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C-reactive protein (CRP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) provide prognostic information in patients with stable coronary heart disease. The aim of the study was to investigate whether combined use of NT-proBNP and CRP improves risk stratification in these patients.
Methods
This cohort study included 989 patients with stable coronary heart disease who underwent coronary stenting. CRP and NT-proBNP were measured before angiography. The primary end point of the study was all-cause mortality. Using median values of NT-proBNP (279.9 ng/L) and CRP (1.2 mg/L), patients were divided into 4 groups: low NT-proBNP-low CRP group (305 patients with NT-proBNP<median and CRP<median); low NT-proBNP-high CRP group (190 patients with NT-proBNP<median and CRP≥median; high NT-proBNP-low CRP group (237 patients with NT-proBNP≥median and CRP<median); and high NT-proBNP-high CRP group (257 patients with NT-proBNP≥median and CRP≥median).
Results
During a median follow-up of 3.6 years (interquartile range 3.3 to 4.5 years), there were 85 deaths: 6 deaths in the low NT-proBNP-low CRP group, 11 deaths in the low NT-proBNP-high CRP group, 20 deaths in the high NT-proBNP-low CRP group, and 48 deaths in the high NT-proBNP-high CRP group with Kaplan-Meier mortality estimates of 2.7%, 8.9%, 12.1% and 35.6%, respectively (P <.001). Cox proportional hazards model showed that combination NT-proBNP-CRP was the strongest independent correlate of mortality (hazard ratio [HR] 4.3, 95% confidence interval [CI], 2.0-9.3; P <.001 for high NT-proBNP-high CRP vs low NT-proBNP-low CRP).
Conclusion
Combined use of NT-proBNP and CRP improves long-term risk prediction of mortality in patients with stable coronary heart disease.
Stable coronary heart disease is the most frequent form of ischemic heart disease, and coronary stenting is a common treatment in these patients. Two population-based studies in the US population have reported that annual rates of myocardial infarction in patients with angina were 3% to 3.4%,
allowing an estimation of 30 patients with angina for each hospitalized patient with acute myocardial infarction. Taking into consideration that 550 000 patients with acute myocardial infarction are hospitalized annually,
Application of biomarkers that reliably predict prognosis in such a large group of patients with ischemic heart disease is of paramount clinical importance. Several studies have indicated that increased levels of C-reactive protein (CRP) predict rapid progression of coronary artery disease
Production of C-reactive protein and risk of coronary events in stable and unstable angina. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group.
Recently, N-terminal probrain natriuretic peptide (NT-proBNP) also has been shown to be a strong predictor of mortality in patients with stable coronary heart disease.
In patients with acute coronary syndromes, a multimarker approach to risk stratification has allowed a powerful short- and long-term prediction of heightened risk of death,
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.
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.
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.
Although information available indicates that NT-proBNP and CRP provide unique prognostic information in patients with stable ischemic heart disease, no studies so far have assessed whether combined use of these biomarkers improves the risk stratification regarding mortality.
N-terminal probrain natriuretic peptide and C-reactive protein provide, separately, prognostic information in patients with stable coronary heart disease.
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The present study shows that elevation of both N-terminal probrain natriuretic peptide and C-reactive protein in patients with stable coronary heart disease is associated with a poorer 5-year prognosis than isolated elevation of each of these biomarkers.
•
Combined use of N-terminal probrain natriuretic peptide and C-reactive protein provides better prognostic information compared with the use of each of these biomarkers alone.
We undertook this study to investigate whether combined use of NT-proBNP and CRP improves the risk stratification regarding mortality or other major cardiac events in a large series of patients with stable coronary heart disease after coronary stenting over a long-term follow-up. The hypothesis for the study was that combined use of these biomarkers may provide a better risk stratification in patients with stable coronary heart disease than each of the biomarkers alone.
Methods
Patients
Between September 1999 and February 2002, 1059 patients with stable coronary artery disease underwent coronary angiography with stent implantation in the Deutsches Herzzentrum and Klinikum rechts der Isar in Munich and were recruited in a prospective cohort study to investigate the prognostic value of biochemical biomarkers. Results for prognostic value of NT-proBNP in these patients have been reported.
