Evaluation of B-type natriuretic peptide for risk assessment in unstable

Angina/Non–ST-elevation myocardial infarction: B-type natriuretic peptide

and prognosis in TACTICS-TIMI 18
David A. Morrow, James A. de Lemos, Marc S. Sabatine, Sabina A. Murphy, Laura
A. Demopoulos, Peter M. DiBattiste, Carolyn H. McCabe, C. Michael Gibson,
Christopher P. Cannon, and Eugene Braunwald
J. Am. Coll. Cardiol. 2003;41;1264-1272
doi:10.1016/S0735-1097(03)00168-2

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Journal of the American College of Cardiology Vol. 41, No. 8, 2003
© 2003 by the American College of Cardiology Foundation ISSN 0735-1097/03/$30.00
Published by Elsevier Science Inc. doi:10.1016/S0735-1097(03)00168-2

Evaluation of B-Type Natriuretic

Peptide for Risk Assessment in Unstable
Angina/Non–ST-Elevation Myocardial Infarction
B-Type Natriuretic Peptide and Prognosis in TACTICS-TIMI 18
David A. Morrow, MD, MPH,* James A. de Lemos, MD,† Marc S. Sabatine, MD, MPH,*
Sabina A. Murphy, MPH,‡ Laura A. Demopoulos, MD,§ Peter M. DiBattiste, MD,§
Carolyn H. McCabe, BS,* C. Michael Gibson, MD, MS, FACC,‡ Christopher P. Cannon, MD, FACC,*
Eugene Braunwald, MD, FACC*
Boston, Massachusetts; Dallas, Texas; and West Point, Pennsylvania
OBJECTIVES This study was designed to evaluate B-type natriuretic peptide (BNP) for risk assessment and
clinical decision making over a range of cut points, alone and with cardiac troponin I (cTnI),
in patients with non–ST-elevation acute coronary syndromes (ACS).
BACKGROUND B-type natriuretic peptide holds promise for risk stratification. Additional evidence regarding
optimal decision limits, use in combination with troponin, and use in targeting therapy is
needed before acceptance into clinical use for ACS.
METHODS We evaluated BNP at baseline in 1,676 patients with non–ST-elevation ACS randomized to
early invasive versus conservative management.
RESULTS Patients with elevated BNP (⬎80 pg/ml; n ⫽ 320) were at higher risk of death at seven days
(2.5% vs. 0.7%, p ⫽ 0.006) and six months (8.4% vs. 1.8%, p ⬍ 0.0001). The association
between BNP and mortality at six months (adjusted odds ratio [OR] 3.3; 95% confidence
interval [CI] 1.7 to 6.3) was independent of important clinical predictors, including cTnI and
congestive heart failure (CHF). Patients with elevated BNP had a fivefold higher risk of
developing new CHF by 30 days (5.9% vs. 1.0%, p ⬍ 0.0001). B-type natriuretic peptide
added prognostic information to cTnI, discriminating patients at higher mortality risk among
those with negative (OR 6.9; 95% CI 1.9 to 25.8) and positive (OR 4.1; 95% CI 1.9 to 9.0)
baseline cTnI results. No difference was observed in the effect of invasive versus conservative
management when stratified by baseline levels of BNP (pinteraction ⱖ 0.6).
CONCLUSIONS Elevated BNP (⬎80 pg/ml) at presentation identifies patients with non–ST-elevation ACS
who are at higher risk of death and CHF and adds incremental information to cTnI.
Additional work is needed to identify therapies that may reduce the risk associated with
increased BNP. (J Am Coll Cardiol 2003;41:1264 –72) © 2003 by the American College of
Cardiology Foundation

