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Clinical Chemistry 53: 1800-1807, 2007. First published August 23, 2007; 10.1373/clinchem.2007.087957
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(Clinical Chemistry. 2007;53:1800-1807.)
© 2007 American Association for Clinical Chemistry, Inc.

Lipids, Lipoproteins, and Cardiovascular Risk Factors

Clinical Application of C-Reactive Protein Across the Spectrum of Acute Coronary Syndromes

Benjamin M. Sciricaa, David A. Morrow, Christopher P. Cannon, James A. de Lemos, Sabina Murphy, Marc S. Sabatine, Stephen D. Wiviott, Nader Rifai, Carolyn H. McCabe, Eugene Braunwald for the Thrombolysis in Myocardial Infarction (TIMI) Study Group

aAddress correspondence to this author at: TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02461. Fax 617-734-7329; e-mail bscirica{at}partners.org.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: High-sensitivity C-reactive protein (hsCRP) is associated with adverse cardiovascular outcomes in acute coronary syndromes (ACS). The ability to formulate recommendations regarding clinical use of hsCRP is limited by a paucity of data regarding several key issues. The purpose of this study was to evaluate hsCRP across the spectrum of ACS.

Methods: hsCRP was measured on admission in 3225 patients with ACS. hsCRP concentrations were compared in patients who suffered an adverse cardiac outcome within 10 months of study entry and in patients who had no adverse event. Because of heterogeneity in the relationship between hsCRP and clinical outcomes, evaluation was limited to patients from whom samples were collected within 48 h of symptom onset.

Results: Patients in the highest quartile of hsCRP compared to those in the lowest quartile were at increased risk of death at 30 days [adjusted hazard ratio (adjHR) 4.6, P <0.001] and 10 months (adjHR 3.9, P <0.001). In patients with unstable angina/non–ST-elevation myocardial infarction (STEMI), hsCRP >3 mg/L was associated with increased 10-month mortality (adjHR 2.3, P = 0.002), whereas in STEMI a relationship with mortality was seen at hsCRP >10 mg/L (adjHR 3.0, P = 0.008). Increased concentrations of hsCRP were strongly associated with the development of heart failure at 30 days (adjHR 8.2, P = 0.001) and 10 months (adjHR 2.6, P = 0.014).

Conclusion: Increased baseline concentrations of hsCRP are strongly associated with mortality and heart failure across the ACS spectrum. hsCRP measurement should be performed early after presentation and index diagnosis-specific cutpoints should be used.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Inflammation is an important contributor to atherothrombosis, both accelerating atherosclerosis and precipitating acute plaque rupture (1). The serum or plasma concentration of high-sensitivity C-reactive protein (hsCRP) 1 , a marker of inflammation, is increased in patients with acute coronary syndrome (ACS) compared with individuals without established vascular disease as well as in patients with chronic stable angina (2)(3)(4)(5). At least 10 studies have demonstrated an independent association between the concentrations of hsCRP and survival in patients with non-ST elevation ACS (NSTEACS) (2)(3)(5)(6)(7)(8). On the basis of these data, an expert committee convened by the American Heart Association and Centers for Disease Control and Prevention has provided a Class IIa recommendation that hsCRP may be useful as an independent marker of prognosis in patients with ACS (9). However, despite this recommendation, the development of practice guidelines for measuring hsCRP in the clinical setting has been limited in part by a paucity of data regarding several key issues for clinical application, including the optimal timing of measurement, appropriate decision limits, and implications for treatment (10). In addition to these limitations, less and conflicting data are available regarding the prognostic relevance of hsCRP measured at the time of presentation in patients with ST-elevation myocardial infarction (STEMI) (11)(12)(13) and the relationship between concentrations of hsCRP and the risk of heart failure after ACS. The Orbofiban in Patients with Unstable Coronary Syndromes (OPUS)–Thrombolysis in Myocardial Infarction (TIMI) 16 trial of patients with unstable angina (UA), non-STEMI (NSTEMI), and STEMI provided the opportunity to address several issues relevant to clinical implementation, as well as to evaluate the risk associated with hsCRP across the entire spectrum of ACS.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The trial design and results of the OPUS–TIMI 16 trial have been reported (14). Briefly, 10 288 patients with acute myocardial infarction (MI) or high-risk UA were enrolled within 72 h from the onset of symptoms. Eligible patients were treated with aspirin daily and were randomized in a 1:1:1 fashion to receive 1 of 2 dosing regimens of the oral glycoprotein IIb/IIIa inhibitor orbofiban or placebo. Patients were seen in follow-up at 14 and 30 days and every 3 months thereafter. Because of an increase in mortality in one of the orbofiban groups, the study was terminated prematurely after a median follow-up of 10 months (14). In accordance with the study design, hsCRP concentrations were measured in the 1592 patients who experienced the primary 10-month composite endpoint of death, recurrent MI, nonfatal stroke, or recurrent ischemia at rest. hsCRP concentration was also measured in 1633 patients with similar proportions of baseline characteristics and diagnosis who did not experience the primary endpoint and were chosen as a representative sample group of the remainder of the OPUS-TIMI 16 cohort.