Patients with congestive heart failure with a New York Heart Association (NYHA) class III and IV (70 patients) were excluded. Nine hundred eighty-nine patients with angiographic confirmation of stable coronary artery disease make up the cohort for the present study. The diagnosis of stable coronary artery disease was based on the presence of angina symptoms—in a patient already diagnosed to have coronary artery disease—that were occurring without a change in their pattern during the preceding 2 months. Patients with acute coronary syndromes diagnosed on the basis of characteristics of anginal status, electrocardiographical changes or increased levels of creatine kinase MB or cardiac troponin were not included in the study. Furthermore, patients with advanced renal disease, acute inflammatory states, or malignancies were excluded. All patients gave informed consent before recruitment in the study. The study protocol was approved by the institutional ethics committee.
Definitions
Coronary artery disease was diagnosed in the presence of coronary stenoses ≥50% lumen obstruction in at least one of the three major coronary arteries. Congestive heart failure was graded according to New York Heart Association (NYHA) Classification. Angina was graded according to the Canadian Cardiovascular Society classification system.
Arterial hypertension was defined in the presence of active treatment with antihypertensive agents or otherwise as a systolic blood pressure of more than 140 mm Hg or diastolic blood pressure of more than 90 mm Hg at least on 2 separate occasions. Hypercholesterolemia was defined as a documented total cholesterol value equal to or >240 mg/dL before initiation of statin therapy. Smokers were defined as those currently smoking any tobacco. Diabetes mellitus was defined if patients were under an active treatment with insulin or oral hypoglycemic agents. For patients on dietary treatment alone, documentation of abnormal fasting blood glucose or glucose tolerance test according to the World Health Organization criteria were required for the diagnosis of diabetes.
Blood was collected before angiography in tubes containing ethylenediaminetetraacetic acid (Sarstedt, Nümbrecht, Germany) and promptly centrifuged at 1550 g for 10 minutes. After separation, plasma aliquots were stored frozen at −80°C until assayed within batches. Blood count, serum lipids, and other metabolites were determined immediately after collection using standard methods.
NT-proBNP measurements were performed on a Roche Elecsys 1010 automated analyser (Roche Diagnostics, Mannheim, Germany). The Roche NT-proBNP sandwich electrochemiluminescent assay uses 2 polyclonal antibodies that recognize epitopes located in the N-terminal part (1-76 amino acid residues) of proBNP (1-108 amino acid residues). The measuring range, defined by the lower detection limit and the maximum of the master curve, provided by the manufacturer is 5-35 000 ng/L. The functional sensitivity, or the lowest analyte concentration that can be reproducibly measured with a between-run coefficient of variation of 20%, is <50 ng/L. NT-proBNP concentrations in healthy subjects depend on age and sex. In women, the 95th percentile of NT-proBNP concentration increases from 152 pg/mL (at <55 years of age) to 265 pg/mL (at >65 years of age). In men of the same age, the 95th percentile of NT-proBNP concentration increases from 75.8 pg/mL to 157 pg/mL.
Plasma concentrations of high-sensitivity C-reactive protein (hsCRP) were measured fully automated with a latex-enhanced immunoturbidometric assay on a Cobas Integra (Roche Diagnostics, Mannheim, Germany). The C-reactive protein assay has an analytical sensitivity of 0.085 mg/L and a measuring range up to 160 mg/L. The upper limit of the reference range in healthy adults is 5 mg/L.
Laboratory personnel involved in the laboratory measurements were unaware of clinical or angiographic outcome of the patients.
Angiographic Evaluation and Stent Implantation
Digital angiograms were analyzed offline with an automated edge detection system (CMS; Medis Medical Imaging Systems, Nuenen, The Netherlands). The complexity of lesions was defined according to the modified American College of Cardiology/American Heart Association grading system.
Multivessel Angioplasty Prognosis Study Group Coronary morphologic and clinical determinants of procedural outcome with angioplasty for multivessel coronary disease. Implications for patient selection.
Class B2 and C lesions were considered complex. Left ventricular end-diastolic pressure was measured before angiography. Left ventricular ejection fraction was calculated using left ventricular angiograms. Left ventricular end-diastolic pressure was measured before angiography.
Stent implantation and periprocedural care were performed according to standard criteria. Bare metal stents were used. Antiplatelet therapy consisted of clopidogrel (600 mg as a loading dose followed by 75 mg/day for at least 4 weeks) and aspirin (200 mg/day administered orally and continued indefinitely). As a standard practice in our institution, all patients were scheduled to undergo coronary angiography 6 months after the procedure or whenever they showed symptoms or signs of myocardial ischemia. Restenosis was defined as a diameter stenosis ≥50% at the target lesion at follow-up angiography.