B-type natriuretic peptide (BNP) is a cardiac neurohormone ular function (8,10,11). We recently extended these findings
that is synthesized in ventricular myocardium and released across the spectrum of patients with acute coronary syn-
in response to increased ventricular wall stress (1–3). Its dromes (ACS), including those with unstable angina (UA),
diverse actions include natriuresis, vasodilation, inhibition among whom elevated levels of BNP predicted a twofold to
of the renin-angiotensin-aldosterone system, and inhibition threefold higher risk of death by 10 months (12). Together,
of sympathetic nerve activity (4). First studied as a diagnos- these data suggest that measurement of BNP in patients
tic and prognostic marker among patients with congestive presenting with suspected ACS could be an important
heart failure (CHF) (5–7), BNP was subsequently found to addition to our current tools for risk stratification.
predict outcomes in patients with acute myocardial infarc- Before considering BNP for routine clinical application in
tion (MI) (8,9). Specifically, when measured between one ACS, consistent findings from independent data sets are
and four days after presentation with transmural infarction, needed. Moreover, the optimal decision limits for prognos-
an elevated plasma concentration of BNP was associated tic evaluation must be defined, and careful assessment of the
with increased mortality risk, independently of left ventric- utility of BNP in combination with cardiac troponin is
required. Lastly, the utility of BNP for directing therapeutic
From the *Cardiovascular Division, Department of Medicine, Brigham & Wom-
decision making requires testing. We thus evaluated the
en’s Hospital, Boston, Massachusetts; †Donald W. Reynolds Cardiovascular Re- predictive capacity of BNP over a range of clinical thresh-
search Center, University of Texas Southwestern Medical Center, Dallas, Texas; olds, alone and in combination with cardiac troponin I
‡Harvard Clinical Research Institute, Boston, Massachusetts; and §Merck & Co,
West Point, Pennsylvania. The TACTICS-TIMI 18 study was sponsored by Merck
(cTnI), among patients with non–ST-elevation ACS en-
& Co. Biosite Incorporated (San Diego, California) performed testing for B-type rolled in the Treat Angina with Aggrastat and Determine
natriuretic peptide. Gottlieb C. Friesinger, II, MD, acted as Guest Editor for this Cost of Therapy with an Invasive or Conservative Strategy
paper.
Manuscript received October 27, 2002; revised manuscript received December 4, (TACTICS)-Thrombolysis In Myocardial Infarction
2002, accepted December 26, 2002. (TIMI) 18 trial (13). We also assessed whether BNP is
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BNP testing. The protocol specified that blood samples be

