1. health and fitness
2. disease

ORIGINAL INVESTIGATION
Comparison of N-Terminal Pro–B-Natriuretic
Peptide, C-Reactive Protein, and Creatinine
Clearance for Prognosis in Patients
With Known Coronary Heart Disease
Dietrich Rothenbacher, MD, MPH; Wolfgang Koenig, MD; Hermann Brenner, MD, MPH
Background: The purpose of this study was to investigate the prognostic role of N-terminal pro–Bnatriuretic peptide (NT-proBNP) serum level compared
with C-reactive protein (CRP) level and creatinine clearance (CrCl) for the subsequent risk of cardiovascular
events in a large cohort of patients with stable coronary
heart disease (CHD).
Methods: Serum concentrations of NT-proBNP and CRP
and CrCl were measured at baseline in a cohort of 1051
patients aged 30 to 70 years with CHD. The Cox proportional hazards model was used to determine the prognostic value of NT-proBNP, CRP, and CrCl on a combined cardiovascular disease (CVD) end point (fatal and
nonfatal myocardial infarction and stroke).
Results: During follow-up (mean of 48.7 months), 95
patients (9.0%) experienced a secondary CVD event. Patients in the top quartile of the NT-proBNP distribution
at baseline had a hazard ratio (HR) of 3.34 (95% confidence interval [CI], 1.74-6.45) for subsequent second-
P
ary CVD events compared with those in the bottom quartile (P for trend ⬍.001) after controlling for age, sex,
smoking status, history of diabetes mellitus, initial management of CHD, rehabilitation clinic, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and treatment with lipid-lowering drugs. For CRP,
the corresponding HR was 1.76 (95% CI, 0.96-3.24) (P
value for trend, .06). Patients with CrCl levels lower than
60 mL/min had an HR of 2.39 (95% CI, 1.06-5.40) compared with patients with a CrCl of 90 mL/min or higher
(P for trend, .002). If all 3 markers were included simultaneously in 1 model, NT-proBNP still showed predictive ability for recurrent CVD events.
Conclusion: N-terminal proBNP may be a clinically useful marker weeks after an acute coronary event and may
provide complementary prognostic information to established risk determinants.
Arch Intern Med. 2006;166:2455-2460
REVALENCE OF CORONARY
heart disease (CHD) will increase within the next years,
and CHD will be the number 1 cause of disability and
death by the year 2020 worldwide.1 Therefore, beside new avenues and concepts of
primary prevention, improved secondary
preventive strategies of CHD are necessary to reduce the burden of disease and
recurrent complications for the individual as well as for society.
Author Affiliations:
Department of Clinical
Epidemiology and Aging
Research, German Cancer
Research Center, Heidelberg,
Germany (Drs Rothenbacher
and Brenner); and Department
of Internal Medicine
II–Cardiology, University
of Ulm Medical Center, Ulm,
Germany (Dr Koenig).
CME course available at
www.archinternmed.com
The use of biological markers for diagnostic purposes and risk stratification represents one promising area in cardiology.
Meanwhile convincing evidence suggests that CHD is an inflammatory process, and a variety of inflammatory markers such as C-reactive protein (CRP) may
(REPRINTED) ARCH INTERN MED/ VOL 166, DEC 11/25, 2006
2455
play a role in disease risk assessment.2 In
addition, renal impairment is also an independent risk factor for CHD.3
B-type natriuretic peptide (BNP) and
the N-amino terminal (NT)-proBNP (the
latter with a much longer half-life than
For editorial comment
see page 2428
BNP4) have been initially introduced as
markers to aid in the diagnosis of congestive heart failure (CHF), to estimate the
severity of cardiac dysfunction, and to
guide the management and adjustment of
pharmacotherapy. 4-7 In addition, evidence is accumulating that raised BNP and
NT-proBNP plasma/serum levels are of
prognostic value because they are independently associated with adverse prognosis in several cardiac disorders, including CHF and acute CHD,5,8,9 and they may
allow identifying subjects at risk for ad-
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verse cardiovascular disease (CVD) events to tailor
therapy.10 Recent studies also demonstrated their prognostic value in predicting all-cause mortality in patients
with prevalent CHD.11-13 Whether elevated NT-proBNP
serum levels in patients with CHD reflect a specific pathomechanism of cardiac disease, which is independent
from other basic concepts of atherogenesis such as vascular inflammation and renal disease, is under debate.