End Points of the Study and Follow-up
The primary end point of the study was all-cause mortality. Deaths were classified as cardiovascular or noncardiovascular, on the basis of the information obtained from hospital records, death certificates, or phone contact with relatives of the patient or attending physicians. Myocardial infarction, angiographic restenosis (restenosis in the 6-month angiography), and target vessel revascularization (clinical restenosis) also were evaluated. Clinical follow-up consisted of telephone interviews at 1 month, 1 year, and 3-5 years after the initial procedure. All patients were advised to contact our outpatient clinic or their referring physicians whenever they experienced cardiac symptoms. In case of symptoms, at least one clinical and electrocardiographical checkup was performed. The diagnosis of myocardial infarction was based on the presence of typical chest pain accompanied by either the appearance of pathologic Q-waves on an electrocardiogram or an increase of creatine kinase/creatine kinase MB (CK/CK-MB) >3 times the upper limit of normal. Target vessel revascularization was defined as coronary bypass surgery or repeat percutaneous transluminal coronary angioplasty performed during the follow-up period due to symptoms or signs of myocardial ischemia in the presence of angiographic restenosis. Collection of baseline characteristics of the patients, follow-up information, as well as adjudication of adverse events was performed by medical staff unaware of NT-proBNP or CRP levels.
Statistical Analysis
Data are presented as median (with 25th and 75th percentiles) or counts and proportions (percentages). The distribution of the data was analyzed with one-sample Kolmogorov-Smirnov test. Categorical data were compared with chi-squared test. Continuous data were compared with Kruskal-Wallis rank-sum test. Survival analysis was performed by applying the Kaplan-Meier method. Differences in survival were assessed with the log-rank test. The Cox proportional hazards model was used to assess the independent correlates of mortality. The following variables were entered into the multivariable model: age, sex, body mass index, diabetes, arterial hypertension, current smoking, hypercholesterolemia, previous myocardial infarction, previous coronary artery bypass graft surgery, previous balloon angioplasty, systolic blood pressure, atrial fibrillation, NYHA class, angina class, serum creatinine, statin therapy, beta-blocker therapy, left ventricular ejection fraction, left ventricular end-diastolic pressure, number of affected vessels, complex lesions, minimal lumen diameter before stenting, NT-proBNP and CRP, or the combination NT-proBNP-CRP. All analyses were performed using S-plus statistical package (S-PLUS, Insightful Corp, Seattle, Washington). A P value <.05 was considered to indicate statistical significance.
Results
The median values of NT-proBNP and CRP concentrations were 279.9 ng/L and 1.2 mg/L. Overall, during a median follow-up of 3.6 years (interquartile range 3.2-4.5 years), there were 85 deaths. There were 17 deaths among patients with NT-proBNP level less than the median and 68 deaths among patients with NT-proBNP level at or above the median (Kaplan-Meier estimates of mortality 5.2% and 19.2%; odds ratio [OR] 4.3, 95% confidence interval [CI], 2.6-6.9; log-rank test P <.001). There were 26 deaths among patients with CRP level less than the median and 59 deaths among patients with CRP level at or above the median (Kaplan-Meier estimates of mortality 6.8% and 18.3%; OR 2.8, 95% CI 1.8-4.3; log-rank test P<.001). Cox proportional hazards model was used to identify the independent correlates of all-cause mortality (see Methods for variables entered into the model). NT-proBNP and CRP were entered into the model as separate categorical variables. The model showed that age (hazard ratio [HR] 2.89; 95% CI 1.83-4.55; P<.001 for 10-year increase), CRP (HR 2.30; 95% CI 1.40-3.78; P=.001 for CRP ≥ median vs CRP<median), smoking (HR 2.30; 95% CI 1.18-4.48; P=.015), NT-proBNP (HR 2.00; 95% CI 1.05-3.58; P=.031 for NT-proBNP≥median vs NT-proBNP<median), and NYHA class (HR 1.70; 95% CI 1.04-2.79; P=.034 for NHA II vs NYHA I) were independent correlates of mortality.