The median time from the onset of ischemic symptoms to enrollment was 40 h (interquartile range 25–60 h). At the time of enrollment, blood specimens were collected in citrate-treated tubes and centrifuged to isolate plasma. The plasma component was frozen and shipped on dry ice to the TIMI Biomarker Core Laboratory (Boston, MA), where samples were stored at –70 °C until analysis. hsCRP was measured with an FDA-cleared high-sensitivity cardiac CRP assay (N Latex CRP assay, Dade Behring). The sensitivity of the assay was 0.1 mg/L, and reproducibility rates at concentrations of approximately 0.5, 55, and 138 mg/L were 5.5%, 2.9%, and 3.6%, respectively. Performance of this assay in the core laboratory in serum obtained from 104 healthy adult blood donors demonstrated a mean CRP concentration of 2.15 mg/L and a 99th percentile concentration of 15.5 mg/L (8).

Sequential sandwich immunoassays for the quantification of B-type natriuretic peptide and cardiac troponin I were performed in 384-well microtiter plates with an automated system (Tecan Genesis robotic sample processor 200/8). The amount of analyte was quantified on the basis of the extent of binding of alkaline phosphatase to conjugated antibody. Cardiac troponin I was measured using the ACS:180 Assay (Bayer). We used a diagnostic cutpoint of 0.1 µg/L because data from the manufacturer demonstrated a CV of 13% at 0.1 µg/L and because in the core laboratory the minimal detectable concentration of 0.1 µg/L was measured as 2 SD above the mean signal for 37 replicate measurements of the 0 calibrator. In addition, the 97.5th percentile among 158 healthy controls was given as <0.1 µg/L in data provided to us by the manufacturer (15). Plasma specimens were shipped to Biosite Diagnostics (San Diego, CA), where they were thawed and analyzed. The analytic sensitivities of the B-type natriuretic peptide and cardiac troponin I immunoassays were approximately 5 µg/L and 50 µg/L, respectively. Creatinine kinase-MB analyses were performed by each participating hospital. Estimated creatinine clearance was calculated using the Cockcroft–Gault formula.