Abbreviations and Acronyms obtained at enrollment by trained study personnel in citrate-
ACS ⫽ acute coronary syndrome(s) anticoagulated tubes and plasma isolated within 60 min of
BNP ⫽ B-type natriuretic peptide sample acquisition. Plasma samples were stored at ⫺20°C or
CHF ⫽ congestive heart failure colder at the enrolling site until shipped to the TIMI
CI ⫽ confidence interval
CK-MB ⫽ creatine kinase-MB
Biomarker Core Laboratory, where they were maintained at
cTnI ⫽ cardiac troponin I ⫺80°C. Aliquots were shipped frozen to Biosite Incorpo-
HF ⫽ heart failure rated (San Diego, California), where they were thawed and
MI ⫽ myocardial infarction analyzed using an established immunoassay (12) by person-
NSTEMI ⫽ non–ST-elevation myocardial infarction nel blinded to treatment allocation and clinical outcomes.
OR ⫽ odds ratio
TIMI ⫽ Thrombolysis In Myocardial Infarction
The primary decision limit of 80 pg/ml was pre-specified
UA ⫽ unstable angina based on our previous work with this assay (12).
Levels of cTnI were measured in the TIMI Biomarker
Core Laboratory using the ACS:180 Chemiluminescence
useful in identifying patients who will derive greater benefit cTnI Immunoassay (Bayer Diagnostics, Tarrytown, New
from an early invasive management strategy. York) (14). The minimum detectable concentration is 0.03
ng/ml. A prognostic decision limit of 0.1 ng/ml was used for
all analyses based on previous work with this assay (15).
METHODS
Statistical methods. Plasma concentrations of BNP are
Study population and treatment. A total of 2,220 patients described as the median and interquartile range. The base-
were enrolled in TACTICS-TIMI 18 between December line characteristics of patients with and of those without
18, 1997, and December 22, 1999. The study design and elevated levels of BNP were compared using the Wilcoxon
primary results have been described previously (13). Patients Rank Sums test for continuous variables and the chi-
ⱖ18 years old were eligible for enrollment if they experi- squared test for categorical variables. Correlation coefficients
enced UA within the preceding 24 h, were candidates for reported between continuous variables are based on a
coronary revascularization, and had at least one of the non-parametric method (Spearman correlation). Analysis of
following: ST segment depression (ⱖ0.05 mV) or transient findings from the TIMI Angiographic Core Laboratory
ST elevation, T wave (ⱖ0.3 mV) inversion in ⱖ2 leads, were performed for the subset of patients participating in
elevated cardiac markers of necrosis, or documented coro- the TACTICS-TIMI 18 angiographic substudy. Data re-
nary disease. Exclusion criteria included persistent ST- garding the number of diseased coronary arteries were based
segment elevation, recent revascularization, factors associ- on local interpretation in all patients undergoing angiogra-
ated with increased risk of bleeding, severe CHF or phy.
cardiogenic shock, important systemic disease, or serum The univariate association between BNP and clinical
creatinine ⬎2.5 mg/dl. outcomes, alone and stratified by cTnI, was evaluated using
Patients were treated with aspirin, intravenous unfrac- the chi-square test for dichotomized comparisons and the
tionated heparin, and tirofiban (Merck and Co., West chi-square test for trend across BNP quartiles. The log-rank
Point, Pennsylvania) and were randomized to an early test was performed for the Kaplan-Meier probability esti-
invasive or conservative strategy. Patients in the early mates (Fig. 1). Using logistic regression, the relationship
invasive strategy were to undergo coronary angiography between BNP (dichotomized) and outcomes was adjusted
between 4 and 48 h after randomization, and revasculariza- for the effects of age, gender, diabetes, ST-segment depres-
tion when feasible based on coronary anatomy. Patients in sion on the presenting ECG, history of CHF, evidence of
the conservative strategy were treated medically and were to heart failure (HF) at presentation, and baseline cTnI result.
undergo coronary angiography and revascularization only if Age was treated as a continuous variable. ST depression and
they manifested recurrent ischemia at rest or with provoc- baseline cTnI were dichotomized at thresholds of ⱖ0.05
ative testing. The study protocol was approved by the mV and ⱖ0.1 ng/ml, respectively. Clinical follow-up
institutional review boards of each participating hospital, through six months was complete among ⬎99% of patients,
and patients provided written informed consent. supporting the use of logistic regression as opposed to Cox
End points. Patients were followed up for six months for proportional hazard modeling. The primary cut point for
the development of recurrent clinical events, including BNP (80 pg/ml) was pre-specified based on our previous
death from any cause, new or recurrent MI, rehospitaliza- work with this assay (12). In addition, an exploratory
tion for ACS, and new or worsening CHF. Each of these analysis of the predictive capacity of BNP at thresholds
end points, except new/worsening CHF, were adjudicated across the range of 40 to 160 pg/ml was performed using
by an independent clinical end points committee, blinded to logistic regression. The relative predictive value at each
treatment assignment. The index diagnosis was established threshold was assessed using the chi-squared values and
by the investigator based on local electrocardiographic and adjusted risk relationships from logistic regression.
laboratory data. Testing for heterogeneity in the effect of the invasive
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Figure 1. Kaplan-Meier estimates of the probability of death (A) and death or congestive heart failure (CHF) (B) through six months among patients with
baseline concentration of B-type natriuretic peptide (BNP) ⬎80 pg/ml and ⱕ80 pg/ml. The p values are based on the log-rank test.

strategy between patients with and those without elevated pg/ml) in patients with index diagnoses of UA and non–
levels of BNP was performed using logistic regression with ST-elevation myocardial infarction (NSTEMI), respec-
terms for the main effects and for the interaction of BNP tively. The plasma concentration of BNP exceeded 80 pg/ml
status with treatment allocation. Analyses were performed in 25.2% (n ⫽ 153) of patients presenting with NSTEMI,
using STATA v7-intercooled (STATA Corp., College 15.6% (n ⫽ 167) of patients diagnosed with UA, and 10.1%
Station, Texas). A p value (two-tailed) ⬍0.05 was consid- (n ⫽ 67) of those with baseline levels of cTnI ⬍0.1 ng/ml.
ered statistically significant. Elevated levels of BNP were detected among 13.6% (n ⫽
135) of those with UA and no history or current evidence of
RESULTS HF.
A total of 1,676 samples were available for determination of Patients with elevated levels of BNP were older, more
BNP levels at enrollment in TACTICS-TIMI 18. The often female, and more likely to have a history of HF and
baseline characteristics of those without available samples diabetes (Table 1). At presentation, patients with elevated
were similar to those included in this substudy (data not BNP more frequently had ST-segment depression and
shown). Median (25th to 75th percentile) levels of BNP tachycardia (⬎100 beats/min). There was no association
were 20 pg/ml (⬍5 to 54 pg/ml) and 38 pg/ml (10 to 81 between elevated levels of BNP and a history of prior MI. A
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Table 1. Univariate Associations With Elevated Levels of BNP