In the present study, we investigated the prognostic
role of NT-proBNP serum levels for the subsequent risk
of cardiovascular events in a large cohort of patients with
stable CHD weeks after the first clinical manifestation or
diagnosis, after controlling for potential confounders, and
compared it with the prognostic value of a serum marker
of systemic inflammation (CRP) and renal function (creatinine clearance [CrCl]).
METHODS
Information on left ventricular function (LVF) was derived
from (1) the most recent left ventricular cineangiography (available in 680 patients [67%]) or (2) from echocardiographic study
when available (available in 821 patients [78%]). This way, LVF
could be assessed in 964 patients (91.7%). Data on LVF were
collected from patients’ medical charts and were documented on
a 4-point semiquantitative scale as normal (ejection fraction [EF],
⬎65%), as mild depression (EF, 50%-65%), moderate depression (EF, 35%-50%), or severe depression (EF, ⬍35%).
In all patients, active follow-up was conducted 1, 3, and 4.5
years after discharge from the rehabilitation center. Information regarding secondary cardiovascular events and treatment
since discharge was obtained from the primary care physician
by means of a standardized questionnaire. If a patient had died
during follow-up, the death certificate was obtained from the
local public health department, and the main cause of death
was coded according to the ICD-9. Secondary cardiovascular
events were defined either as CVD as the main cause of death
(as stated in the death certificate), nonfatal myocardial infarction (MI), or ischemic stroke. All nonfatal secondary events were
reported by the primary care physicians.
STUDY POPULATION
All patients with CHD (International Classification of Diseases,
Ninth Revision [ICD-9] codes 410-414) aged 30 to 70 years and
participating in an in-hospital rehabilitation program between
January 1999 and May 2000 in 2 cooperating clinics (Schwabenland-Klinik, Isny, and Klinik am Su¨dpark, Bad Nauheim, Germany) were enrolled in the study, and clinically relevant CHD
was defined by a greater than 50% diameter stenosis of 1 or more
major epicardial coronary arteries. In Germany, every post–
acute coronary syndrome patient by law has the right to receive
institutionalized cardiac rehabilitation in a specialized center,
which is used by most patients. This in-hospital rehabilitation
program after acute coronary syndrome usually begins within
the first weeks after discharge from the acute care hospital. Although we recruited patients only in 2 such in-patient rehabilitation centers (one in the south of Germany and the other in the
middle of Germany), these specialized centers serve a large geographic area with a radius of up to 200 km, and therefore, patients were referred from a large number of different acute care
hospitals. In the present study, only patients who were admitted within 3 months after the acute event or coronary artery bypass grafting (CABG) were included. Of all eligible patients, 58%
agreed to participate. The mean interval from the acute event to
recruitment was 43 days (interquartile range, 36-51 days).
All subjects gave written informed consent. The study was
approved by the ethics boards of the Universities of Ulm and
Heidelberg and of the physicians’ chamber of the States of BadenWu¨rttemberg and Hessen (Germany).
DATA COLLECTION
At the beginning of the in-hospital rehabilitation program, all
participants filled out a standardized questionnaire containing sociodemographic information and medical history. In addition, information was taken from the patients’ hospital medical charts, which also included information from the acute care
hospital. From all patients, a 12-lead electrocardiogram (ECG)
was recorded at the beginning of the rehabilitation and evaluated according to a standardized protocol by a trained investigator. Intrarater (interrater) reliability was determined in 100
randomly chosen ECGs by a blinded second rating from the
same investigator 4 weeks later and from an independent second investigator. The ␬ coefficients were 1 (0.88) for sinus tachycardia (⬎100/min), 0.85 (1.0) for atrial flutter or fibrillation,
and 0.96 (0.73) for infarction location.
LABORATORY ANALYSIS
Blood was drawn at baseline at the end of the rehabilitation phase
in a fasting state under standardized conditions and stored at
−80°C until analysis. N-terminal proBNP was measured from
plasma by means of a 1-step enzyme immunoassay based on
electrochemiluminescence (Elecsys; Roche Diagnostics,
Mannheim, Germany). The interassay coefficient was between
3.1% and 7.2%. C-reactive protein was determined by a highsensitivity assay (N Latex CRP mono; Dade Behring, Marburg). For measurement of creatinine, in one hospital the conventional kinetic Jaffe method (interassay coefficient of variation,
2.4%-5.7%) was used, whereas in the other hospital measurement was done by an enzymatic creatinine p-aminophenazone
method (interassay coefficient of variation, 1.2%-2.2%). Creatinine clearance was calculated according the CockcroftGault formula.14 Serum lipid measurements were performed by
routine methods in both participating clinics. All markers were
measured in a blinded fashion.
