|
| HOME | SUBSCRIPTIONS | CURRENT ISSUE | PAST ISSUES | CARDIOSOURCE | SEARCH | HELP | FEEDBACK |
|
|
|
|||||||||
|
|||||||||||
|
J Am Coll Cardiol, 2003; 41:916-924, doi:10.1016/S0735-1097(02)02969-8 © 2003 by the American College of Cardiology Foundation |
* Department of Medical Sciences, Cardiology, Uppsala, Sweden
|| Clinical Chemistry, Uppsala, Sweden
Department of Medicine, Alberta, Canada
Centocor, Malvern, Pennsylvania, USA
Duke CRI, Durham, North Carolina, USA
¶ Thoraxcenter, Erasmus Medical Center, Rotterdam, The Netherlands
# Cleveland Clinic Foundation, Cleveland, Ohio, USA
Manuscript received August 12, 2002; revised manuscript received October 9, 2002, accepted November 11, 2002.
* Reprint requests and correspondence: Dr. Stefan James, Department of Cardiology, Thoraxcenter, Academic Hospital, 751 85 Uppsala, Sweden.
stefan.james{at}thorax.uas.lul.se
 |
Abstract |
|---|
 Top Abstract MethodsResultsDiscussionReferences |
|---|
BACKGROUND: Both CRP and TnT predict risk of future coronary events in patients with ACS. However, the relationships between the levels of the markers and the individual end points are still unclear.
METHODS: Baseline levels of CRP and TnT were determined in 7,108 patients with ACS not undergoing early revascularization in the Global Use of Strategies To Open occluded arteries trial IV (GUSTO-IV) trial and related to outcome at 30 days.
RESULTS: Quartiles of TnT related to 30-day mortality, which was 1.1%, 3.7%, 3.7%, and 7.4% (p < 0.001) and to the rate of MI: 2.5%, 6.7%, 7.2%, and 5.6% (p < 0.001). Quartiles of CRP also related to 30-day mortality, which was 2.0%, 3.3%, 3.9%, and 6.3% (p < 0.001), whereas there was no relationship to the 30-day rate of MI: 5.6%, 4.7%, 5.2%, and 5.9% (p = 0.48). On multivariable analysis, both TnT and CRP were independent predictors of mortality, but only TnT was a predictor of MI. The combination of CRP and TnT provides an even better risk stratification of mortality, with 0.3% and 9.1% death rates, respectively, when both markers are in the bottom versus top quartiles.
CONCLUSIONS: In ACS, baseline levels of TnT and CRP are independently related to 30-day mortality. Any detectable elevation of TnT, but not of CRP, is also associated with an increased risk of subsequent MI. Regarding mortality, the combination of both markers provides a better risk stratification than either one alone.
| ||||||||||||||||||||||
|
Methods |
|---|
|
TopAbstractMethodsResultsDiscussionReferences |
|---|
21 years of age with one or more episodes of angina lasting 5 min within 24 h of admission and either a positive cardiac TnT or TnI test (above the upper limit of normal for the local assay) or 0.5 mm of transient or persistent ST-segment depression. The study was conducted in a double-blind fashion with patients randomly assigned to three treatment groups: abciximab infusion for 24 h or 48 h or corresponding placebo infusion. All patients received aspirin, 150 to 325 mg/day orally for long-term treatment, as well as either unfractionated heparin infusion for 48 h (n = 6,826) or subcutaneous dalteparin every 12 h for five to seven days (n = 974). Coronary angiography was not to be performed during or within 12 h after completion of study agent infusion. Laboratory analyses. Venous blood samples were collected in evacuated tubes through a direct venous puncture at baseline and 8, 16, 24, 36, and 48 h after randomization. After centrifugation, serum was frozen at –20°C in aliquots and sent for central laboratory analyses of creatine kinase, MB isoenzyme (CK-MB) levels. One aliquot of the serum samples at baseline was stored at –70°C and sent in batches of 500 to the Department of Clinical Chemistry, Uppsala, Sweden, for analyses of TnT and CRP. One batch was unfortunately lost during transportation. The levels of TnT were determined by a third-generation assay on an Elecsys (Roche Diagnostics, Basel, Switzerland), with the detection limit at 0.01 µg/l and a total coefficient of variance (CV) of 8% at 0.05 µg/l and 4.1% to 6.0% between 0.1 and 11 µg/l. The CRP concentrations were measured with a chemiluminescent enzyme-labeled immunometric assay (Immulite CRP, Diagnostic Products Corp., Los Angeles, California). The detection limit was 0.1 mg/l, with a total CV of 5.6% at 2 mg/l and 5% at 10 mg/l.
