Clinical Application of C-Reactive Protein Across
the Spectrum of Acute Coronary Syndromes
Benjamin M. Scirica,*David A. Morrow, Christopher P. Cannon, James A. de Lemos,
Sabina Murphy, Marc S. Sabatine, Stephen D. Wiviott, Nader Rifai,
Carolyn H. McCabe, and Eugene Braunwald for the
Thrombolysis in Myocardial Infarction (TIMI) Study Group
(hsCRP) is associated with adverse cardiovascular out-
comes 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 com-
pared in patients who suffered an adverse cardiac out-
come 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 com-
pared 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 myo-
cardial infarction (STEMI), hsCRP >3 mg/L was associ-
ated 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 asso-
ciated with the development of heart failure at 30 days
(adjHR 8.2, P ? 0.001) and 10 months (adjHR 2.6, P ?
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.
© 2007 American Association for Clinical Chemistry
Inflammation is an important contributor to atherothrom-
bosis, both accelerating atherosclerosis and precipitating
acute plaque rupture (1). The serum or plasma concen-
tration of high-sensitivity C-reactive protein (hsCRP)2, a
marker of inflammation, is increased in patients with
acute coronary syndrome (ACS) compared with individ-
uals without established vascular disease as well as in
patients with chronic stable angina (2–5). 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–
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 develop-
ment 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, appropri-
ate 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) (11–13) and
the relationship between concentrations of hsCRP and the
* Address correspondence to this author at: TIMI Study Group, Cardio-
vascular Division, Department of Medicine, Brigham and Women’s Hospital,
75 Francis St., Boston, MA 02461. Fax 617-734-7329; e-mail bscirica@
Received February 24, 2007; accepted August 1, 2007.
Previously published online at DOI: 10.1373/clinchem.2007.087957
2Nonstandard 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.
Clinical Chemistry 53:10
acute coronary syndrome: a GUSTO-IV substudy. J Am Coll Cardiol
17. Mueller C, Buettner HJ, Hodgson JM, Marsch S, Perruchoud AP,
Roskamm H, et al. Inflammation and long-term mortality after
non-ST elevation acute coronary syndrome treated with a very
early invasive strategy in 1042 consecutive patients. Circulation
18. Sabatine MS, Morrow DA, de Lemos JA, Gibson CM, Murphy SA,
Rifai N, et al. Multimarker approach to risk stratification in non-ST
elevation acute coronary syndromes: simultaneous assessment
of troponin I, C-reactive protein, and B-type natriuretic peptide.
19. Zebrack JS, Muhlestein JB, Horne BD, Anderson JL. C-reactive
protein and angiographic coronary artery disease: independent
and additive predictors of risk in subjects with angina. J Am Coll
20. Oltrona L, Ottani F, Galvani M. Clinical significance of a single
measurement of troponin-I and C-reactive protein at admission in
1773 consecutive patients with acute coronary syndromes. Am
Heart J 2004;148:405–15.
21. Nikfardjam M, Mullner M, Schreiber W, Oschatz E, Exner M,
Domanovits H, et al. The association between C-reactive protein
on admission and mortality in patients with acute myocardial
infarction. J Intern Med 2000;247:341–5.
22. Pietila KO, Harmoinen AP, Jokiniitty J, Pasternack AI. Serum
C-reactive protein concentration in acute myocardial infarction and
its relationship to mortality during 24 months of follow-up in
patients under thrombolytic treatment. Eur Heart J 1996;17:
23. Tommasi S, Carluccio E, Bentivoglio M, Buccolieri M, Mariotti M,
Politano M, et al. C-reactive protein as a marker for cardiac
ischemic events in the year after a first, uncomplicated myocardial
infarction. Am J Cardiol 1999;83:1595–9.
24. Zebrack JS, Anderson JL, Maycock CA, Horne BD, Bair TL,
Muhlestein JB. Usefulness of high-sensitivity C-reactive protein in
predicting long-term risk of death or acute myocardial infarction in
patients with unstable or stable angina pectoris or acute myocar-
dial infarction. Am J Cardiol 2002;89:145–9.
25. Pepys MB, Hirschfield GM, Tennent GA, Gallimore JR, Kahan MC,
Bellotti V, et al. Targeting C-reactive protein for the treatment of
cardiovascular disease. Nature 2006;440:1217–21.
26. de Winter RJ, Fischer J, Bholasingh R, van Straalen JP, de Jong T,
Tijssen JG, et al. C-reactive protein and cardiac troponin T in risk
stratification: differences in optimal timing of tests early after the
onset of chest pain. Clin Chem 2000;46:1597–603.
27. Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand
M, et al. ACC/AHA guidelines for the management of patients with
ST-elevation myocardial infarction; a report of the American Col-
lege of Cardiology/American Heart Association Task Force on
Practice Guidelines (Committee to Revise the 1999 Guidelines for
the management of patients with acute myocardial infarction).
J Am Coll Cardiol 2004;44:E1–211.
28. Vasan RS, Sullivan LM, Roubenoff R, Dinarello CA, Harris T,
Benjamin EJ, et al. Inflammatory markers and risk of heart failure
in elderly subjects without prior myocardial infarction: the Framing-
ham Heart Study. Circulation 2003;107:1486–91.
29. Varo N, de Lemos JA, Libby P, Morrow DA, Murphy SA, Nuzzo R, et
al. Soluble CD40L: risk prediction after acute coronary syn-
dromes. Circulation 2003;108:1049–52.
30. Kennon S, Price CP, Mills PG, Ranjadayalan K, Cooper J, Clarke H,
et al. The effect of aspirin on C-reactive protein as a marker of risk
in unstable angina. J Am Coll Cardiol 2001;37:1266–70.
31. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL,
Belder R, et al. Intensive versus moderate lipid lowering with
statins after acute coronary syndromes. N Engl J Med 2004;350:
32. Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH,
et al. C-reactive protein levels and outcomes after statin therapy.
N Engl J Med 2005;352:20–8.
Clinical Chemistry 53, No. 10, 2007