To compare baseline characteristics between patients who died and those who survived, we used a t-test or, for nongaussian data, a Wilcoxon 2-sample test for continuous variables. A {chi}2 test was performed for comparison of categorical variables. Continuous variables were compared with a Spearman’s correlation test. We performed a Cox proportional hazard analysis to calculate the adjusted risks of the following endpoints in relation to baseline concentrations of hsCRP: death, recurrent MI, recurrent ischemia requiring urgent revascularization, and new or worsening congestive heart failure at 30 days and 10 months. The relative hazard related to hsCRP was adjusted for the effects of age, sex, body mass index (BMI), diabetes, hypercholesterolemia, prior MI, peripheral arterial disease, cerebrovascular disease, prior aspirin use, prior statin use, smoking status, index diagnosis, Killip class, and treatment with orbofiban. Patients were categorized according to a prespecified decision limit (15 mg/L) on the basis of our prior work with this assay (8) and on quartiles of the baseline concentration of hsCRP. In addition, we performed an exploratory analysis to evaluate other decision limits proposed in the literature (5)(7)(16). Other biomarkers were included in the multivariable model as continuous variables.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The strength of the association between CRP and clinical outcomes diminished as the time from the index event to the time of CRP measurement lengthened. Formal statistical testing of the relationship of concentrations of hsCRP, mortality, and time from onset of chest discomfort to enrollment demonstrated significant heterogeneity in the association between hsCRP and mortality between patients enrolled before and after 48 h from the onset of chest discomfort (P for interaction = 0.0027 for 30-day mortality and 0.08 for 10-month mortality) (Fig. 1 ). All subsequent analyses were therefore performed in patients randomized within 48 h of chest discomfort (n = 1992).


Figure 1
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  		Figure 1. The risk of short- and long-term mortality by hsCRP quartile stratified according to timing of hsCRP measurement to index event.

P value for interaction = 0.0027 for 30-day mortality and 0.08 for 10-month mortality. Note the lack of relationship between concentrations of hsCRP and mortality in samples measured >48 h after index event. The relationship between hsCRP quartile and timing of hsCRP measurement was consistent regardless of index diagnosis (P for interaction was 0.08 for STEMI; 0.02 for NSTEMI; and 0.001 for unstable angina).

The median concentration of hsCRP was 9.1 mg/L with an interquartile range of 3.4 to 25.5 mg/L. Concentrations of hsCRP were significantly higher in patients with STEMI (17.8 vs 10.6 in NSTEMI vs 5.8 mg/L in UA, P <0.001) or diabetes (9.8 vs 8.8 mg/L, P = 0.047), and in smokers (10.1 vs 8.1 mg/L, P <0.001). Interestingly, admission hsCRP concentrations were significantly lower in ACS patients who were already on aspirin (7.3 vs 10.2 mg/L, P <0.001) or a statin (6.9 vs 9.6 mg/L, P <0.001). There was a significant, although moderate, association between concentrations of hsCRP and peak creatinine kinase muscle/brain isoenzyme ({rho} = 0.337, P <0.001), cardiac troponin I ({rho} = 0.397, P <0.001), and B-type natriuretic peptide ({rho} = 0.2629, P <0.001).

The 1992 patients with hsCRP measurements performed within 48 h of chest pain onset included 99 patients who died by day 30 and an additional 86 patients who died between day 30 and 10 months. Table 1 presents the baseline characteristics of those patients who died, those who were alive and had hsCRP measured, and those patients alive at 10 months in the entire OPUS-TIMI 16 trial.


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  		Table 1. Baseline characteristics of those patients who died by 10 months, and those alive with or without measured hsCRP concentrations.

Increased baseline concentrations of hsCRP were associated with increased risk of death at 30 days and 10 months, even after adjustment for traditional risk factors of atherosclerosis and clinical presentation. The risk of death increased in a stepwise fashion across increasing quartiles of baseline hsCRP such that patients in the highest quartile had a >4-fold increased risk of death at 30 days [adjusted hazard ratio (adHR) 4.6, 95% CI 2.2–9.9, P <0.001] and 10 months (adHR 3.9, 95% CI 2.3–6.3, P <0.001) compared with those in the lowest quartile (Fig. 2 ).


Figure 2
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  		Figure 2. Risk of short- and long-term mortality and congestive heart failure according to hsCRP quartile.

The relative hazard related to hsCRP was adjusted for age, sex, BMI, diabetes, hypercholesterolemia, prior MI, peripheral arterial disease, cerebrovascular disease, prior aspirin use, prior statin use, smoking status, index diagnosis, Killip class, and treatment with orbofiban.