STATISTICAL ANALYSIS
Median levels of NT-proBNP were calculated according to levels of various sociodemographic characteristics, various cardiovascular risk factors, and levels of ECG findings. Associations of these factors with the NT-proBNP distribution were
tested for statistical significance by the nonparametric KruskalWallis test. A (partial) Spearman rank correlation coefficient
between NT-proBNP, CRP, and CrCl was calculated after adjustment for age and sex.
The relation of NT-proBNP, CRP, and CrCl levels with CVD
events during follow-up was assessed by the Kaplan-Meier
method. The Cox proportional hazards model was used to assess the independent association of NT-proBNP distribution with
the risk of secondary CVD events. Besides a model adjusting
for age and sex, the following potential confounders were considered in multivariable analyses: age, sex, body mass index (BMI
[calculated as weight in kilograms divided by height in meters
squared]), smoking status, duration of school education, family status, history of MI, history of hypertension, history of diabetes mellitus, severity of CHD , intake of ␤-blockers, intake
of angiotensin-converting enzyme inhibitors, intake of diuretics, intake of lipid-lowering drugs, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, atrial flutter or fibrillation, left ventricular hypertrophy, anterior infarction location,
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posterior infarction location, and hospital site. To avoid overadjustment, the latter covariates were added only if they were significant predictors of a secondary event at an ␣ level of .10 or if
their inclusion changed the parameter estimates for the main variables (NT-proBNP) by more than 10%.
To compare their prognostic value with that of NTproBNP, CRP and CrCl levels were included instead of NTproBNP in additional analyses in the adjusted model (model
2), and, finally, NT-proBNP, CRP, and CrCl categories were
included simultaneously (model 3). Finally, hazard ratios (HRs)
were additionally adjusted for LVF (no or only little impairment, modest or severe impairment) (model 4).
A receiver operating curve was constructed after adjustment for covariates, and the area under the curve with its 95%
confidence interval (CI) was calculated. In addition, Somers
D, a measure of association that provides a rank correlation between predicted and observed probabilities, was calculated for
the various models. Somers D ranges between −1 and ⫹1; 0
reflects no association at all. All statistical procedures were carried out with the SAS statistical software package (release 8.2
[1999]; SAS Institute Inc, Cary, NC ).
Table 1. N-Terminal Pro–B-Natriuretic Peptide (NT-proBNP)
Distribution According to Various Variables
Variable
P
Value*
(continued)
Table 2 gives the results of multivariable analysis. Compared with patients in the bottom quartile of the NTproBNP distribution at baseline, patients in the top quartile had an HR of 3.34 (95% CI, 1.74-6.45) for a CVD event
during follow-up after adjustment for multiple covariates
(P for trend, ⬍.001). The respective HR for CRP was 1.76
(95% CI, 0.96-3.24) (P for trend, .06). Compared with patients with a CrCl of 90 mL/min or higher at baseline, patients with a CrCl lower than 60 mL/min had an HR of
2.39 (95% CI, 1.06-5.40) (P for trend, .002) after adjustment for multiple covariates.
If all 3 markers were considered simultaneously and adjustment was done for potential confounders, NTproBNP level showed by far the strongest association with
secondary CVD events. Results were similar if all 3 markers were included as continuous variables. If the final model
was controlled for LVF, the HR decreased; however, NTproBNP values were still strong predictors of CVD events.