BNP < 80 pg/ml BNP > 80 pg/ml
(n ⴝ 1,356) (n ⴝ 320) p Value
Demographics
Age, yrs 60 (52, 69) 69 (61, 76) ⬍ 0.0001
Age ⬎65 yrs 33.8 62.7 ⬍ 0.0001
Female 31.2 43.4 ⬍ 0.0001
Risk factors
Smoking status
Current 28.8 24.1 0.1
Past 38.2 41.4 0.3
Diabetes 25.4 33.8 0.003
History of hypertension 64.8 70.0 0.08
Cardiovascular history
Prior MI 38.7 41.3 0.4
Prior HF 3.9 16.9 ⬍ 0.001
Peripheral vascular disease 6.8 9.7 0.07
Cerebrovascular disease 5.3 6.6 0.4
Prior PCI 30.4 17.8 ⬍ 0.001
Prior CABG 21.6 22.2 0.8
Presenting characteristics
Heart rate, beats/min 73 (64, 82) 75 (65, 88) 0.02
Heart rate ⬎100 beats/min 4.8 10.0 ⬍0.001
Systolic BP, mm Hg 133 (120, 150) 135 (120, 156) 0.1
Systolic BP ⬍100 mm Hg 2.7 2.2 0.6
ST depression ⱖ1.0 mm 19.0 27.8 ⬍ 0.001
Index diagnosis MI 33.6 47.8 ⬍ 0.001
Data are shown as n (%) for dichotomous variables and median (25th, 75th percentile) for continuous variables.
BNP ⫽ B-type natriuretic peptide; BP ⫽ blood pressure; CABG ⫽ coronary artery bypass grafting; HF ⫽ heart failure;
MI ⫽ myocardial infarction; PCI ⫽ percutaneous interventions.

modest correlation between baseline levels of BNP and peak BNP remained predictive of mortality after the addition of
creatine kinase-MB (CK-MB) was evident (␳ ⫽ 0.27, p ⬍ peak CK-MB (as a measure of infarct size) to the clinical
0.001). Patients with elevated BNP were more likely to have model (OR 3.3, 95% CI 1.8 to 6.3).
multi-vessel (ⱖ2) coronary artery disease (74% vs. 60%, p ⬍ When BNP was evaluated as a semi-continuous variable,
0.0001). In the sub-group of patients with films submitted mortality risk increased in a graded fashion with rising levels
for interpretation by the TIMI Angiographic Core Labo- of BNP (Fig. 2). As reflected by the respective chi-square
ratory (n ⫽ 416), similar rates of impaired epicardial flow statistics and ORs, the predictive capacity of baseline
(TIMI flow grade 0/1/2: 37.3% vs. 34.7%, p ⫽ 0.7) and measurement of BNP in this population was maximal
myocardial perfusion (TIMI myocardial perfusion grade between 80 and 120 pg/ml, with a pattern of increasing
0/1: 52.6% vs. 53.8%, p ⫽ 0.9) were evident in the culprit mortality risk becoming evident at a concentration of BNP
territory among patients with and among those without ⬎80 pg/ml (Fig. 2). Although the chi-square statistic was
elevated BNP, respectively. slightly higher at a threshold of 100 pg/ml, this difference in
Prediction of clinical events. Patients with baseline levels discriminatory capacity did not achieve statistical signifi-
of BNP ⬎80 pg/ml were at significantly higher risk of death cance compared with 80 pg/ml (likelihood ratio test chi-
by 30 days after presentation (5.0% vs. 1.2%, p ⬍ 0.0001). square ⫽ 1.84, p ⫽ 0.9). Five percent (n ⫽ 83) of
The higher mortality risk associated with elevated BNP was the population had BNP levels between 80 pg/ml and
evident as early as seven days (2.5% vs. 0.74%, p ⫽ 0.006) 100 pg/ml.
and persisted through six months of follow-up (p ⬍ 0.0001, Increasing levels of BNP (by quartile) were associated
Fig. 1A). The association between elevated levels of BNP with, at most, a weak trend toward higher risk of recurrent
and mortality at six months was independent of other ischemic events (Table 2). At a decision limit of 80 pg/ml,
important clinical predictors available at presentation, in- BNP was not predictive of an increased risk for new/
cluding age, gender, diabetes, ST-segment depression, his- recurrent MI (5.3% vs. 5.2%, p ⫽ 1.0) or rehospitalization
tory of CHF, CHF at presentation, and baseline cTnI result for ACS (13.4% vs. 12.2%, p ⫽ 0.6) through six months of
(odds ratio [OR] 3.3; 95% confidence interval [CI] 1.7 to follow-up. In contrast, patients with elevated BNP at
6.3). Among patients with UA and no history or clinical presentation had a nearly sixfold higher risk of developing
evidence of HF at presentation, elevated levels of BNP were new or worsening CHF by 30 days (5.9% vs. 1.0%, p ⬍
associated with a threefold higher risk of death through six 0.0001), including those with UA (2.9% vs. 0.1%, p ⬍
months (OR 3.4; 95% CI 1.2 to 9.7) after adjusting for each 0.0001). The predictive association between baseline levels
these clinical predictors. Moreover, the baseline level of of BNP and CHF persisted at six months (9.1% vs. 1.8%,
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BNP in UA/NSTEMI April 16, 2003:1264–72