The risk of death at 10 months remained significantly greater in the highest quartile of hsCRP after adjusting for the extent of myocardial necrosis (adHR 4.8, 95% CI 2.5–9.2, P <0.001 with creatinine kinase muscle/brain isoenzyme and adHR 4.2, 95% CI 2.2–7.8, P <0.001 with troponin), B-type natriuretic peptide (adHR 5.2, 95% CI 1.7–16.3, P = 0.004), estimated creatinine clearance (adHR 3.3, 95% CI 2.0–5.5, P <0.001), or the combination of B-type natriuretic peptide, estimated creatinine clearance, and troponin (adHR 3.8, 95% CI 1.2–11.6, P = 0.02).

There was a consistent and significant association between hsCRP concentrations and the development of new or worsening heart failure. Even small increases in hsCRP were associated with higher rates of heart failure at 30 days and 10 months (Fig. 2Up ). There was no relationship between hsCRP concentrations and recurrent MI or recurrent ischemia (Table 2 ).


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  		Table 2. Risk of short- and long-term outcomes in patients with an hsCRP concentration >15 mg/L drawn within the first 48 h after symptom onset.

In addition to the primary analysis of the prespecified decision limit (15 mg/L), we evaluated the prognostic relationship in relation to other previously described cutpoints. Among patients with UA/NSTEMI, even relatively small increases (>3 mg/L) were associated with increased mortality. By contrast, in patients presenting with STEMI, an association with mortality was seen only with cutpoints of 10 and 15 mg/L, and no association was observed with the lower cutpoint of 3 mg/L (Table 3 ).


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  		Table 3. Risk of death as a short- or long-term outcome associated with different baseline hsCRP concentrations.

The relationship between hsCRP and mortality was highly consistent across a variety of subgroups examined, including those who had or had not received aspirin, lipid-lowering therapy before or after presentation, and orbofiban. The risk of death in the highest compared to the lowest quartile of hsCRP was consistent in multiple subpopulations (Fig. 3 ).


Figure 3
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  		Figure 3. Risk of 10-month mortality among patients with the highest quartile of hsCRP compared to lowest quartile among several subgroups. cTnI, cardiac troponin I.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This results of this study provide several insights relevant to the interpretation of concentrations of hsCRP in patients with ACS. Because this study is one of the largest to investigate early determination of hsCRP in this population, our finding of a strong and independent relationship between baseline hsCRP and short- and long-term mortality in OPUS-TIMI 16 provides important weight to the aggregate evidence regarding this biomarker for risk assessment in ACS. The significant relationship between hsCRP and the risk of death in patients with STEMI confirms the hypothesis that hsCRP is related to mortality and thus resolves conflicting results from previous studies. This study also provides valuable information for the formulation of more specific guidelines for implementation of hsCRP testing in ACS, particularly regarding appropriate cutpoints for and the optimal timing of hsCRP measurement. This report is one of the first to point out an association between increased concentrations of hsCRP in patients with ACS and the subsequent risk of developing heart failure. In addition, we observed lower hsCRP concentrations on admission in patients on prior aspirin or statin therapy, a finding that supports the hypothesis that these agents may affect the inflammatory processes in ACS.

In patients presenting with ACS, hsCRP concentrations are more than 10-fold higher than in patients with stable coronary disease or no known coronary disease (2). In prior studies, increased concentrations of hsCRP have been shown to be associated with mortality in patients with UA and NSTEMI (3)(4)(7)(8)(16). This risk relationship is independent of cardiac markers of necrosis such as troponin (7)(8)(16)(17)(18) and extent of coronary artery disease (19). We found that risk of death was consistent among most subpopulations, including patients with STEMI, patients with diabetes, smokers, and patients treated with aspirin and lipid-lowering agents, even after we controlled for baseline risk factors and extent of myocardial necrosis. In addition, hsCRP was a strong independent predictor of short-term mortality (30 days), a finding that is consistent with several (8)(20) but not all prior reports (12)(21). Thus, this study supports the relationship between hsCRP and short-term mortality.