The median values of NT-proBNP or CRP were used as cutoff points to divide patients into the groups with low (<median) or high (≥median) concentrations of NT-proBNP and CRP. There were 495 patients in the low NT-proBNP or CRP groups and 494 in the high NT-proBNP or CRP groups. To test our assumption that combined use of both biomarkers increases the prediction of increased risk of death, patients were divided into 4 groups: low NT-proBNP-low CRP group (305 patients with NT-proBNP<median and CRP<median); low NT-proBNP-high CRP group (190 patients with NT-proBNP<median and CRP≥median); high NT-proBNP-low CRP group (237 patients with NT-proBNP≥median and CRP<median); and high-NT-proBNP-high CRP group (257 patients with NT-proBNP≥median and CRP≥median). Baseline characteristics of all 4 groups are shown in Table 1. As seen in Table 1, the majority characteristics differed significantly among the groups. Patients in the high NT-proBNP-high CRP group, as compared with patients in the low NT-proBNP-low CRP group were older, more often women, and more likely to have diabetes, arterial hypertension, and a history of previous infarction. Furthermore, patients in the high NT-proBNP–high CRP group had more advanced NYHA class and were more often in atrial fibrillation than the patients in the group with low NT-proBNP–low CRP. Table 2 shows main angiographic and procedural data. There were significant differences among groups regarding left ventricular ejection fraction, left ventricular end-diastolic pressure, number of narrowed coronary arteries, complexity of lesions, and minimal lumen diameter before stenting. The remaining, mostly procedural characteristics appeared to differ little among the patients in different groups. There was no correlation between concentrations of NT-proBNP and CRP (r2 = 0.026).
Table 1Baseline Characteristics
Characteristic
Low NT-proBNP Low CRP (n = 305)
Low NT-proBNP High CRP (n = 190)
High NT-proBNP Low CRP (n = 237)
High NT-proBNP High CRP (n = 257)
P Value
Age (years)
61.7 [55.0; 67.8]
62.4 [57.5; 69.0]
69.8 [62.7; 76,3]
71.3 [64.4; 77.4]
<.001
Women
39 (12.8)
32 (16.8)
68 (28.7)
69 (26.8)
<.001
Body mass index (kg/m2)
26.5 [24.6; 28.7]
28.0 [25.9; 29.9]
25.9 [23.7; 28.5]
26.7 [24.3; 29.3]
<.001
Diabetes
58 (19.0)
43 (22.6)
61 (25.7)
96 (37.4)
<.001
Arterial hypertension
162 (53.1)
110 (57.9)
152 (64.1)
159 (61.9)
.047
History of smoking
133 (43.6)
100 (52.6)
106 (44.7)
117 (45.5)
.236
Current smoking
37 (12.1)
33 (17.4)
36 (15.2)
29 (11.3)
.210
Hypercholesterolemia
145 (47.5)
96 (50.5)
102 (43.0)
102 (39.7)
.092
Previous myocardial infarction
93 (30.5)
64 (33.7)
113 (47.7)
125 (48.6)
<.001
Previous coronary artery surgery
33 (10.8)
31 (16.3)
51 (21.5)
43 (16.7)
.008
Previous percutaneous ballon angioplasty
167 (54.8)
100 (52.6)
124 (52.3)
151 (58.8)
.462
Systolic blood pressure (mm Hg)
150.0 [130.0; 169.0]
150.0 [133.0; 170.0]
160.0 [140.0; 180.0]
150.0 [130.0; 170.0]
.037
Atrial fibrillation
3 (1.0)
1 (0.5)
18 (7.6)
28 (10.9)
<.001
NYHA class
<.001
1
273 (89.5)
159 (83.7)
171 (72.2)
180 (70.0)
2
32 (10.5)
31 (16.3)
66 (27.8)
77 (30.0)
Angina class
.006
1
80 (26.3)
60 (31.6)
90 (38.0)
103 (40.1)
2
124 (40.7)
56 (29.5)
68 (28.7)
79 (30.7)
3
88 (28.8)
64 (33.7)
71 (29.9)
70 (27.2)
4
13 (4.2)
10 (5.2)
8 (3.4)
5 (2.0)
Serum creatinine (mg/dL)
1.1 [1.0; 1.2]
1.1 [1.0; 1.3]
1.1 [1.0; 1.2]
1.2 [1.0; 1.4]
<.001
High sensitivity C-reactive protein (mg/L)
0.9 [0.5; 1.1]
2.2 [1.4; 4.2]
0.9 [0.6; 1.1]
2.4 [1.6; 6.4]
<.001
NT-proBNP (ng/L)
117.9 [68.2; 117.6]
112.2 [69.6; 187.2]
568.2 [386.4; 1161.0]
825.4 [442.1; 1770.0]
<.001
Therapy at discharge
Statins
275 (90.2)
153 (80.5)
205 (86.5)
211 (82.1)
.008
Beta blockers
277 (91.0)
164 (86.3)
219 (92.4)
234 (91.1)
.176
Angiotensin-converting enzyme inhibitors
245 (80.3)
147 (77.4)
208 (87.8)
219 (85.2)
.015
Nitrates
13 (4.3)
7 (3.7)
9 (3.8)
9 (3.5)
.970
Calcium antagonists
6 (2.0)
2 (1.0)
9 (3.8)
4 (1.6)
.197
Data are median [25th; 75th percentiles] or number of patients (%).