Definition of end points.
A 12-lead electrocardiogram was obtained at randomization, 48 h, or seven days and at 30 days. Myocardial infarction was defined as either a new, significant Q-wave (0.04 s or at least a quarter of the R wave amplitude in two or more contiguous leads) or CK-MB at least three times the upper limit of normal. For patients with CK-MB elevation at study entry, a new episode of chest pain in combination with a new CK-MB elevation was required for MI diagnosis during the initial seven days, as presented in detail in the GUSTO-IV–ACS report (12). After coronary artery bypass graft surgery, a new, significant Q-wave was the only criterion. A clinical end-point committee blinded to treatment assignment adjudicated all suspected cases of MI.
Statistical methods.
The present evaluation of CRP and TnT on outcome was performed using pre-defined analyses. The material was divided into strata based on quartiles of the respective CRP and TnT levels. For continuous variables, means were expressed with one standard deviation, and for variables not normally distributed, medians were shown with 25th to 75th percentiles. The outcomes of death and/or MI at 48 h, seven days, and 30 days were compared between the different strata of patients. Differences were evaluated with the chi-square test (linear by linear association). Odds ratios (OR), with 95% confidence intervals (CI), were presented. A p value <0.05 was considered statistically significant. The independence of relationships between the patient strata of the two markers and the outcomes of death/MI, death, and MI at 30 days was assessed in three different models of multiple logistic regression analysis. A number of known risk factors were entered into the models: age, male gender, body weight, smoking, previous angina, stroke, heart failure, diabetes mellitus, hypertension, hypercholesterolemia, previous revascularization, previous MI, current treatment with beta-blockers and angiotensin-converting enzyme inhibitors, aspirin treatment before inclusion, ST-segment depression 0.5 mm, and randomized treatment (abciximab for 24 or 48 h or placebo). Model 1 also included quartiles of TnT and CRP. Model 2 included the bottom versus the three upper quartiles of either marker in addition to the quartiles of the other variable. Finally, model 3 included the top versus the three lower quartiles in addition to the quartiles of the other variable. Additional logistic regression analyses were performed to test for the interaction between TnT and CRP quartiles.
|
Results |
|---|
|
TopAbstractMethodsResultsDiscussionReferences |
|---|
|
|
Troponin T in relation to outcome. The rate of the primary combined end point of death or MI (Fig. 1a) in the GUSTO-IV–ACS study was increasing with higher TnT quartiles at all time points of follow-up (p < 0.001). Also, mortality was markedly increasing with increased TnT quartiles from 1.1% to 7.4% between the first and fourth quartile at 30 days (Fig. 1b). There was a large increase from the first to second quartile (1.1% vs. 3.7%) and from the third to fourth quartile (3.7% vs. 7.4%). The rate of MI was increasing from the first to second quartile (2.5% vs. 6.7% at 30 days). No further increase was observed between the upper three quartiles (Fig. 1c). There was even a trend toward a lower rate of MI in the fourth quartile as compared with the third quartile (5.6% vs. 7.2%). On multiple logistic regression analysis, increasing TnT quartile was independently related to both death (OR 1.63, 95% CI 1.43 to 1.87) and MI (OR 1.23, 95% CI 1.11 to 1.37) at 30 days (Table 3). Also, when entered into the regression model as a continuous variable, TnT was a significant independent predictor of mortality (OR 1.25, 95% CI 1.10 to 1.42). The first and third quartile limits independently predicted mortality, whereas only the first quartile limit independently predicted MI. The relationship between TnT and CRP levels and cardiac events was similar when performed only for the 5,756 patients included with the ST-segment depression criterion. In this group, the 30-day mortality rates for increasing TnT quartiles were 1.1%, 3.8%, 4.9%, and 8.6% (p < 0.001) and the corresponding MI rates were 2.6%, 7.0%, 8.0%, and 6.6% (p < 0.001). There was no difference in outcome at 30-day follow-up between the randomized treatment groups at different quartiles of TnT.