stemi
Prior observations relating hsCRP and prognosis in STEMI have led to conflicting results. Several small studies involving fewer than 200 patients with STEMI found an association between hsCRP concentrations and short-term (but not long-term) mortality at extremely high cutoff concentrations of hsCRP (e.g., >200 mg/L) (11)(22)(23). Two other studies did not find such a relationship (12)(24). A study of 1044 patients with STEMI found an increased long-term risk of death with concentrations of hsCRP >13.5 mg/L (13). Among the patients in OPUS-TIMI 16 who presented with a STEMI, an increased concentration of hsCRP (>10 mg/L) was associated with an increase in the long-term risk of death after we controlled for baseline characteristics. The finding of an increased hsCRP at presentation in a patient with STEMI is not likely to alter decisions about reperfusion therapy. Recent observations, however, highlight the potential for the development of treatments directed at inflammation as a mediator of reperfusion injury in patients with ischemic injury (25).

Prior studies have used a variety of cutpoints to define increased concentrations of hsCRP, with 3, 10, and 15 mg/L being most commonly used (4)(7)(8). In our study, we found that the appropriate cutpoint differed according to index diagnosis. For patients with STEMI, higher cutpoints appear to offer better discrimination regarding short- and long-term risk. In contrast, in patients with UA/NSTEMI, hsCRP concentrations >3 mg/L are associated with increased mortality. This difference is likely due to the greater extent of necrosis in STEMI and the subsequent inflammatory response.

The optimal timing for measurement and cutpoints for hsCRP in patients with ACS has remained unclear. Most studies have used baseline hsCRP measurements and measured timing from the time of admission. Few studies have actually accounted for the time from symptom onset, which may be important because earlier measurements are less likely to be affected by degree of necrosis or concomitant illness or procedures. The effects of such confounding variables in previous studies may account for the lack of association of hsCRP with outcomes after adjustment for other biomarkers and baseline characteristics (16)(26). In this analysis, measurements of hsCRP performed within 48 h of the clinical onset of the index event were more closely associated with mortality than were measurements taken further from the index event. This finding suggests that early measurement of hsCRP, which may best reflect the inflammatory status influencing the index event, are the most useful for identifying those patients at highest risk. As with lipids (27), measurement of hsCRP within the first 24 h of ACS presentation may offer important prognostic information and could be added to critical pathways to improve the treatment of patients with ACS.

There are few data regarding hsCRP concentrations and the risk of heart failure in patients with ACS. Several studies found a relationship between increased concentrations of hsCRP and future episodes of heart failure among elderly patients with no known cardiovascular disease (28), between hsCRP and heart failure in patients with STEMI (12), or an association between hsCRP and heart failure when these variables were used as a part of a composite endpoint in patients with ACS (18)(29). In our study, the relationship between even mild increases in baseline hsCRP >3 mg/L was strongly and independently associated with the development of heart failure, suggesting that the intensity of the inflammatory response increases the risk of mechanical consequences and complications of ischemic injury and therefore may play a role in the development of heart failure. Increased concentrations of hsCRP may then help to identify patients at risk of developing congestive heart failure after ACS and prompt closer surveillance and more aggressive therapy and perhaps novel therapy aimed at prevention of adverse remodeling.

The initial early increase in hsCRP detected at the time of ACS may not only be the most specific marker of the initial inflammatory event but may also play a pathogenic role in the subsequent myocardial injury sustained after an ischemic insult. Experimental data indicate that hsCRP may be a direct participant in the innate immune response to ischemic injury, binding to damaged myocardium and activating complement, thereby expanding infarct size. In animal models of ischemia, the addition of exogenous CRP increases myocardial infarct size, whereas the inhibition of CRP with a directed small molecule diminished the damage promoted by exogenous CRP (25).