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NT-proBNP
Distribution
Median
Sociodemographic Characteristics and Cardiovascular Risk Factors
All
1051 568.4 (IQR,
278.3-1101.0)
Sex
Female
159
666.4
.005
Male
892
543.9
Age, y
30-39
23
185.0
40-49
127
372.0
⬍.001
50-59
307
408.7
60-70
594
689.2
School education, y
⬍10
627
551.7
.59
ⱖ10
424
584.5
Family status
Married
876
543.9
.04
Other
175
729.8
BMI
⬍25
296
653.1
25-30
565
542.8
⬍.001
⬎30
189
508.6
Smoking status
Never
335
620.6
Former
665
541.4
.22
Current
51
666.2
History of diabetes
Yes
180
669.7
.001
No
871
546.9
History of MI
Yes
612
621.7
⬍.001
No
439
502.4
History of hypertension
Yes
585
642.7
.002
No
466
478.5
Angiographic score, No. of affected
vessels
0/1
272
381.9
2
280
529.3
⬍.001
3
449
712.0
RESULTS
Overall, 1206 patients with a diagnosis of CHD within the
past 3 months were included at baseline during the inhospital rehabilitation program. Four-year follow-up information was complete for 1051 patients (87.2%).
Table 1 gives the distribution (median) of NTproBNP values according to various sociodemographic factors, cardiovascular risk factors, and ECG findings. Women
and patients in the older age groups had statistically significantly higher NT-proBNP values, as did those with a
BMI less than 25, patients with a history of diabetes, MI,
and hypertension, those with a high angiography score,
those who underwent CABG, and those with impaired LVF.
As determined from 12-lead routine ECG, subjects with
atrial flutter or fibrillation, signs of left ventricular hypertrophy, ECG signs of anterior infarction location and,
to a lesser degree, ECG signs of posterior infarction location also had higher NT-proBNP serum concentrations compared with patients without these findings.
Spearman rank correlation coefficient (r) was r=0.22
(P⬍.001) between NT-proBNP and CRP and r = −0.24
(P⬍.001) between NT-proBNP and CrCl. C-reactive protein and CrCl were not correlated with each other in a
statistically significant way.
During follow-up (mean [SD], 48.7 [15.9] months)
95 patients (9.0%) experienced a secondary CVD event.
Thirty patients (2.9%) died from CVD, 35 patients (3.3%)
had a nonfatal MI, and in 30 patients (2.9%), a stroke
was diagnosed.
Of patients in the top quartile of the NT-proBNP distribution, 16.5% experienced an event compared with
4.5%, 4.7%, and 9.1% in the first, second, and third quartile, respectively (P⬍.001) (Figure). Of patients in the
top quartile of the CRP distribution,12.6% experienced
an event compared with 7.6%, 7.2%, and 8.7% in the first,
second, and third quartile, respectively (P = .09). Of patients with a CrCl lower than 60 mL /min,13.6% experienced an event compared with 6.7% and 11.7% in the
categories of 90 mL /min or higher and 60 to lower than
90 mL/min, respectively (P = .002).
No. of
Patients
Table 1. N-Terminal Pro–B-Natriuretic Peptide (NT-proBNP)
Distribution According to Various Variables (cont)
No. of
Patients
Variable
NT-proBNP
Distribution
Median
Quartile
Proportion of Event-Free Survivors
Sociodemographic Characteristics and Cardiovascular Risk Factors
Initial management of CHD
Conservative
191
558.9
PCI
361
474.0
⬍.001
CABG
499
647.6
LVF, degree of impairment
No/only little
750
464.4
Modest/severe
214
1228.0
⬍.001
Unknown
87
416.3
Electrocardiographic Characteristics
Sinus tachycardia
Yes
No
Atrial flutter or fibrillation
Yes
No
Left ventricular hypertrophy
Yes
No
Anterior infarction location
Yes
No
Posterior infarction location
Yes
No
48
1003
723.1
568.4
NT-proBNP, ng/mL
1
2
3
4
P
Value*
≤278.3 (Bottom Quartile)
>278.3 ≤568.4
>568.4 ≤1101
>1101 (Top Quartile)
Fatal and Nonfatal
CVD Event During P Value
(Log-Rank
Follow-up,
No. (%)
Test)
No. (Row %)
of Patients
263 (25)
263 (25)
264 (25)
261 (25)
13 (4.5)
15 (4.7)
24 (9.1)
43 (16.5)
<.001
1.00
0.95
0.90
0.85
0.80
0.75
0.70
.07
0
250
500
750
1000
1250
1500
1750
2000
2250
Days
29
1022
1354.0
554.1
⬍.001
28
986
889.2
550.6
.005
211
840
993.5
504.1
⬍.001
223
828
653.0
542.0
.004
Abbreviations: BMI, body mass index (calculated as weight in kilograms
divided by height in meters squared); CABG, coronary artery bypass grafting;
CHD, coronary heart disease; IQR, interquartile range; LVF, left ventricular
function; PCI, percutaneous coronary intervention.
