's disease naive to anti-TNF therapy. The optimal induction dosing regimen for adalimumab in this study was 160 mg at week 0 followed by 80 mg at week 2. Adalimumab was well tolerated.

Analytical performance and clinical efficacy for cardiovascular risk estimation of an Olympus immunoturbidimetric high-sensitivity C-reactive protein assay

Increased C-reactive protein (CRP) concentration within the reference interval (<10.0 mg/L) is a strong predictor of cardiovascular disease (CVD) in apparently healthy adults. Cutoff points for use of CRP in estimating CVD risk are <1, 1-3 and >3 mg/L for low, average and high relative risk, respectively. For measuring CRP concentrations to assess cardiovascular risk, high-sensitivity CRP (hsCRP) assays have been developed. The aim of this study was to evaluate the analytical performance and clinical efficacy for cardiovascular risk estimation of the Olympus immunoturbidimetric latex CRP assay (sensitive application). The comparative method used was the CardioPhase* hsCRP assay, approved by the Food and Drug Administration for use in CVD risk assessment. The imprecision of the Olympus hsCRP assay in the concentration range 0.2-10.0 mg/L was 0.38-8.16% within runs and 3.75-9.63% between runs. For method comparison studies, 194 fresh serum samples were selected to cover the interval 0.15-10.0 mg/L CRP. Comparison of the Dade Behring and Olympus methods was performed using weighted Deming regression analysis (slope 0.99 mg/L, intercept 0.002 mg/L, S(y,x)=0.02 mg/L, r=0.992) and a Bland-Altman relative difference plot (mean difference -0.002%, SD=0.040%). The agreement between the Dade Behring and Olympus methods for relative risk class assignments was 95.4%. Statistical analysis of the agreement between the two methods for each relative risk class showed that the differences between the methods were not statistically significant (p>0.10). Although previous reports found poor performance of the Olympus CRP tests for use in cardiovascular and peripheral vascular risk estimation, our study proved good analytical performance and clinical efficacy of the Olympus hsCRP assay for this use.

Plasma C-Reactive Protein in Early Pregnancy and Preterm Delivery

Systemic maternal infections have been associated with preterm delivery. The authors examined the association of C-reactive protein (CRP), a marker of inflammation, with preterm delivery. This nested case-control study was conducted within Project Viva in Massachusetts between 1999 and 2002. Subjects were 117 women who delivered preterm (< 37 weeks' gestation) and 117 controls (term deliveries) matched on age, race/ethnicity, and smoking status. High-sensitivity CRP assays were performed on early-pregnancy (5.3-19.3 weeks' gestation) plasma samples. Odds ratios and 95% confidence intervals were estimated by using conditional logistic regression adjusted for matching factors, gestational age at blood collection, and prepregnancy body mass index. Median concentration of CRP was 3.2 mg/liter in cases versus 2.4 mg/liter in controls. No significant association was found between quartiles of CRP and preterm delivery. However, CRP levels exceeding the threshold defined in the literature were associated with increased risk of preterm delivery (odds ratio = 2.55, 95% confidence interval: 1.05, 6.02 for CRP > or = 8 mg/liter). The association was stronger among cases who experienced spontaneous delivery (odds ratio = 4.64, 95% confidence interval: 0.94, 22.96) versus indicated delivery (odds ratio = 1.42, 95% confidence interval: 0.44, 4.61). These findings suggest that very high CRP levels in early pregnancy are associated with preterm delivery.

Level of High-Sensitivity C-Reactive Protein Is Predictive of 30-Day Outcomes in Patients With Acute Myocardial Infarction Undergoing Primary Coronary Intervention

C-reactive protein (CRP) has been well recognized as a strong independent predictor of short-term and long-term mortality after non-ST-segment elevation acute coronary syndromes. However, limited studies have been conducted correlating CRP levels within 6 h following the onset of ST-segment elevation (ST-se) acute myocardial infarction (AMI) to mortality. The purpose of this study was to evaluate the predictive value of CRP measured by high-sensitivity CRP assay (hsCRP) on 30-day clinical outcomes in patients with ST-se AMI of onset < 6 h undergoing primary percutaneous coronary intervention (PCI). We conducted a prospective cohort study in 146 consecutive patients with ST-se AMI of onset < 6 h who were undergoing primary PCI. Blood samples for hsCRP were obtained in the catheterization laboratory before coronary angiography. Patients were classified into high (group 1: hsCRP > 2.37 mg/L, n = 73) and low (group 2: hsCRP </= 2.37 mg/L, n = 73) hsCRP groups according to the median value of hsCRP after AMI. Univariate analysis demonstrated that the 30-day composite major adverse cardiac events (MACE) [death, recurrent ischemia, and re-occlusion] were significantly higher in group 1 than in group 2 (23.3% vs 4.1%, p = 0.0008). Multiple stepwise logistic regression analysis demonstrated that high hsCRP (p = 0.001), cardiogenic shock (p = 0.0003), and low left ventricular ejection fraction (p = 0.032) were independent predictors of 30-day MACE. Prospective evaluation of the hsCRP in ST-se AMI of onset < 6 h allows accurate risk stratification of individuals at risk of 30-day MACE after primary PCI.