|
|
1.84). For the 5,756 patients included with ST-segment depression, the outcome was similar at 30 days for the strata of patients based on increasing CRP quartiles. Thus, in this subpopulation, the 30-day mortality rates were 2.2%, 3.4%, 4.2%, and 6.8% (p < 0.001), and the corresponding MI rates were 5.8%, 5.0%, 5.6%, and 6.4% (p = 0.4). There was no difference in outcome at 30-day follow-up between the randomized treatment groups at different quartiles of CRP.
|
0.01 µg/l) had a very low event rate, but, still, an increased level of CRP (>1.84 vs. 1.84 mg/l) was associated with raised 30-day mortality (1.5% vs. 0.3%; OR 5.1, 95% CI 1.2 to 21.7). Also in the top quartile of TnT (>0.47 µg/l), an increased level of CRP (>1.84 vs. 1.84 mg/l) was related to increased mortality (7.9% vs. 3.6%; OR 2.30, 95% CI 1.15 to 2.60). Similarly, in the bottom (1.84 mg/l) as well as the top quartile (>9.62 mg/l) of CRP, a raised TnT level (>0.01 vs. 0.01 µg/l) was associated with raised mortality (3.0% vs. 0.3%; OR 10.3, 95% CI 2.5 to 43.2 and 7.5% vs. 1.4%; OR 5.7, 95% CI 2.3 to 14.2, respectively). There was no significant (p = 0.4) interaction between the markers, as evaluated by the interaction term "CRP–TnT" entered into the logistic regression model, in addition to CRP and TnT.
|
|
Discussion |
|---|
|
TopAbstractMethodsResultsDiscussionReferences |
|---|
There was a very low 30-day mortality (1.1%) and MI rate (2.5%) in patients without detectable TnT, in agreement with previous studies (6,13). The mortality increased with higher quartiles of TnT. In accordance with the FRagmin during InStability in Coronary artery disease (FRISC-II) study (14), any detectable TnT was associated with a marked increased rate of MIs, probably reflecting a thrombotic coronary lesion, with increased risk of subsequent occlusion and/or downstream embolization. However, patients in the highest compared with the two middle quartiles had a trend toward a lower rate of MI, probably due to a larger proportion of already completed MIs. Thus, increasing TnT levels are associated with a continuous rise in mortality, whereas any detectable TnT (i.e., >0.01 µg/l) is associated with a raised risk of MI without a significant further risk at higher TnT levels. The frequent core laboratory analyses of CK-MB and the rigorous MI definition requiring a new episode of chest pain and new CK-MB elevation make the possibility that an MI has resulted from the same event as the initial TnT elevation unlikely.