Figure 2. Mortality risk stratified by B-type natriuretic peptide (BNP) levels over range of 40 to 160 pg/ml. The odds ratio (ORs) and chi-squared (␹2)
statistics in the table below the chart are based on BNP results dichotomized at the lower bound of the range.

p ⬍ 0.0001) and was independent of the patient’s age, among those with both negative (OR 6.9; 95% CI 1.9 to
history of HF, ST deviation, or baseline troponin result 25.8) and positive (OR 4.1; 95% CI 1.9 to 9.0) baseline
(OR 3.0; 95% CI 1.6 to 5.7). As such, a baseline level of cTnI results (Fig. 3, left). Specifically, among patients with
BNP ⬎80 pg/ml was a strong, independent predictor of cTnI ⬍0.1 ng/ml, those with a BNP level ⬎80 pg/ml were
death or CHF at six months after presentation (16.3% vs. at significantly higher risk of death through 30 days (4.5%
3.6%, adjusted OR 3.2; 95% CI 2.0 to 5.1, Fig. 1B). vs. 0.7%, p ⫽ 0.004) and six months (7.5% vs. 1.2%, p ⫽
Stratification by BNP and troponin results. Consistent 0.0003). B-type natriuretic peptide results (dichotomized at
with previous work in TACTICS-TIMI 18 (16), an ele- 80 pg/ml) did not substantially alter the risk estimates for
vated level of cTnI at presentation was an important recurrent MI among patients either with (4.6% vs. 5.3%,
predictor of death (3.8% vs. 1.8%, p ⫽ 0.02) and MI (6.4% p ⫽ 0.6) or without (3.0% vs. 1.7%, p ⫽ 0.4) elevated levels
vs. 3.2%, p ⫽ 0.004) by six months in the subset of patients of cTnI. Thus, use of BNP and cTnI in combination
with data on BNP. B-type natriuretic peptide measure- enabled identification of patients with negative BNP or
ments added significant prognostic information to cTnI, troponin who were at increased risk of death or MI (Fig. 3,
discriminating patients at ⬎4-fold higher mortality risk right). Specifically, among patients with a negative cTnI

Table 2. Risk of Cardiac Events Through Six Months Stratified by Quartile of Elevated BNP
Quartile of BNP
0* 1 2 3 4 p Value†
BNP (pg/ml) ⬍5 5–21 ⬎21–42 ⬎42–83 ⬎ 83 —
N 448 320 300 304 304 —
New or recurrent MI 4.6 4.4 5.7 6.9 5.3 0.6
Rehospitalization for ACS 11.8 10.0 13.3 14.1 13.5 0.5
HF 1.3 1.9 2.7 1.6 9.5 ⬍ 0.0001
Death or CHF 2.2 4.4 4.7 4.0 16.8 ⬍ 0.0001
Data reported as event rates (%). *Patients with BNP levels below the detection limit of the assay. †Based on chi-square for trend.
ACS ⫽ acute coronary syndrome; BNP ⫽ B-type natriuretic peptide; CHF ⫽ congestive heart failure; HF ⫽ heart failure;
MI ⫽ myocardial infarction.