Levels and Values of Serum High-Sensitivity C-Reactive Protein Within 6 Hours After the Onset of Acute Myocardial Infarction

C-reactive protein (CRP), which has been suggested to directly enhance inflammation in plaques, is rapidly synthesized and secreted in the liver 6 h after an acute inflammatory stimulus. Therefore, serum levels of CRP within 6 h after the onset of acute myocardial infarction (AMI) merely reflect a chronic and persistent inflammatory process and are not due to acute myocardial damage. We hypothesized that the serum CRP level, which would abnormally elevate thereafter, is followed by a plaque rupture in the clinical setting of AMI. CRP was prospectively measured by high-sensitivity CRP assay (hs-CRP) in 157 consecutive patients (106 patients within 6 h, and 51 patients >/= 6 h but < 12 h after the onset of AMI) with ST-segment elevation AMI undergoing primary percutaneous coronary intervention (PCI). Serum levels of hs-CRP were also measured in 30 patients with stable angina undergoing elective PCI and in 30 healthy control subjects. The serum level of hs-CRP was significantly higher in patients with an onset of AMI < 6 h than in patients with angina pectoris (2.7 +/- 2.3 mg/L vs 1.4 +/- 0.7 mg/L, p < 0.0001 [mean +/- SD]) and in healthy subjects (2.7 +/- 2.3 mg/L vs 1.0 +/- 0.6 mg/L, p < 0.0001). There were no significant differences in serum levels of hs-CRP in patients with an onset of AMI </= 3 h than in those patients with an onset of AMI > 3 h but < 6 h (2.7 +/- 2.5 mg/L vs 2.7 +/- 2.2 mg/L, p = 0.87). However, the serum level of hs-CRP was significantly higher in patients with an onset >/= 6 h than in patients with an onset < 6 h (14.1 +/- 16.5 mg/L vs 2.7 +/- 2.3 mg/L, p < 0.0001). Serum levels of hs-CRP were significantly higher in patients with an onset of AMI < 6 h than in healthy subjects and in patients with angina pectoris undergoing PCI. The inflammatory process has been proved as one of the mechanisms causing plaque rupture. Elevated serum hs-CRP levels in patients with AMI < 6 h may portend vulnerable plaque rupture.

Analytical performance of the Synchron LX®20 Pro, BN™II and IMMAGE® high sensitivity C-reactive protein assays and concordance in cardiovascular risk stratification

Background: C-reactive protein (CRP) can provide valuable prognostic information for risk of cardiovascular events. Several automated high sensitivity CRP immunoassays are currently available for risk assessment. Methods: The analytical performance of the Synchron LX®20 Pro, BN™II and IMMAGE® high sensitivity CRP assays were evaluated and concordance within cardiovascular risk tertiles was examined for 529 serum samples. Results: All three assays exhibited satisfactory between-run imprecision based on CVs≤9.0% over a wide range of CRP concentrations. The LX20 Pro and BN II were linear over an extensive measuring range, whereas the IMMAGE exhibited a slight deviation from linearity producing results with a positive bias at CRP levels between 0.7 and 2.6 mg/l. Moderately hemolyzed samples interfered with the LX20 Pro and IMMAGE CRP assays, whereas moderate lipemia interfered with the BN II. Correlation studies revealed that the LX20 Pro and IMMAGE produced results 8.2% lower and 5.1% lower, respectively, compared with the BN II. There was good agreement among methods for cardiovascular risk assessment. Conclusions: All three CRP assays exhibited acceptable analytical performance for cardiovascular risk assessment. Although results by the LX20 Pro and IMMAGE were lower than the BN II, there was good agreement within each cardiovascular risk assessment tertile.