CRP = C-reactive protein; NT-proBNP = N-terminal pro-brain natriuretic peptide; NYHA = New York Heart Association.
There were 957 patients eligible for 6-month coronary angiography. Six-month coronary angiography was performed in 245 of 293 patients (83.6%) in the low NT-proBNP-low CRP group, 159 of 188 patients (84.6%) in the low NT-proBNP-high CRP group, 190 of 231 patients (82.3%) in the high NT-proBNP-low CRP group, and 175 of 245 patients (71.4%) in the high NT-proBNP-high CRP group. Angiographic restenosis was found in 73 patients (29.8%) in the low NT-proBNP-low CRP group, 48 patients (30.2%) in the low NT-proBNP-high CRP group, 58 patients (30.5%) in the high NT-proBNP-low CRP group, and 52 patients (29.7%) in the high NT-proBNP-high CRP group (P = .997).
Clinical Outcome
During a median follow-up of 3.6 years (interquartile range 3.2-4.5 years), there were 85 deaths. Of them, 6 deaths were in the low NT-proBNP-low CRP group, 11 deaths were in the low NT-proBNP-high CRP group, 20 deaths were in the high NT-proBNP-low CRP group, and 48 deaths were in the high NT-proBNP-high CRP group; Kaplan-Meier mortality estimates were: 2.7%, 8.9%, 12.1% and 35.6%, respectively (OR 10.1, 95% CI 5.1-20.0; P<.001 for high NT-proBNP-high CRP vs low NT-proBNP-low CRP group; OR 2.8, 95% CI 1.1-7.2 for high-CRP-low NT-proBNP vs low NT-proBNP-low CRP; P=.034; and OR 4.4, 95% CI 1.9-10.1 for high NT-proBNP-low CRP vs low NT-proBNP-low CRP; P<.001; Figure). Myocardial infarction occurred in 12 patients in the low NT-proBNP-low CRP group, 16 patients in the low NT-proBNP-high CRP group, 13 patients in the high NT-proBNP-low CRP group, and 21 patients in the high NT-proBNP-high CRP group; Kaplan-Meier estimates of myocardial infarction rates were: 4.0%, 8.7%, 7.5% and 8.6%, respectively (OR 2.1, 95% CI 1.1-4.2, P=.034 for high NT-proBNP-high CRP vs low NT-proBNP-low CRP group). Target vessel revascularization was required in 87 patients in the low NT-proBNP-low CRP group, 41 patients in the low NT-proBNP-high CRP group, 51 patients in the high NT-proBNP-low CRP group, and 54 patients in the high NT-proBNP-high CRP group (Kaplan-Meier estimates were: 29.4%, 22.0%, 24% and 23.6%, respectively; P=.117).
Figure 1Mortality estimates in patients according to combined NT-proBNP and CRP biomarkers. lNT-proBNP&lCRP indicates low NT-proBNP-low CRP group; lNT-proBNP&hCRP, low NT-proBNP-high CRP group; hNT-proBNP&lCRP, high NT-proBNP-low CRP group and hNT-proBNP&hCRP, high NT-proBNP-high CRP group.
Fifty-four deaths were classified as of cardiovascular origin. Of them, 3 deaths occurred in the low NT-proBNP-low CRP group, 7 deaths occurred in the low NT-proBNP-high CRP group, 14 occurred in the high NT-proBNP-low CRP group, and 30 deaths occurred in the high NT-proBNP-high CRP group. Kaplan-Meier estimates of cardiovascular mortality were: 1.5%, 6.0%, 9.5% and 17.7%, respectively (OR 12.6, 95% CI 5.0-31.7; P<.001, for high NT-proBNP-high CRP vs low NT-proBNP-low CRP).
