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304 Puri et al. NT-ProBNP as a Predictor in AMI
Indian Heart J 2005; 57: 304–310
N-Terminal ProBrain Natriuretic Peptide as a Predictor of
Short-Term Outcomes in Acute Myocardial Infarction
Aniket Puri, Varun S Narain, Sanjay Mehrotra
, Sudhanshu K Dwivedi, Ram K Saran, Vijay K Puri
Department of Cardiology, King George Medical University, Lucknow
Original Article
Background: Risk stratification and prediction of high risk for mortality in patients with acute coronary
syndromes is based on clinical evaluation, electrocardiogram, biochemical markers and various risk assessment
scores. There is emerging evidence that N-terminal probrain natriuretic peptide possesses several characteristics
of an ideal biomarker. In this study we looked into the role of N-terminal probrain natriuretic peptide in risk
stratification and prediction of short-term events including mortality in patients presenting with acute coronary
syndrome.
Methods and Results: A total of 120 consecutive patients admitted with a diagnosis of acute myocardial
infarction, including both ST elevation myocardial infarction (n=80) and non-ST elevation myocardial infarc-
tion (n=40) were enrolled. Serum N-terminal probrain natriuretic peptide was measured using electro-
chemiluminiscence assay (Roche Diagnostics), on the Elecsys 2010 system. On two-dimentional
echocardiography, modified Simpson’s technique was used to measure the ejection fraction along with end-
systolic volume. Various other demographic variables, echocardiographic parameters and risk scores were also
assessed. Follow-up at day 30 included a two-dimentional echocardiographic evaluation and assessment for
worsening heart failure, recurrent ischemia, and repeat hospitalization. Death due to cardiovascular cause by
30 days was also noted. The mean value of N-terminal probrain natriuretic peptide for the whole cohort was
2307±2287 pg/ml (271.4±269.1 pmol/L). For the purpose of comparative analysis, the median value was
determined [1403 pg/ml (165 pmol/L)]. In patients having N-terminal probrain natriuretic peptide above me-
dian, the end-systolic volume was higher while ejection fraction was significantly lower at baseline (p<0.05).
At 30 days follow-up, there was a further decline in ejection fraction from 47.7±11.4 to 43.9±9.9 (p<0.05),
and clinical outcomes were worse in this group. There was a 5% mortality in the entire study group and all
patients who died had N-terminal probrain natriuretic peptide above median. On multivariate logistic regres-
sion analysis, N-terminal probrain natriuretic peptide above median (OR=32.79, 95% CI 8.74 - 123.1, p<0.001)
emerged as the strongest predictors of adverse outcomes, including 30-day mortality (p<0.001).
Conclusions: N-terminal probrain natriuretic peptide emerged as a strong prognostic tool across the spec-
trum of acute myocardial infarction and had the strongest predictive value for short-term adverse outcomes
including death. (Indian Heart J 2005; 57: 304–310)
Key Words: N-terminal probrain natriuretic peptide, Acute myocardial infarction, Coronary artery disease
Correspondence: Dr Aniket Puri, B-58 Sector A, Mahanagar, Lucknow
226006. e-mail: aniket1@sancharnet.in
R
isk stratification of patients presenting with acute ST
elevation myocardial infarction (STEMI) or non-ST
elevation myocardial infarction (NSTEMI), is fundamental
in determining prognosis and choosing appropriate care.
Currently, risk prediction is based on clinical evaluation,
electrocardiogram (ECG), biochemical markers and various
risk assessment scores. Recently there has been
considerable interest in the measurement of plasma
neurohormones as indicators of left ventricular (LV) dys-
function. There is emerging evidence that these neuro-
hormones, mainly natriuretic peptides possess several
characteristics of an ideal biomarker. Brain natriuretic
peptide (BNP) and its N-terminal fragment (NT-proBNP)
aid in the diagnosis and prognostication of patients with
congestive heart failure (CHF).
1
Evidence is forthcoming
on the correlation of BNP and NT-proBNP levels with LV
dilation, remodeling, ventricular dysfunction, and death
among patients presenting with acute myocardial
infarction (AMI).