*Kruskal-Wallis test.
Finally, in Table 3 we quantified the incremental contribution of all 3 markers to risk prediction in the presence of classic risk factors. According to receiver operating curve analyses, the addition of NT-proBNP to the
basic model improved the predictive accuracy of the model
(area under the curve from 0.69 to 0.71) more than inclusion of CRP and CrCl; it did not improve further if
all 3 variables were included simultaneously.
Figure. Distribution of N-terminal pro–B-natriuretic peptide (NT-proBNP) in
quartiles and proportion of patients (N = 1051) without secondary fatal and
nonfatal cardiovascular disease (CVD) events during follow-up.
It has been reported that in patients with acute MI, plasma
levels of NT-proBNP could be divided in 2 phases: the first
peak appearing days after the acute event as an acutephase response to the injured tissue5,15 and the second peak
appearing weeks thereafter as a result of impaired LVF.5
All subjects in the present study were included weeks
after the acute manifestation of CHD or CABG procedure and were in a clinically stable condition. Higher values were seen in women and in older subjects as described by others.16 We found indicators of the severity
of CHD (number of affected epicardial vessels) positively associated with NT-proBNP levels. Furthermore,
patients with a history of MI or diabetes, various ECG
findings such as atrial flutter or fibrillation, and signs of
anterior or posterior infarction had higher NT-proBNP
levels. The latter might be related to previous myocardial damage in response to ischemia, which most likely
leads to elevated left ventricular diastolic filling pressure and in consequence, to the secretion of BNP.
COMMENT
PROGNOSTIC VALUE OF NT-proBNP,
CRP, AND CrCl
This prospective cohort study including 1051 patients aged
30 to 70 years with stable CHD at baseline demonstrates
that increased NT-proBNP levels are strongly and independently associated with secondary CVD events and show
a superior predictive utility when directly compared with
markers of renal function and inflammation. Notably, the
relationship persisted after adjustment for LVF.
DETERMINANTS OF NT-proBNP PLASMA LEVELS
B-type natriuretic peptide is a hormone that is produced
and secreted mainly from ventricular cardiomyocytes as
a response to an increased wall stress and has biological
effects that counterbalance the effects of the reninangiotensin and the sympathetic nervous system.7 Compared with BNP, NT-proBNP has a much longer half-life.
Despite adjusting for several potential confounding factors, the prognostic value of NT-proBNP concentrations
was still statistically significant. It remained so even after
adjustment for CRP and CrCl levels, both relevant markers associated with secondary cardiovascular events in patients with CHD.2,3 A recent study in patients with acute
coronary syndromes showed that NT-proBNP added prognostic information to measures of inflammation and renal impairment for subsequent mortality.17 The fact that
the prognostic information of NT-proBNP level was still
evident if controlled for LVF at baseline suggests that additional prognostic information (besides the ones related
to CHF or left ventricular hypertrophy) might play a role.
This is supported by a recent population-based study including 3346 middle-aged subjects without CHF, in whom
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Table 2. N-Terminal Pro–B-Natriuretic Peptide (NT-proBNP), Creatinine Clearance (CrCl), and CRP at Baseline and Association
With Fatal and Nonfatal Cardiovascular Events During Follow-Up: Results of Multivariate Analyses*
Measure
NT-proBNP, ng/mL
ⱕ278.3 (bottom quartile)
⬎278.3 to ⱕ564.7
⬎564.7 to ⱕ1097
⬎1097 (top quartile)
P for trend
CRP, mg/L
ⱕ1.24 (bottom quartile)
⬎1.24 to ⱕ 3.51
⬎3.51 to ⱕ 8.61
⬎8.61 (top quartile)
P value for trend
CrCl, mL/min
ⱖ90
60 to ⬍90
⬍60
P for trend
Model 1
Model 2
Model 3
Model 4
1.00
1.07 (0.51-2.26)
1.78 (0.89-3.55)
3.33 (1.74-6.35)
⬍.001
1.00
1.04 (0.49-2.22)
1.73 (0.86-3.49)
3.34 (1.74-6.45)
⬍.001
1.00
1.04 (0.49-2.23)
1.64 (0.81-3.33)
2.89 (1.44-5.65)
⬍.001
1.00
0.99 (0.46-2.13)
1.49 (0.73-3.04)
2.35 (1.14-4.88)
.007
1.00
0.93 (0.49-1.74)
1.06 (0.58-1.94)
1.60 (0.91-2.83)
.08
1.00
0.99 (0.53-1.88)
1.08 (0.58-2.01)
1.76 (0.96-3.24)
.06
1.00
0.90 (0.47-1.70)
0.90 (0.48-1.70)
1.35 (0.72-2.53)
.30
1.00
0.88 (0.46-1.67)
0.87 (0.46-1.65)
1.29 (0.69-2.43)
.38
1.00
1.59 (1.01-2.51)
1.79 (0.81-3.93)
.03
1.00
2.23 (1.36-3.64)
2.39 (1.06-5.40)
.002
1.00
1.75 (1.07-2.85)
1.34 (0.58-3.12)
.09
1.00
1.76 (1.08-2.88)
1.39 (0.59-3.23)
.09
Abbreviations: CI, confidence interval; CRP, C-reactive protein.