Reference material needs in clinical laboratory science

In 1968, clinical chemistry was considered to be the field most in need of certified reference materials (CRMs). While significant progress has been made in this area, new diagnostic assays are continually being developed that create a need for new CRMs. Members of the clinical laboratory community help to identify reference material needs. Professional and governmental organizations, such as IFCC, AACC, NCCLS, CDC, and the national metrological institutes (NMIs), respond to develop protocols and materials. Several measurands are presented as examples. In the late 1950s and early 1960s, in response to a need for standardization of lipid and lipoprotein measurements, CDC developed a reference system that included secondary reference materials. Over the years, the process of preparation of these materials was refined, eventually leading to the development of NCCLS guideline for preparation of commutable frozen serum pools for use as secondary reference materials (C37-A). This protocol was used for the preparation of NIST SRM 1951a (lipids in frozen (liquid) human serum). In the 1980s, a need for a reference material for blood lead was identified. CDC and NIST cooperated to develop SRM 955 (lead in bovine blood). More recently, efforts have been initiated to standardize high-sensitivity C-reactive protein (hsCRP) assays. In this case, a CRM for CRP existed (CRM 470, developed by IFCC and available from IRMM), but at concentrations in the acute phase reactant range and not in the low range needed for hsCRP assays. CDC coordinated a study to evaluate diluted CRM470 and other candidate materials as secondary reference materials for hsCRP assays.

Minimal Inflammation, Acute Phase Response and Avoidance of Misclassification of Vitamin A and Iron Status in Infants – Importance of a High-Sensitivity C-Reactive Protein (CRP) Assay

The acute phase response is known to affect many biological parameters used to assess the iron and vitamin A status. Usually, C-reactive protein (CRP) values higher than 5 to 10 mg/L are taken as indicative of this response. Here we report changes occurring at much lower CRP values. A range of parameters (clinical chemistry, retinol, vitamin E, carotenoids, thyroid status, blood count, immunology) were measured in 101 healthy one-year-old children with no or only minimal symptoms of airway infection and CRP values below 6 mg/L on routine testing. Additionally, CRP values were measured by a high-sensitivity assay (detection limit 0.2 mg/L). When determined by a more sensitive assay, CRP values (median, 0.26 mg/L) revealed highly significant associations with parameters known to be influenced by the acute phase response. Using a limit of 0.6 mg/L (75th percentile), significantly lower levels were observed for transthyretin, iron, retinol, and beta-carotene in the group with the higher CRP levels. This relationship was confirmed intra-individually in a subgroup of 21 children who underwent a second blood draw about four weeks after the first one. The acute phase response is triggered at very low inflammatory levels with CRP values considerably lower than 5 to 10 mg/L, and can occur in apparently healthy children. A high-sensitivity CRP assay is necessary to detect this low level, and in the case of iron or vitamin A, it can help to avoid misclassification of the nutritional status.

Relationship of destructive periodontal disease to the acute-phase response.

Destructive periodontal diseases have been associated with an increased risk of atherosclerotic complications; however, the potential mechanisms are yet to be defined. Inflammation plays a central role in atherosclerosis since C-reactive protein (CRP), an acute-phase protein monitored as a marker of inflammatory status, has been identified as a major risk factor for atherosclerotic complications. Recent reports that destructive periodontal diseases can increase CRP values present the possibility that the acute-phase response may link these 2 disease processes. The objective of the present investigation was to determine the effect of destructive periodontal disease status, severity, and progression on components of the acute-phase response in an urban minority population. Clinical measurements recorded included probing depth, attachment level, gingival erythema, bleeding upon probing, suppuration, and plaque. Disease progression was defined as a >2 mm loss of attachment 2 months post-baseline. Serum antibody was measured by enzyme-linked immunosorbent assay. CRP was measured using a high-sensitivity CRP (hsCRP) assay. A commercial laboratory measured serum glucose (non-fasting), albumin, cholesterol, high-density lipoprotein (HDL), triglycerides, low-density lipoprotein (LDL), and iron. Increased serum IgG antibody to Porphyromonas gingivalis, but not to 5 other species, was associated with periodontal disease status, increased severity, and progression as were age, male gender, and smoking. Cholesterol and LDL were increased in disease, and HDL and iron were increased in health. hsCRP, glucose, and cholesterol increased with disease progression. By regression analysis, IgG antibody to P. gingivalis correlated with age, probing depth, and hsCRP, and negatively correlated with albumin and iron. By logistic regression, subjects who experienced multiple sites of disease progression and elevated antibody to P. gingivalis increased the odds ratio of hsCRP>2.08 mg/l by 14.1 and 5.6, respectively. These results suggest that destructive periodontal disease and disease progression are associated with changes in serum components consistent with an acute-phase response.