2,3
Elevated levels of BNP and NT-proBNP
directly reflect the degree of ventricular dysfunction and
may indicate the extent or severity of the ischemic insult
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Indian Heart J 2005; 57: 304–310
Puri et al. NT-ProBNP as a Predictor in AMI 305
correlating with adverse outcomes. In this study we looked
at the value of NT-proBNP in predicting short-term
outcomes in patients with STEMI and NSTEMI.
Methods
A total of 120 patients admitted to the coronary care unit in
our hospital with AMI, including both STEMI and NSTEMI
were enrolled for the study, from August 2003 to July 2004.
Diagnosis of STEMI was based as per the current ACC/AHA
guidelines, on the presence of ischemic chest pain, ST
elevation
≥
0.1 mv on ECG in more than one lead and
increased markers of myocardial necrosis, namely creatinine
kinase (CK) MB and troponin-T. Diagnosis of NSTEMI was
made for patients
≥
18 years of age admitted with typical
angina within the preceding 24 hours, a positive troponin-
T test (>0.10 ng/ml) along with at least one of the following:
ST segment depression (
≥
0.05 mv), T inversion (
≥
0.1 mv) in
≥
2 leads, or angiographically documented coronary disease
in the past.
4
Patients presenting with a history of renal
failure, chronic heart failure or cardiogenic shock at the time
of entry were excluded from the study. The age, sex, detailed
clinical history including that of diabetes mellitus, smoking,
hypertension, family history of coronary artery disease
(CAD), hospitalization for CAD or ischemic heart disease were
noted. A thorough clinical examination including measuring
the body weight (Wt), pulse rate (PR), systolic blood pressure
(SBP), determination of Killip class and ECG was done. TIMI
risk scores, separate for STEMI,
5
NSTEMI,
6
and the PREDICT
7
score were also assessed. The PREDICT score is a more
thorough clinical and ECG score which also includes the
Charlson’s index for co-morbidities such as the presence of
diabetes, liver disease, cancer etc.
7
An informed consent for
participating in the study was taken from all patients.
Blood sampling: The best predictive value for NT-proBNP
was reported from blood sampling between 72 and 120
hours in the STEMI groups and within 8 hours in the
NSTEMI group.
8,9
In our subgroup of STEMI, blood was
drawn in a fasting state at a mean of 85 hours after the
event, while in the NSTEMI subgroup it was taken within
8 hours of onset of symptoms with a mean of 6.1 hours.
Sample volumes of 20 µL were collected in EDTA vials and
assayed using the Elecsys 2010 NT-proBNP electro-
chemiluminiscence sandwich assay kit provided by Roche
Diagnostics, at an ISO 9001:2000-certified laboratory.
This test is a 2 polyclonal antibody directed against NT-
proBNP and has a measuring range of 5-35000 pg/ml. The
total leucocyte count (TLC) was also ascertained for each
patient.
All patients were subjected to a detailed echocardio-
graphy (Echo) and Doppler evaluation at day 7 or
pre-discharge. Follow-up two-dimensional echo-
cardiography (2D Echo) was done at day 30. Qualitative
and quantitative assessment of segmental and global
LV function was done in all patients with a Hewlett Packard
Sonos 5500 machine and Hewlett Packard calculation
program. Modified Simpson’s technique was used to
determine the end-diastolic volume (EDV), end-systolic
volume (ESV) and ejection fraction (EF). Mitral inflow
velocities, E and A waves as well as the deceleration time
(DT) were recorded.
Clinical end points of worsening heart failure, re-
current ischemia, repeat hospitalization for cardio-
vascular (CV) causes and CV deaths during these 30 days
were recorded. Worsening heart failure was defined as a
deterioration in Killip’s class of > 1 grade. Recurrent
ischemia was defined as one with a worsening of NYHA
functional class of > 1 grade during the 30 days and
required a step-up of anti-anginal therapy. Those who could
not be stabilized on medical therapy and required
hospitalization either for recurrent ischemia or worsening
heart failure were included in the group of repeat
hospitalizations. The entire study was cleared by the ethics
committee of the university and conformed to the
guidelines set for good clinical practice.