*Data are given as hazard ratio (95% confidence interval) unless otherwise specified. Model 1 was adjusted for age and sex; model 2, for age, sex, smoking
status, history of diabetes mellitus, initial management of coronary heart disease (conservative, percutaneous coronary intervention, and coronary artery bypass
grafting), rehabilitation clinic, high-density lipoprotein cholesterol level, low-density lipoprotein cholesterol level, and treatment with lipid-lowering drugs
(according to variable selection criteria); model 3 for variables in model 2 plus NT-proBNP, CRP, and CrCl simultaneously in 1 model; and model 4, for variables in
model 3 plus left ventricular ejection fraction.
plasma natriuretic peptide levels were of prognostic relevance for subsequent atrial fibrillation, stroke, and allcause mortality.18 Notably, in the latter study the prognostic value was already evident at relatively low levels,
which are usually not related to CHF.
Our findings extend those of a recent report in which
NT-proBNP in 1034 patients with CHD provided prognostic information on all-cause mortality independent of
LVF.11 Our data show that especially the risk for secondary CVD events is increased in patients with CHD and high
NT-proBNP levels, and therefore NT-proBNP measurement may be useful for better risk stratification in patients with manifest CHD, suggesting a possible shift in
emphasis from CRP level to natriuretic peptide levels in
the future. The independence of NT-proBNP level from
CRP level in relation to future cardiovascular events has
also been suggested in a recent analysis including 570 patients with stable CHD.12 In a substudy from the Heart Outcomes Prevention Evaluation (HOPE) trial, only the inclusion of NT-proBNP improved the predictive ability by
increasing the area under the curve, whereas various inflammatory markers did not, although they all showed a
statistically significant association with a combined CVD
end point.19 Although CRP levels were associated tentatively with CVD events in our study, they did not significantly predict secondary CVD events. This finding is in
accordance with recent observations by Danesh et al20 and
Campbell et al.21 C-reactive protein level may be a better
predictor in primary prevention and younger subjects.
Whereas other studies reporting on the association between inflammatory markers and study end points represent highly selected populations from randomized clinical trials,22,23 our study consisted of “everyday” patients
from 1 large geographic area; for example, the Aggrastatto-Zocor (A-to-Z) Trial was conducted internationally,
Table 3. Predictive Accuracy of Various Multivariate Models
as Measured by an Increase in the Area Under the Receiver
Operating Characteristic Curve (AUROC) and Somers D
Model Adjusted for
(1) Age, sex, smoking status, history of
DM, initial management of CHD,
rehabilitation clinic, HDL-C, LDL-C, and
treatment with lipid-lowering drugs
(2) Factors in (1) plus NT-proBNP
(3) Factors in (1) plus CRP
(4) Factors in (1) plus CrCl
(5) All factors
Somers
D
0.69 (0.63-0.75)
0.38
0.71 (0.66-0.77)
0.69 (0.63-0.75)
0.70 (0.64-0.75)
0.71 (0.65-0.77)
0.42
0.38
0.39
0.42
Abbreviations: CHD, coronary heart disease; CI, confidence interval; CrCl,
creatinine clearance; CRP, C-reactive protein; DM, diabetes mellitus; HDL-C,
high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein
cholesterol; NT-proBNP, N-terminal pro–B-natriuretic peptide.