In the present study, increased CRP levels during the acute stage of unstable CAD were related to increased mortality, in accordance with previous findings (5–8). In this large patient cohort, this relation to increased mortality was evident early and further accentuated throughout 30-day follow-up. However, there was no association between the CRP levels and the risk of MI, which has not been shown previously. No previous study on inflammatory markers in ACS has contained a sufficient number of patients, enabling separation of the end points of death and MI. However, for the placebo group (n = 447) in the Chimeric 7E3 AntiPlateleT in Unstable angina REfractory to standard treatment (CAPTURE) trial, there was an increased mortality in patients with CRP >10 mg/l, without a corresponding rise in the occurrence of MI during the initial six months (7). Also, the FRISC trial (n = 965) reported an increased mortality for patients with increasing CRP levels, without any increase in the combined end point of death/MI (5), indicating the absence of a relationship between CRP levels and MI over a follow-up period of five months.
The use of a positive troponin test as an inclusion criterion might have influenced the associations between troponin levels and outcome, but this seems unlikely given that the relationship between TnT and CRP levels and cardiac events was similar when the test was performed only in the 5,756 patients included with the ST-segment depression criterion.
What might be the reason for the relationship between CRP and subsequent mortality, but not MI, in the acute phase of unstable CAD, despite the well-established relationship between CRP elevation and subsequent coronary events in the chronic phase of atherosclerotic disease (2,15–17)? In the acute phase of unstable CAD, the pronounced elevation of CRP is transient and likely related to an acute-phase reaction (18). Some patients with unstable CAD might have a hyper-responsiveness of the inflammatory system, which might exaggerate the acute-phase reaction and increase the immune system reaction (19). Such a mechanism is supported by the observations of co-localization of CRP and activated complement in infarct-related myocardium (20). C-reactive protein may contribute to inflammation by activation of complement, which may, in turn, mediate myocardial damage, induce arrhythmias, and provoke contractile dysfunction (21). Such an interpretation is in accordance with the relationships between the CRP level and the occurrence of cardiac rupture, left ventricular aneurysm formation, and mortality after acute MI (22). The pronounced CRP elevation in unstable CAD might also indicate a process different from the low-grade CRP elevation in the chronic phase of atherosclerosis, which is associated with subsequent coronary events among healthy individuals (2,16,23) and after MI (17). In unstable CAD and chronic atherosclerotic disease, there is a lasting elevation of the fibrinogen level (18), which might indicate an underlying chronic low-grade inflammatory condition that is associated with a raised risk of later MI in both conditions.
Despite the prognostic capacity of TnT regarding mortality, adding CRP further improved the risk stratification. On multivariable analysis, when correcting for a large number of clinical risk factors, including TnT, increasing CRP quartiles was an independent predictor of mortality. With TnT and CRP as continuous variables, the ORs were lower but still significant. Based on the present findings, the combination of these two markers seems to identify three different risk groups (Tables 4 and 5) : one very low-risk group without detectable TnT and CRP <1.84 mg/l; one medium-risk group; and one high-risk group with TnT >0.47 µg/l and CRP >9.62 mg/l, with corresponding 30-day mortality rates of <0.3%, 3% to 5%, and >9%, respectively. These strata could prove useful in the selection of more aggressive treatment for individual patients. Similar relationships were found by Morrow et al. (8) in the Thrombolysis In Myocardial Infarction (TIMI)-11A substudy (n = 437), in which rapid TnT assays with a detection limit of 0.2 µg/l were used. However, in the current larger study, the influence of CRP levels on mortality was evident even in patients without any detectable TnT.
|
Clinical implications. In ACS, the levels of troponin and CRP provide important, different, and complementary prognostic information. With increasing levels of any of the markers, there is a commensurate rise in mortality. At any detectable troponin, there is also a raised risk of a later MI. The combination of both markers allows the best prediction of mortality. The use of the combination of these markers will provide an important tool for the selection of patients for clinical trials and also for identification of patients for different treatment alternatives.