Statistical analysis: SPSS 11.5 software was used for
analysis of the data obtained. The student's t test, fisher
exact test and chi-square test were used to test the
significance between the study groups. Risk analysis was
carried out by calculating the odds ratio (OR) and 95%
confidence interval (CI). Patients were grouped according
to the median value of NT-proBNP into the above median
and below median cohorts, respectively. A univariate
analysis was done followed by multivariate binary logistic
regression analysis. This was done to take into account the
confounding, multiplicative effects of the presence of more
than one factor in each patient. The receiver operator curve
(ROC) and area under the curve (AUC) were also
ascertained to test the significance of the results. The
number of patients in the subgroups (STEMI and NSTEMI)
were adequately represented for statistical significance. The
body weight, pulse rate, SBP, Killip class, TLC, TIMI score
and PREDICT score were analyzed in each group.
Comparison of all parameters with echo indices (i.e. ESV,
EF, DT) was performed.
Results
Eighty patients presenting with STEMI and 40 patients
with NSTEMI were enrolled. The mean age of the patients
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Indian Heart J 2005; 57: 304–310
was 55±11 years, and 80% of them were males. The entire
cohort included diabetics (30%), hypertensive (41.2%),
dyslipidemic (53.3%), smokers (61%), obese (31%), those
with a positive family history of CAD (28.3%) and those
having previous MI (5%). All patients of STEMI were
thrombolyzed and patients with NSTEMI were managed
with aggressive medical therapy including heparin for up
to 7 days. All patients were treated as per the standard
guidelines set for medical treatment and this was left to the
discretion of the physician on an intention-to-treat basis.
NT pro-BNP levels: NT-proBNP levels in the full cohort
ranged from 21 to 13490 pg/ml. The mean levels were
2307±2287 pg/ml (271.4±269.1 pmol/L) with the
median NT-proBNP as 1403 pg/ml (165 pmol/L). The
conversion factor from pmol/L to pg/ml is approximately
8.5. Within this cohort the levels were higher in the STEMI
subgroup with the median value being 1738 pg/ml (mean
2650±2760) versus NSTEMI where median level was
1034 pg/ml (mean 1626±1915 pg/ml).
Baseline characteristics and variables in patients above
and below median are shown in Table 1. ESV was higher
while EF and DT were lower in the above median group;
TLC was also significantly higher in this group (p<0.05).
No significant difference between the two groups was noted
with respect to other variables. These differences were
notably maintained at day 30 but in those with above
median levels of NT-proBNP, a further significant decline
in EF was noted (p<0.05). A non-significant decline in EF
was noted in the below median group also (Table 2). The
number of patients having EF below 40% was significantly
more in the above median group (
χ
2
= 16.88, OR= 10.23,
95% CI 2.63 – 46.48) ( p<0.01).
At 30-day clinical follow-up there was a significantly
higher incidence of recurrent ischemia (p<0.001),
worsening heart failure (p=0.02) and repeat hospitalizations
(p=0.002) in the above median group. There was a 5%
mortality at 30-day follow-up (Table 3). The mean NT-
proBNP level in patients who died was extremely high
[7049±2998 pg/ml (median 7149 pg/ml)] compared to
patients who survived [OR: 5.27 (p<0.001)] (Table 4).
Subgroup analysis - STEMI: The mean levels of NT-
proBNP were 2650±2760 pg/ml and the median was 1738
pg/ml. Baseline characteristics showed that ESV was higher
while EF was lower in the above median group (p<0.01).