In one previous study of patients with NSTEACS, hsCRP concentrations were not predictive of adverse outcomes in patients with prior aspirin use but were predictive in patients not taking aspirin on admission (30). Patients in our cohort taking aspirin or statins at the time of randomization had lower baseline concentrations of hsCRP compared to those not taking aspirin, but prior treatment with aspirin or statin did not mitigate the prognostic association with hsCRP.

This clinical trial involved a selected population that may have included fewer patients with inflammatory disorders than found in the general population. Additional investigation of the optimal decision limits and timing of measurement in adequately sized, prospective, community-based studies will also be valuable in directing clinical use of hsCRP in this setting. Nevertheless, this study is one of the few that has included the entire spectrum of patients presenting with ACS. hsCRP was measured once at presentation and not in a serial fashion, and therefore confounding variables may have been present that potentially affected timing of presentation. Moreover, the impact on the prognostic value of hsCRP according to when the sample was measured may differ based on the extent of necrosis as an inflammatory stimulus. We have controlled for these variables as well as possible in our multivariable models.

Assessment of hsCRP on admission provides independent prognostic information and thereby improves the ability to identify those patients at highest risk of death and heart failure (18). Our data indicate that to aid in risk stratification, hsCRP should optimally be measured early (within the first 48 h) after onset of symptoms with specific cutpoints that are appropriate for the index diagnosis and are higher than those in stable patients at risk for atherosclerotic disease. Although our observations provide evidence to address several unanswered questions with respect to clinical application of hsCRP in patients presenting with ACS, routine measurement is not likely to be recommended until specific therapeutic responses are identified. At present, measurement of hsCRP in selected patients for whom additional information regarding prognosis is desired by the clinician is reasonable (Class IIa recommendation) (10).

Intensive statin therapy has been shown to decrease cardiac events (31), an effect mediated in part by a decrease in hsCRP (32), and may allow for targeted anti-CRP therapy (25). Our data highlight the importance of understanding the clinical utility of CRP in ACS to make use of therapies known to decrease inflammation while we continue to search for treatments that may be particularly beneficial for patients with increased hsCRP concentrations.


   Acknowledgments
 
Grant funding/support: OPUS-TIMI 16 was sponsored by GD Searle. The TIMI Study Group has received research support from Merck & Co., Inc.; Bristol-Myers Squibb Pharmaceutical Research Institute; Sanofi-Aventis, Millennium Pharmaceuticals, Inc.; Nuvelo, Inc.; AstraZeneca Pharmaceuticals LP; CV Therapeutics, Inc.; Inotek Pharmaceuticals Corporation; Eli Lilly and Company; Schering-Plough Research Institute; Integrated Therapeutics Corporation; Bayer Healthcare LLC; Ortho-Clinical Diagnostics, Inc.; Sanofi-Synthelabo Recherche; GlaxoSmithKline; Amgen, Inc.; Beckman Coulter, Inc.; Biosite Incorporated; Roche Diagnostics Corporation; Roche Diagnostics GmbH; Pfizer, Inc.; Accumetrics, Inc.; The National Institutes of Health; and Novartis Pharmaceuticals.

Financial disclosures: B.M.S. has received honoraria for educational material from Sanofi-Aventis and CV Therapeutics, is a consultant to Chroma Therapeutics and Prolexys, and is on the Speaker’s Bureau of Pfizer.


   Footnotes
 
1 Nonstandard abbreviations: hsCRP, high-sensitivity C-reactive protein; ACS, acute coronary syndrome; NSTEACS, non-ST elevation ACS; STEMI, ST-elevation myocardial infarction; OPUS, Orbofiban in Patients with Unstable Coronary Syndromes; TIMI, Thrombolysis in Myocardial Infarction; UA, unstable angina; NSTEMI, non-STEMI; MI, myocardial infarction; BMI, body mass index; adHR, adjusted hazard ratio.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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