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Figure 3. Risk of death or myocardial infarction (MI) at 30 days stratified by B-type natriuretic peptide (BNP) and cardiac troponin I (cTnI). NEG ⫽
negative; POS ⫽ positive.

who had elevated BNP, the risk of death or MI was 7.5%; 1.7 to 9.1 for CHF and OR 3.3, 95% CI 1.8 to 6.0 for death
whereas in those with a negative BNP detected as being at or CHF).
higher risk only by cTnI, the risk of death or MI through 30 Effect of management strategy. Consistent with the pri-
days was 6.4%. Patients with both a negative BNP and cTnI mary results of TACTICS-TIMI 18, among the subset of
were at very low risk of death (0.7%) or of death or MI (2.0%). patients with BNP data, the invasive management strategy
B-type natriuretic peptide also added important informa- conferred a 30% relative reduction in the risk of death or MI
tion to cTnI for predicting the risk of CHF (Fig. 4). In (OR 0.70; 95% CI 0.46 to 1.04) and a 23% reduction in the
contrast with assessment of the risk for recurrent MI, risk of the primary composite endpoint of death, MI, or
patients with elevated BNP were at significantly higher risk rehospitalization for ACS at six months (OR 0.77; 95% CI
of CHF and death or CHF, regardless of troponin status. 0.60 to 1.0) compared with the conservative strategy. When
Although in multivariable analysis cTnI contributed inde- results were stratified by baseline BNP, no appreciable
pendent information with respect to the risk of CHF (OR difference was observed in the effect of invasive versus
3.4; 95% CI 1.2 to 10.2) and of death or CHF (OR 2.1; conservative management among patients with higher levels
95% CI 1.04 to 4.20), BNP tended toward a stronger of BNP (pinteraction ⱖ 0.6, Table 3). Stratification by both
association with each of these end points (OR 3.9, 95% CI cTnI and BNP revealed a pattern of reduced risk of death or

Figure 4. Risk of congestive heart failure (CHF) at 30 days stratified by B-type natriuretic peptide (BNP) and cardiac troponin I (cTnI). NEG ⫽ negative;
POS ⫽ positive.

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Table 3. Effect of Invasive Versus Conservative Management on demonstrated that our prospectively defined decision limit
Outcomes at Six months Stratified by BNP Level of 80 pg/ml with this assay appears to be a threshold above
OR p Value for which mortality risk begins to increase in ACS. This study
INV CON (95% CI) Interaction also reveals variation in the relative predictive capacity of
Mortality BNP and troponin with respect to individual clinical end
BNP ⬎80 pg/ml 7.9 9.0 0.87 (0.4–1.9) 0.6 points, with BNP exhibiting a stronger relationship with
BNP ⱕ80 pg/ml 1.9 1.6 1.2 (0.5–2.7) death and CHF, and cardiac troponin being predictive of
Death, MI or
rehospitalization
death and recurrent ischemic events. It is likely that this
for ACS difference accounts in part for differences in the ability of
BNP ⬎80 pg/ml 18.3 26.3 0.63 (0.4–1.1) 0.8 these markers to predict response to a specific therapy, such
BNP ⱕ80 pg/ml 14.7 17.3 0.82 (0.6–1.1) as an early invasive management strategy. When used
Data reported as event rates (%). together in a combined strategy, these two markers provide
ACS ⫽ acute coronary syndrome; BNP ⫽ B-type natriuretic peptide; CI ⫽
confidence interval; CON ⫽ conservative management; INV ⫽ invasive manage-
a more effective tool for identifying patients at increased risk
ment; MI ⫽ myocardial infarction; OR ⫽ odds ratio. for clinically important recurrent cardiac events related to
both ischemia and HF. Such information is likely to
recurrent ischemic events with the invasive strategy among enhance our ability to appropriately triage higher-risk pa-
those with elevated cTnI, regardless of BNP status (Fig. 5). tients and more reliably identify low-risk patients who may
be candidates for less intensive evaluation and therapy.
DISCUSSION At this time, the implications of elevated BNP for
As a putative measure of the hemodynamic consequences of decisions regarding therapy in ACS are not as clear. We
acute myocardial ischemia and infarction, BNP is a biomar- found no interaction between BNP and the effect of the
ker that has recently shown promise for risk assessment early invasive management strategy. These results are not
among patients with non–ST-elevation ACS (12,17,18). entirely unexpected when one considers that BNP appears
We now have confirmed prospectively our initial retrospec- to be a stronger predictor of mortality and HF than of
tive observations that BNP is a novel marker of increased recurrent non-fatal ischemic events and that the benefit of
risk of death and CHF in patients presenting with UA and the early invasive strategy in this study accrued primarily
NSTEMI (with or without CHF). In addition, our data from a reduction in recurrent ischemic events. These find-
provide new insights into the prognostic relationships be- ings contrast with those for cardiac troponin, which is a
tween BNP and individual clinical outcomes that will be strong predictor of benefit from early invasive management,
valuable in guiding clinical use of this marker. Specifically, and provide direct evidence that different biomarkers carry
we have demonstrated a strong association between the different implications for therapy (13,16). Further investi-
plasma concentration of BNP at presentation and subse- gation is needed to identify therapies that may favorably
quent mortality or new CHF in an independent population modify the risk associated with increased levels of BNP in
of patients with UA and NSTEMI. Moreover, we have ACS.