Killip class and TLC were also significantly higher in this
group (p<0.05). 2D Echo at day 30 revealed that difference
in ESV and EF was maintained with a further decrease in
Table 1. Baseline variables in groups having NT-proBNP
above median and below median (1403 pg/ml)
Below median
Above median
p value
(n=60)
(n=60)
Age (years)
54.0 ± 11.0
55.40 ±11.0
0.45
Index diagnosis:
STEMI
33 (55%)
47 (78.3%)
0.006*
NSTEMI
27 (45%)
13 (21.7%)
0.006*
Smokers (n=73, 61%)
34 (56.6%)
39 (65%)
0.36
Obese (n=37, 31%)
21 (35%)
16 (26.7%)
0.32
Hypertensive (n=54, 41.2%)
27 (45%)
27 (45%)
NS
Dyslipidemia (n=64, 53.3%)
34 (56.6%)
30 (50%)
0.69
Family history (n=34, 28.3%)
17 (28.3%)
17 (28.3%)
0.46
Previous MI (n=4.3%)
0
4 (6.6%)
NS
ESV (ml)
47.0±22.0
63.0±27.0
0.043*
EF (%)
57.8 ± 9.9
47.7 ± 11.4
0.001*
DT (seconds)
140.3 ± 35.6
127.4 ± 35.4
0.05*
Wt (kg)
63.0 ± 8.0
60.9 ± 8.0
0.20
SBP (mmHg)
127.0 ± 21.6
125.5 ± 21.4
0.70
Pulse rate (beats/min)
85.0 ± 17.5
84.0 ± 19.0
0.60
TLC
10173 ± 2210
12000 ± 3082
0.001*
* statistically significant
In the above median cohort ESV was significantly higher (p = 0.043), EF was signifi-
cantly lower (p < 0.001), DT was significantly lower (p < 0.05) and TLC was signifi-
cantly higher (p < 0.001). No statistical difference was seen with respect to age,
smoking, obesity, hypertension, diabetes, dyslipidemia, family history, SBP, PR and
body weight in the two groups
NT-proBNP: N-terminal probrain natriuretic peptide; STEMI: ST elevation myocar-
dial infarction; NSTEMI: non-ST elevation myocardial infarction; MI: myocardial in-
farction; ESV: end-systolic volume; EF: ejection fraction; DT: deceleration time; Wt:
body weight; SBP: systolic blood pressure; TLC: total leucocyte count; PR: pulse rate
Table 2. Comparison of echocardiographic variables at baseline and at 30 days
NT-proBNP below median (1403 pg/ml)
NT-proBNP above median (1403 pg/ml)
Comparison of
(n=60) (mean ± SD)
(n=60) (mean ± SD)
echo index at 30 days
Baseline
30 days
p value
Baseline
30 days
p value
p value
ESV
47.0 ± 22.0
50.0 ± 18.8
0.40
63.0 ± 27
68.5 ± 30.5
0.30
<0.001*
EF
57.8 ± 9.9
55 ± 8.6
0.10
47.7 ± 11.4
43.9 ± 9.9
0.05*
<0.001*
DT
140.3 ± 35.6
141.6 ± 34.5
0.85
127.4 ± 35.4
134.4 ± 37.7
0.30
0.30
* statistically significant
Worsening of EF at 30 days reached a significant trend (p=0.05) in patients with NT-proBNP above median
Comparison of 30-day echo indices between two groups showed that ESV is significantly higher (p<0.001) and EF is significantly lower (p < 0.001) in patients with NT-BNP
above median
NT-proBPN: N-terminal probrain natriuretic peptide; ESV: end-systolic volume; EF: ejection fraction; DT: deceleration time
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Puri et al. NT-ProBNP as a Predictor in AMI 307
EF noted in the above median group (p<0.01). In the latter
group, 30-day clinical follow-up also revealed a
significantly higher incidence of recurrent ischemia
(p<0.01), worsening heart failure and Killip class (p<0.05),
while no difference was noted in repeat hospitalizations
(p=0.10) and mortality (p=0.65).
Subgroup analysis-NSTEMI: The mean levels of NT-
proBNP were 1626±1915 pg/ml and the median was 1034
pg/ml. As in STEMI, the baseline characteristics showed
higher ESV and lower EF in the above median group
(p<0.05). Also, 30-day 2D Echo revealed that difference in
ESV and EF was maintained with a further decrease in EF
in the above median group (p<0.05). Thirty-day clinical
follow-up showed a higher incidence of recurrent ischemia,
worsening heart failure, repeat hospitalizations and
mortality in the above median group but none reached
statistical significance.
Regression analysis: In the full study cohort, on
univariate analysis and estimation of the
β
-coefficient,
NT-proBNP above median and EF < 40% emerged as
strong predictors of worsening heart failure, recurrent
ischemia, repeat hospitalization and death at 30 days
post-event. While TLC was not a predictor of death, it
was significantly associated with other adverse outcomes.