and subjects originated from over 40 different countries
and had a special risk profile at baseline (mean CRP level,
20 mg/L; current smokers, approximately 40%).23
B-type natriuretic peptide synthesis occurs in the necrotic as well as in the healthy myocardium.24 Furthermore, BNP levels were shown to increase after exercise
testing in patients with stable CHD, and levels reflected
the size of the ischemic territory.25 In 112 patients undergoing exercise testing, it was demonstrated that transient ischemia may result in an immediate rise in BNP
level and, to a lesser degree, in NT-proBNP levels.26 The
elevation of NT-proBNP level in patients with CHD may
be a result of a recurrent MI even if necrosis has not occurred10,27; however, in the context of our study, it is difficult to separate ischemia from impaired LVF.
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AUROC
(95% CI)
STUDY LIMITATIONS
The following limitations of our study should be considered. Although we had a large sample of patients with CHD,
fatal CVD events were rare in this population. This is explained by the fact that case fatality is highest before hospitalization and during the early in-hospital phase. Furthermore, we could successfully follow up 87.2% of the
patients; patients lost to follow-up were in general younger
and had lower BMI, NT-proBNP, and CRP values.
Not all patients were willing or able to participate in an
in-hospital rehabilitation program. This may be a further
reason for the slight underrepresentation of more severely
ill patients in our sample, but on the other side, almost half
of the patients had extensive (3 vessel) disease. Underrepresentation of severely ill patients does not adequately explain the positive findings between NT-proBNP serum concentration and CVD events but suggests that the true
prognostic value of this marker may even be stronger than
shown in our study. Information of global LVF was available for most patients; however, when this semiquantitative assessment was compared with quantitative ejection
fraction (available for 471 patients) derived from left ventricular cineangiograms, excellent agreement was found
(mean ejection fraction in semiquantitative global LVF categories: normal, 69.6%; mild depression, 54.9%; moderate depression, 44.1%; and severe depression, 30.0%).
In conclusion, despite these limitations, our data are
in support of an important prognostic value of NTproBNP among patients with known CHD and suggest that
NT-proBNP level is a useful prognostic marker that provides complementary information to markers of inflammation and renal function and to other established risk
determinants.
Accepted for Publication: August 30, 2006.
Correspondence: Wolfgang Koenig, MD, Department of
Internal Medicine II–Cardiology, University of Ulm Medical Center, Robert-Koch Str 8, D-89081 Ulm, Germany
(wolfgang.koenig@uniklinik-ulm.de).
Author Contributions: Dr Rothenbacher had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the
data analysis. Study concept and design: Rothenbacher and
Brenner. Acquisition of data: Rothenbacher, Koenig, and
Brenner. Analysis and interpretation of data: Rothenbacher and Koenig. Drafting of the manuscript: Rothenbacher. Critical revision of the manuscript for important
intellectual content: Koenig and Brenner. Statistical analysis: Rothenbacher and Brenner. Obtained funding: Rothenbacher, Koenig, and Brenner. Administrative, technical,
and material support: Rothenbacher and Brenner. Study
supervision: Rothenbacher and Brenner.
Financial Disclosure: None reported.
Acknowledgment: We highly appreciate the excellent
technical assistance of Gerlinde Trischler. We thank
Roche, Mannheim (Germany), for providing the NTproBNP reagents.
REFERENCES
1. Murray CJ, Lopez AD. Mortality by cause for eight regions of the world: Global
Burden of Diseases Study. Lancet. 1997;349:1269-1276.
2. Rosenson RS, Koenig W. High-sensitivity C-reactive protein and cardiovascular
risk in patients with coronary heart disease. Curr Opin Cardiol. 2002;17:325-331.
3. Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for
development of cardiovascular disease. Circulation. 2003;108:2154-2169.
4. Smith MW, Espiner EQ, Yandle TG, Charles CJ, Richards AM. Delayed metabolism of human brain natriuretic peptide reflects resistance to neural endopeptidase.
J Endocrinol. 2000;167:239-246.
5. Morita E, Yasue H, Yoshimura M, et al. Increased plasma levels of brain natriuretic peptide in patients with acute myocardial infarction. Circulation. 1993;
88:82-91.
6. de Lemos JA, Morrow DA, Bentley JH, et al. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med. 2001;
345:1014-1021.