|
References |
|---|
|
TopAbstractMethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  M. P. Bonaca and D. A. Morrow Defining a Role for Novel Biomarkers in Acute Coronary Syndromes Clin. Chem., September 1, 2008; 54(9): 1424 - 1431. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Bogaty, L. Boyer, S. Simard, F. Dauwe, R. Dupuis, B. Verret, T. Huynh, F. Bertrand, G. R. Dagenais, and J. M. Brophy Clinical utility of C-reactive protein measured at admission, hospital discharge, and 1 month later to predict outcome in patients with acute coronary disease. The RISCA (recurrence and inflammation in the acute coronary syndromes) study. J. Am. Coll. Cardiol., June 17, 2008; 51(24): 2339 - 2346. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Morrow, M. S. Sabatine, M.-L. Brennan, J. A. de Lemos, S. A. Murphy, C. T. Ruff, N. Rifai, C. P. Cannon, and S. L. Hazen Concurrent evaluation of novel cardiac biomarkers in acute coronary syndrome: myeloperoxidase and soluble CD40 ligand and the risk of recurrent ischaemic events in TACTICS-TIMI 18 Eur. Heart J., May 1, 2008; 29(9): 1096 - 1102. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. A. Kavsak, D. T. Ko, A. M. Newman, G. E. Palomaki, V. Lustig, A. R. MacRae, and A. S. Jaffe Risk Stratification for Heart Failure and Death in an Acute Coronary Syndrome Population Using Inflammatory Cytokines and N-Terminal Pro-Brain Natriuretic Peptide Clin. Chem., December 1, 2007; 53(12): 2112 - 2118. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. M. Scirica, D. A. Morrow, C. P. Cannon, J. A. de Lemos, S. Murphy, M. S. Sabatine, S. D. Wiviott, N. Rifai, C. H. McCabe, E. Braunwald, et al. Clinical Application of C-Reactive Protein Across the Spectrum of Acute Coronary Syndromes Clin. Chem., October 1, 2007; 53(10): 1800 - 1807. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. G. Hage and A. J. Szalai C-Reactive Protein Gene Polymorphisms, C-Reactive Protein Blood Levels, and Cardiovascular Disease Risk J. Am. Coll. Cardiol., September 18, 2007; 50(12): 1115 - 1122. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Afilalo, A. A Majdan, and M. J Eisenberg Intensive statin therapy in acute coronary syndromes and stable coronary heart disease: a comparative meta-analysis of randomised controlled trials Heart, August 1, 2007; 93(8): 914 - 921. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 NACB WRITING GROUP MEMBERS, D. A. Morrow, C. P. Cannon, R. L. Jesse, L. K. Newby, J. Ravkilde, A. B. Storrow, A. H.B. Wu, and R. H. Christenson National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Clinical Characteristics and Utilization of Biochemical Markers in Acute Coronary Syndromes Circulation, April 3, 2007; 115(13): e356 - e375. [Full Text] [PDF]
|
|
|
|
|
|
NACB WRITING GROUP MEMBERS, D. A. Morrow, C. P. Cannon, R. L. Jesse, L. K. Newby, J. Ravkilde, A. B. Storrow, A. H.B. Wu, R. H. Christenson, NACB COMMITTEE MEMBERS, et al. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Clinical Characteristics and Utilization of Biochemical Markers in Acute Coronary Syndromes Clin. Chem., April 1, 2007; 53(4): 552 - 574. [Full Text] [PDF]
|
|
|
|
|
|
D. A. Morrow and J. A. de Lemos Benchmarks for the Assessment of Novel Cardiovascular Biomarkers Circulation, February 27, 2007; 115(8): 949 - 952. [Full Text] [PDF]
|
|
|
|
|
|