Amongst all the parameters studied, only NT-proBNP
below median emerged as a strong predictor for freedom
from adverse events (Table 5). On multivariate logistic
regression analysis, NT-proBNP above median (OR =
32.79, 95% CI 8.74 - 123.1, p<0.001) emerged as a
strong predictor of 30-day adverse outcomes. NT-proBNP
above median was also statistically significant (p<0.001)
for 30-day mortality (Table 6). It is also important to
note that neither the TIMI score nor the PREDICT score
reached any statistical significance to predict adverse
outcomes or mortality at 30 days in both STEMI and
NSTEMI subgroups. The ROC data showed that the AUC
for NT-proBNP above median was 0.835 (95% CI: 0.880 -
0.970) and 0.763 (95% CI: 0.792 - 1.026) for adverse
events and death, respectively.
Discussion
The mechanism of production of natriuretic peptides in
myocardial ischemia is unclear. Myocardial ischemia may
increase regional ventricular wall stretch owing to local
Table 4. Comparison of baseline variables among patients who died (n=6) and who survived (n=114) at the end of 30
days in the cohort
Death (n=6)
Alive (n=114)
t test
p value
Mean ± SD
Mean ± SD
Age (years)
57.8±10.42
54.6±11.30
0.68
0.50
Wt (kg)
57.50±4.60
62.20±8.30
1.37
0.20
SBP (mmHg)
118.0±34.40
126.6±24.5
0.82
0.40
PR (beats/min)
73.0±33.9
85.3±19.2
1.46
0.15
TLC
11533±3220
11063±3093
0.36
0.70
ESV (ml)
98.3±44.2
52.7±24.4
4.26
<0.001*
EF (%)
35.3±3.7
53.6±11.0
4.05
<0.001*
DT (seconds)
134.2±38.52
133.8±35.9
0.03
0.99
NT-proBNP (pg/ml)
7049±2998
2057±2223
5.27
0.001*
(Median 7149)
(Median 1325)
* statistically significant
Patients who died had a significantly higher NT-proBNP levels and ESV and lower EF
Wt: weight; SBP: systolic blood pressure; PR: pulse rate; TLC: total leucocyte count; ESV: end-systolic volume; EF: ejection fraction; DT: deceleration time
Table 3. 30-day clinical follow-up
Full cohort n=120
NT-proBNP
NT-proBNP
p value
Odds ratio (95% CI )
above median
below median
(1403 pg/ml) (n=60)
(1403 pg/ml) (n=60)
Recurrent ischemia
n=39 (33)
n=32 (53)
n=7 (12)
0.001*
8.65 (3.13 – 24.81)
Repeat hospitalization
n=18 (15)
n=15 (25)
n=3 (5)
0.002*
6.33 (1.58 – 29.49)
Death
n=6 (5)
n=6 (10)
n=0
0.014*
OR undefined
* statistically significant
Figure in parentheses show precentage
The number of adverse events including death were more in patients with NT-proBNP above median; NT-proBNP: N-terminal probrain natriuretic peptide
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308 Puri et al. NT-ProBNP as a Predictor in AMI
Indian Heart J 2005; 57: 304–310
depression of myocardial contraction. Mechanical stretch
can activate the JAK/STAT pathway stimulating BNP/NT-
proBNP secretion and augment the messenger RNA
expression.
10,11
, BNP has been used to provide prognostic
information in patients with acute coronary syndrome
(ACS).
12-14
Current knowledge indicates that NT-proBNP
may be a more sensitive and an effective prognostic tool in
these patients.
3,15-17
In the present study we have
demonstrated that NT-proBNP is a powerful predictor of
adverse outcomes including mortality at 30 days in the
group of patients presenting with AMI. On multivariate
analysis, NT-proBNP was found to be as predictive of
mortality and morbidity as the gold standard of low EF.
Using the multivariate regression analysis, NT-ProBNP
emerged as the only predictor of absence of adverse events
at 30-day follow-up after the acute event and this relation
was equally strong across the entire spectrum of AMI
patients.
The interpretation of early natriuretic peptide
measurement in ACS patients can be difficult since levels
of BNP and NT-proBNP vary according to index diagnosis
and rise continuously during the first 24 hours after the
onset of ischemia.