7. Hobbs FDR, Davis RC, Roalfe AK, Hare R, Davies MK, Kenkre JE. Reliability of
N-terminal pro-brain natriuretic peptide assay in diagnosis of heart failure: cohort study in representative and high risk community populations. BMJ. 2002;
324:1498-1500.
8. Mukoyama M, Nakao K, Obata K, et al. Augmented secretion of brain natriuretic
peptide in acute myocardial infarction. Biochem Biophys Res Commun. 1991;
180:431-436.
9. Morrow DA, de Lemos JA, Blazing MA, et al. Prognostic value of serial B-type
natriuretic peptide testing during follow-up of patients with unstable coronary
artery disease. JAMA. 2005;294:2866-2871.
10. Jernberg T, James S, Lindahl B, et al. Natriuretic peptides in unstable coronary
artery disease. Eur Heart J. 2004;25:1486-1493.
11. Kragelund C, Gronning B, Kober L, Hildebrandt P, Steffensen R. N-terminal proB-type natriuretic peptide and long-term mortality in stable coronary heart disease.
N Engl J Med. 2005;352:666-675.
12. Schnabel R, Rupprecht HJ, Lackner KJ, et al. Analysis of N-terminal-pro-brain
natriuretic peptide and C-reactive protein for risk stratification in stable and unstable coronary artery disease. Eur Heart J. 2005;26:241-249.
13. Ndrepepa G, Braun S, Niemo¨ller K, et al. Prognostic value of N-terminal probrain natriuretic peptide in patients with chronic stable angina. Circulation. 2005;
112:2102-2107.
14. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine.
Nephron. 1976;16:31-41.
15. Kushner I. The phenomenon of the acute phase response. Ann N Y Acad Sci.
1982;389:39-48.
16. Redfield MM, Rodeheffer RJ, Jacobsen SJ, Mahoney DW, Bailey KR, Burnett
JC. Plasma brain natriuretic peptide concentration: impact of age and gender.
J Am Coll Cardiol. 2002;40:976-982.
17. James SK, Lindahl B, Siegbahn A, 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. Circulation.
2003;108:275-281.
18. Wang TJ, Larson MG, Levy D, et al. Plasma natriuretic peptide levels and the
risk of cardiovascular events and death. N Engl J Med. 2004;350:655-663.
19. Blankenberg S, McQueen MJ, Smieja M, et al. Comparative impact of multiple biomarkers and N-terminal pro-brain natriuretic peptide in the context of conventional
risk factors for the prediction of recurrent cardiovascular events in the Heart Outcomes Prevention Evaluation (HOPE) Study. Circulation. 2006;114:201-208.
20. Danesh J, Wheeler JC, Hirschfield GM, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl
J Med. 2004;350:1387-1397.
21. Campbell DJ, Woodward M, Chalmers JP, et al. Prediction of myocardial infarction by N-terminal-pro-B-type natriuretic peptide, C-reactive protein, and rennin
in subjects with cerebrovascular disease. Circulation. 2005;112:110-116.
22. Harb TS, Zareba W, Moss AJ, et al. Association between inflammatory markers,
hemostatic, and lipid factors in postinfarction patients. Am J Cardiol. 2003;
91:1120-1123.
23. Morrow DA, de Lemos JA, Sabatine MS, et al. Clinical relevance of C-reactive
protein during follow-up of patients with acute coronary syndromes in the Aggrastat-to-Zocor Trial. Circulation. 2006;114:281-288.
24. Hama N, Itoh H, Shirakami G, et al. Rapid ventricular induction of brain natriuretic peptide gene expression in experimental acute myocardial infarction.
Circulation. 1995;92:1558-1564.
25. Marumoto K, Hamada M, Hiwada K. Increased secretion of atrial and brain natriuretic peptides during acute myocardial ischaemia induced by dynamic exercise in patients with angina pectoris. Clin Sci. 1995;88:551-556.
26. Sabatine MS, Morrow AD, deLemos JA, et al. Acute changes in circulating natriuretic peptide levels in relation to myocardial ischemia. J Am Coll Cardiol. 2004;
44:1988-1995.
27. Bibbins-Domingo K, Ansari M, Schiller NB, Schiller NB, Massie B, Whooley MA.
B-type natriuretic peptide and ischemia in patients with stable coronary disease:
data from the Heart and Soul study. Circulation. 2003;108:2987-2992.
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