E K Iliodromitis, S Kyrzopoulos, I A Paraskevaidis, K G Kolocassides, S Adamopoulos, G Karavolias, and D T Kremastinos Increased C reactive protein and cardiac enzyme levels after coronary stent implantation. Is there protection by remote ischaemic preconditioning? Heart, December 1, 2006; 92(12): 1821 - 1826. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. K. James, J. Lindback, J. Tilly, A. Siegbahn, P. Venge, P. Armstrong, R. Califf, M. L. Simoons, L. Wallentin, and B. Lindahl Troponin-T and N-Terminal Pro-B-Type Natriuretic Peptide Predict Mortality Benefit From Coronary Revascularization in Acute Coronary Syndromes: A GUSTO-IV Substudy J. Am. Coll. Cardiol., September 19, 2006; 48(6): 1146 - 1154. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Jaffe, L. Babuin, and F. S. Apple Biomarkers in Acute Cardiac Disease: The Present and the Future J. Am. Coll. Cardiol., July 4, 2006; 48(1): 1 - 11. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Suleiman, R. Khatib, Y. Agmon, R. Mahamid, M. Boulos, M. Kapeliovich, Y. Levy, R. Beyar, W. Markiewicz, H. Hammerman, et al. Early Inflammation and Risk of Long-Term Development of Heart Failure and Mortality in Survivors of Acute Myocardial Infarction: Predictive Role of C-Reactive Protein J. Am. Coll. Cardiol., March 7, 2006; 47(5): 962 - 968. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Zethelius, N. Johnston, and P. Venge Troponin I as a Predictor of Coronary Heart Disease and Mortality in 70-Year-Old Men: A Community-Based Cohort Study Circulation, February 28, 2006; 113(8): 1071 - 1078. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R L Kennedy and R F Harrison Identification of patients with evolving coronary syndromes by using statistical models with data from the time of presentation Heart, February 1, 2006; 92(2): 183 - 189. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. De Servi, M. Mariani, G. Mariani, and A. Mazzone C-Reactive Protein Increase in Unstable Coronary Disease: Cause or Effect? J. Am. Coll. Cardiol., October 18, 2005; 46(8): 1496 - 1502. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kovacs, P. Henriksson, A. Hamsten, H. Wallen, J. Bjorkegren, and P. Tornvall Hormonal Regulation of Circulating C-Reactive Protein in Men Clin. Chem., May 1, 2005; 51(5): 911 - 913. [Full Text] [PDF]
|
|
|
|
|
|
L. M. Biasucci CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: Clinical Use of Inflammatory Markers in Patients With Cardiovascular Diseases: A Background Paper Circulation, December 21, 2004; 110(25): e560 - e567. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. James and L. Wallentin C-reactive protein provides independent prognostic information on short- and long-term mortality in patients with non-st elevation acute coronary syndrome: Reply J. Am. Coll. Cardiol., September 17, 2003; 42(6): 1145 - 1146. [Full Text] [PDF]
|
|
|
|
|
|
S. De Servi and A. Mazzone Are levels of C-reactive protein and troponin T the best predictors of mortality after acute coronary syndrome? J. Am. Coll. Cardiol., September 17, 2003; 42(6): 1144 - 1145. [Full Text] [PDF]
|
|
|
|
|
|
N. Varo, J. A. de Lemos, P. Libby, D. A. Morrow, S. A. Murphy, R. Nuzzo, C. M. Gibson, C. P. Cannon, E. Braunwald, and U. Schonbeck Soluble CD40L: Risk Prediction After Acute Coronary Syndromes Circulation, September 2, 2003; 108(9): 1049 - 1052. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. K. James, B. Lindahl, A. Siegbahn, M. Stridsberg, P. Venge, P. Armstrong, E. S. Barnathan, R. Califf, E. J. Topol, M. L. Simoons, et al. N-Terminal Pro-Brain Natriuretic Peptide and Other Risk Markers for the Separate Prediction of Mortality and Subsequent Myocardial Infarction in Patients With Unstable Coronary Artery Disease: A Global Utilization of Strategies To Open occluded arteries (GUSTO)-IV Substudy Circulation, July 22, 2003; 108(3): 275 - 281. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | SUBSCRIPTIONS | CURRENT ISSUE | PAST ISSUES | CARDIOSOURCE | SEARCH | HELP | FEEDBACK |