8,18
Concentrations increase very rapidly
and steeply during the first day after the onset of myocardial
ischemia, making the comparison of concentrations
difficult.
9
In our study the mean time to sample collection
was 85 hours in the STEMI subgroup and 6.1 hours in the
NSTEMI subgroup.
Recent studies have provided information on the
sampling times that provide the best predictive value for
NT-proBNP in patients presenting with AMI.
8,9
Measuring
NT-proBNP in STEMI, Talwar et al.
8
declared that samples
collected between 72 and 120 hours provided maximal
prognostic value. In studies on NSTEMI, Jernberg et al.
19
measured NT-proBNP on admission and James et al.
20
measured NT-proBNP at a median of 9.5 hours from
symptom onset. However, it has lately been shown that NT-
proBNP is a strong predictor of mortality irrespective of
sampling time, even up to 4 weeks after the index event.
21
The results of all these studies clearly showed that NT-
proBNP is a strong predictor of mortality irrespective of
sampling time as was also concluded in a subsequent meta-
analysis.
22
It is challenging to derive any prognostic cut-off value,
implying that a single cut-off level cannot be used for NT-
proBNP in the AMI population. In clinical studies,
Table 5. Prediction of death and adverse outcomes (heart failure, recurrent ischemia, repeat hospitalization) and
prediction of freedom from adverse outcomes at 30 days
Variables
Death
Adverse outcomes
No adverse outcomes
β
coefficient
p value
β
coefficient
P value
β
coefficient
p value
Age
0.0067
0.87
0.0062
0.95
0.1274
0.13
PR (beats/min)
0.0621
0.20
-0.0564
0.45
-0.0758
0.51
SBP (mmHg)
-0.0175
0.76
0.1196
0.19
-0.0064
0.95
TLC
-0.0209
0.63
0.4705
0.001*
0.0020
0.98
EF<40%
0.2743
0.01*
0.3988
0.003*
-0.1683
0.30
High risk TIMI score
0.0656
0.25
0.2074
0.07
-0.0242
0.83
NT-proBNP pg/ml
-0.1139
0.03*
0.2589
0.04*
0.2635
0.007*
* Statistically significant
NT-proBNP and EF<40% were strong predictors of death and adverse outcomes at 30 days. Baseline TLC also attained significance for adverse outcome. For absence of adverse
outcomes only NT-proBNP below median attained significance.
PR: pulse rate; SBP: systolic blood pressure; TLC; total leucocyte count; EF; ejection fraction
Table 6. Multivariate logistic regression for adverse outcomes
Coefficient
Std Error
Wald
OR (CI)
p value
Age >60 years
0.66
0.61
1.19
1.94 ( 0.71 – 5.29)
0.28
SBP <110 mmHg
0.18
0.79
0.05
1.20 (0.32 -4.45)
0.82
PR >100 beats/min
-0.52
0.86
0.37
0.59 (0.15 -2.44)
0.55
TLC >11000
-1.35
0.74
3.32
0.26 (0.08 -0.88)
0.07
Killip class>1
0.35
0.72
0.23
1.42 (0.44 -4.62)
0.63
TIMI score
0.37
0.81
0.21
1.45 (0.38 – 5.47)
0.65
NT-proBNP >Median
3.49
0.80
18.85
32.79 (8.74- 123.1)
<0.001*
ESV >60 ml
0.62
0.70
0.80
1.87 (0.59 -5.88)
0.37
EF <40 %
-0.33
1.43
0.05
0.72 (0.07 -7.58)
0.82
Predict >12
-1.31
0.64
4.15
0.27 (0.09 -0.78)
0.04*
* Statistically significant
NT-proBNP above median - a strong predictor adverse outcomes at 30 days (p<0.001) and Predict score >12 (p=0.04) also attained significance. ESV >60ml, EF <40% and NT-
proBNP above median also reached statistical significance (p<0.001) when multiple logistic regression for death was carried out separately
SBP: systolic blood pressure; PR; pulse rate; TLC: total leucocyte count; ESV: end-systolic volume; EF: ejection fraction
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