Results of Multivariable Analysis
Cox proportional hazards model was used to identify the independent correlates of all-cause and cardiovascular mortality (see Methods for variables entered into the model). The combination NT-proBNP–CRP was categorized into 4 categories from 1 (low-NT-proBNP-low CRP) to 4 (high NT-proBNP–high CRP). Independent correlates of all-cause mortality were: combined NT-proBNP-CRP marker (hazard ratio [HR] 4.3, 95% CI, 2.0-9.3; P<.001 for high NT-proBNP-high CRP vs low NT-proBNP-low CRP), age (HR 2.8, 95% CI, 1.8-4.3; P<.001 calculated for a 10-year increase in age) and NYHA class (HR 1.7, 95% CI, 1.1-2.8, P=.031, for NYHA class II vs NYHA class I). Female sex (HR 0.5, 95% CI, 0.3-1.0; P=.053) and left ventricular ejection fraction (HR 1.18, 95% CI, 0.99-1.41, P=.073, calculated for a 10% reduction) were close to reaching statistical significance as independent predictors of all-cause mortality.
Cox proportional hazards model showed that independent correlates of cardiovascular mortality were: combined NT-proBNP-CRP marker (HR 3.9, 95% CI, 1.4-10.5; P<.001 for high NT-proBNP-high CRP vs. low NT-proBNP-low CRP), age (HR 2.8, 95% CI, 1.6-5.0; P<.001, calculated for a 10-year increase), diabetes (HR 1.84, 95% CI, 1.02-3.31; P=.043), left ventricular ejection fraction (HR 1.28, 95% CI, 1.03-1.59; P=.037 calculated for a 10% decrease), and serum creatinine (HR 1.02, 95% CI, 1.01-1.04; P=.040 calculated for a 0.2 mg/dL increase in concentration). Female sex (HR 0.45, 95% CI, 0.19-1.05; P=.064) was close to reaching statistical significance as independent correlate of cardiovascular mortality in this cohort.
Discussion
Recent studies have demonstrated that elevated levels of CRP
Production of C-reactive protein and risk of coronary events in stable and unstable angina. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group.
in patients with stable coronary heart disease provide prognostic information regarding mortality and other major adverse events. To test the hypothesis that combined use of these biomarkers improves risk stratification in patients with stable coronary heart disease, we used a large cohort of well-characterized patients with stable coronary heart disease who underwent an up-to-date invasive (coronary stenting) and medical (chronic) treatment. In contrast to combination approaches that compare patients in top quartiles of biomarkers with those in bottom quartiles of biomarkers, we used a combination approach based on binary cutoff point analysis (median) that allowed categorization of all patients according to elevated levels of none, one, or both biomarkers. This prevented loss of quantitative information. Finally, our cohort of patients was followed for a relatively long follow-up so that our study would provide long-term prognostic information.
The approach of combined use of both biomarkers performed better than either biomarker alone, regarding all-cause and cardiovascular mortality prediction. During a median follow-up of 3.6 years, patients in the low NT-proBNP-low CRP group showed a very low all-cause and cardiovascular mortality. Elevation in the circulating levels of either NT-proBNP or CRP was associated with significant increases in mortality, compared with the group of patients with the low concentration of both biomarkers. On the other hand, as univariate and multivariable analysis showed, the risk of death was significantly higher in the group of patients with elevated levels of NT-proBNP and CRP at the time of coronary intervention, compared with patients with low levels of both biomarkers. Additionally, as survival analysis curves demonstrated, isolated elevation of NT-proBNP levels was a better predictor of mortality than isolated elevation of CRP concentration. This finding is supported by a recent study in which NT-proBNP outperformed CRP as a biomarker for cardiovascular disease and death in elderly nonhospitalized individuals.
N-terminal pro-brain natriuretic peptide, C-reactive protein, and urinary albumin levels as predictors of mortality and cardiovascular events in older adults.
In our study, however, CRP remained an independent correlate of mortality, even when NT-proBNP was included in the multivariable model. This finding is at variance with two recent studies in patients with coronary artery disease, which showed that independent predictivity of CRP was abolished when tested in the multivariable model together with NT-proBNP.
Plasma N-terminal pro-B-type natriuretic peptide for prediction of death or nonfatal myocardial infarction following percutaneous coronary intervention.
Analysis of N-terminal-pro-brain natriuretic peptide and C-reactive protein for risk stratification in stable and unstable coronary artery disease results from the AtheroGene study.