C-reactive protein: a novel marker of cardiovascular risk.

Patients without traditional cardiovascular risk factors continue to suffer from cardiovascular events, which has prompted a search for novel markers to better assess cardiovascular risk. Inflammatory biomarkers have surfaced as prime candidates, given the integral role of inflammation in atherosclerosis. C-reactive protein (CRP) measurements in particular have emerged as powerful predictors of cardiovascular risk in a broad spectrum of patient populations. Newer high sensitivity CRP assays now in use are standardized and reproducible, and can detect variations in CRP below the limit of standard assays. In primary prevention populations, studies have shown up to a 2-4-fold increased risk of cardiovascular events in healthy patients with elevated CRP levels. In this population, models incorporating CRP and lipid parameters appear to predict risk significantly better than lipids alone. In patients with established cardiovascular disease and in patients undergoing percutaneous coronary interventions, CRP levels may help predict short- and long-term prognosis, identifying subgroups of patients at increased risk of recurrent events. CRP levels may also prove useful in targeting therapy for primary and secondary prevention, by identifying patients who would most benefit from medications such as statins and aspirin. This review presents an overview of the data regarding CRP measurement for cardiovascular risk assessment.

Oral contraceptive use and increased plasma concentration of C-reactive protein

We examined, in young adult women, the association between current low dose oral contraceptive (OC) use and plasma levels of C-reactive protein (CRP), an acute phase reactant predictive of cardiovascular disease risk. We conducted a cross-sectional analysis of 30 healthy, non-smoking, non-obese women (18 OC users and 12 nonusers) who were subjects in a randomized diet-controlled trial of the effects of soy intake on sex hormone metabolism. The study was sited at a university outpatient general clinical research center. Fasting plasma CRP levels were measured 4 times during 2 menstrual cycles (2 mid-follicular phase and 2 mid-luteal phase) using a high-sensitivity CRP assay. Differences between OC users and nonusers were examined by 3-way analysis of variance. Multiple regression was used to examine the relationship between OC use and CRP. There were no significant differences in baseline demographic characteristics between OC users and nonusers. Plasma CRP levels (mean ± SE) were 2 times higher among OC users than among non-users (2.0 ± 0.2 versus 0.9 ± 0.3 mg/l, p < 0.0001) independent of diet assignment, diet treatment order, and phase of the menstrual cycle. In a multivariate model, OC use predicted 32 percent of the variance in CRP levels (p < 0.0001). As all CRP levels were within a previously established normal range, further study is indicated to establish the clinical significance of the observed elevated CRP levels in OC users.

Durability of platelet inhibition by clopidogrel

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Accuracy of Cardiovascular Risk Estimation

Middleton (1) describes the effect of analytical variation in high-sensitivity C-reactive protein and lipid assay on cardiovascular risk calculation, using a Monte Carlo simulation technique and the Ridker-Rifai quintile model, and demonstrates that relative risk is over- or underestimated in a substantial proportion of cases. From this he concludes that multiple HDL-cholesterol estimations may reduce misclassification that occurs because of assay imprecision. This is true, but this approach underestimates the imprecision of risk calculation. The factor that is neglected in this investigation of the precision of risk estimation is the important role played by biological variation. We have recently published a similar analysis scenario in which we mathematically modeled a hypothetical “True” population derived from data from the National Health Survey for England. We investigated the effect of combined biological and analytical variation in total cholesterol and HDL-cholesterol, as …

Commutability of the CRM 470 C-reactive protein value in the Dade Behring N High Sensitivity CRP assay.

Certified Reference Material 470 (CRM 470) demonstrates commutability with both the manufacturer's calibrator and with dilutions of serum pools in the Dade Behring N High Sensitivity assay for C-reactive protein (CRP). Both regression and back calibration show similar nonlinearity for all materials, largely due to the method of calibration curve fitting used in this assay. Significant differences in values among the currently available commercial assays can be largely overcome by using appropriate calibration curve fitting and the recommended value transfer protocol, which includes a minimum of two assay runs on each of at least 3 separate days, with weight correction of all reconstitutions and dilutions. An initial weight-corrected dilution should be made each day because of the relatively high level of CRP in CRM 470. In our opinion, the degree of nonlinearity, imprecision, and differences in values in currently available assays renders the use of fixed clinical decision cut-points questionable for high-sensitivity CRP. An alternative approach is suggested.