Although the exact reasons for these discrepancies are unknown, differences between our study and these studies regarding the patients’ characteristics, the length of follow-up, and the end points might provide some explanation. Furthermore, a recent study by Miller et al showed that elevated CRP levels in the general population do not provide incremental prognostic information than that attributable to traditional coronary artery disease risk factors.
High attributable risk of elevated C-reactive protein level to conventional coronary heart disease risk factors the Third National Health and Nutrition Examination Survey.
Our study, however, included patients with clinically stable and angiographically proven CAD in whom the prognostic information provided by elevated CRP levels may differ fundamentally as compared with the prognostic power of this biomarker in the general population.
With regard to the future prediction of myocardial infarction, our study has demonstrated that elevated levels of CRP alone predicted the occurrence of myocardial infarction compared with patients with low levels of both biomarkers; combination with elevated levels of NT-proBNP provided no additive value with respect to myocardial infarction prediction in this cohort of patients with stable coronary heart disease. Inability of NT-proBNP to predict future development of myocardial infarction has been reported in other studies.
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.
This may reflect the fact that BNP (and consequently NT-proBNP) is a regulatory hormone with no direct role in the atherosclerotic plaque rupture and thrombus formation. On the other hand, increased levels of either NT-proBNP or CRP or of both biomarkers did not predict future occurrence of restenosis or the need for target vessel revascularization after coronary stenting. These findings coincide with a recent study by Dibra et al, which showed that increased levels of CRP predict the combined end point of death or myocardial infarction but not restenosis in patients with stable chronic angina.
A recent study by our group also demonstrated that increased levels of NT-proBNP do not predict in-stent restenosis in patients with chronic stable angina.
The increase in the prognostic information provided by combined use of NT-proBNP and CRP in patients with stable coronary heart disease, as evidenced in this study, may be related to the nature of information contained in each of these biomarkers. It is widely accepted that inflammation plays a central role in atherosclerosis and its complications.
Several studies have shown that elevated levels of serum CRP are associated with a heightened risk of future cardiovascular events in patients with and without evidence of coronary heart disease.
Relationship of C-reactive protein to risk of cardiovascular disease in the elderly. Results from the Cardiovascular Health Study and the Rural Health Promotion Project.
C-reactive protein is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromes: a TIMI 11A substudy. Thrombolysis in Myocardial Infarction.
Apart from reflecting the degree of systemic inflammation, CRP also may have a direct role in atherosclerotic plaque rupture and thrombosis with ensuing clinical complications.
Rapid transcriptional activation and early mRNA turnover of brain natriuretic peptide in cardiocyte hypertrophy. Evidence for brain natriuretic peptide as an “emergency” cardiac hormone against ventricular overload.
Experimental studies have demonstrated that ischemia per se increases the circulating levels of brain type natriuretic peptide by the increase in the ventricular stress that activates natriuretic peptide secretion through a variety of molecular mechanisms.
Increased secretion of atrial and brain natriuretic peptides during acute myocardial ischaemia induced by dynamic exercise in patients with angina pectoris.
and that patients with elevated levels of BNP had inducible ischemia, suggesting that increased levels of BNP may predict subsequent coronary events and increased risk of death.
Association of elevated B-type natriuretic peptide levels with angiographic findings among patients with unstable angina and non–ST-segment elevation myocardial infarction.
Plasma levels of N-terminal pro-brain natriuretic peptide in patients with coronary artery disease and relation to clinical presentation, angiographic severity, and left ventricular ejection fraction.
Findings of these studies clearly show that NT-proBNP is a marker of increased homodynamic stress on the left ventricle, as well as of myocardial ischemia. In this setting, combined use of NT-proBNP and CRP provides complementary, rather than overlapping, information that enhances the prediction of increased risk of death in patients with stable coronary heart disease. The fact that our study did not find any correlation between NT-proBNP and CRP further strengthens the assumption that they represent different tools to investigate different aspects of cardiovascular risk.
In conclusion, the present study showed that combined use of N-terminal probrain natriuretic peptide and C-reactive protein improves long-term risk prediction for mortality in patients with stable coronary heart disease.
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Kannel W.B.
Feinleib M.
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Association of elevated B-type natriuretic peptide levels with angiographic findings among patients with unstable angina and non–ST-segment elevation myocardial infarction.
Plasma levels of N-terminal pro-brain natriuretic peptide in patients with coronary artery disease and relation to clinical presentation, angiographic severity, and left ventricular ejection fraction.
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