Figure 5. Effect of the invasive (INV) versus conservative (CON) management strategy stratified by baseline levels of B-type natriuretic peptide (BNP) and
cardiac troponin I (cTnI). ACS ⫽ acute coronary syndrome; NEG ⫽ negative; POS ⫽ positive.

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Additional research is also needed to elucidate the patho- interesting to have data regarding the serial changes in BNP
biologic connections between elevated levels of BNP and concentration among patients presenting with ischemia
the associated higher mortality risk observed in patients without necrosis. Only a baseline sample was obtained for
with non–ST-elevation ACS. We may, however, speculate core lab analysis in TACTICS-TIMI 18, and thus we
as to potential mechanisms (19). Data from both experi- cannot comment on the optimal timing of BNP measure-
mental and clinical studies suggest that the plasma level of ment or kinetics of this marker on the basis of our data.
BNP may reflect the size or severity of the ischemic insult, However, we have extended beyond previous findings in
even in the absence of myocardial necrosis. Specifically, in which BNP was measured at one to three days after
human models of ischemia, BNP levels have been shown to presentation to now demonstrate that elevated levels of
increase transiently both after exercise in patients with stable BNP at presentation are also associated with adverse out-
coronary disease (20) and after uncomplicated coronary comes. It is possible that serial measurements may improve
angioplasty, despite stable intracardiac filling pressures the prognostic performance of BNP.
(21,22). Others have shown the rise in the level of BNP to Conclusions. An elevated plasma concentration of BNP
correlate with the size of an ischemic territory during (⬎80 pg/ml) at presentation in patients with UA and
nuclear stress imaging (23). B-type natriuretic peptide also NSTEMI predicts higher short- and long-term mortality as
appears to provide a very sensitive tool for detecting early well as new-onset CHF. B-type natriuretic peptide adds
CHF (24) and may serve to identify patients with unsus- substantially to risk assessment for mortality based on
pected adverse hemodynamic consequences of coronary cardiac troponin alone, but it did not enhance selection of
ischemia. As such, the available evidence supports a plausi- appropriate candidates for early invasive evaluation in this
ble relationship between BNP and the extent of the isch- study. These findings may be used to guide clinical use of
emic territory as a possible link to the increased risk of CHF BNP for risk assessment and triage in patients with sus-
and fatal complications. It is interesting that there does not pected ACS. Additional work is needed to identify specific
appear to be a stronger association with future ischemic therapies that may reduce the risk associated with increased
BNP.
events or a more profound benefit from revascularization.
Study limitations. The results of this study address the use
of BNP for risk assessment in patients with a high clinical Reprint requests and correspondence: Dr. David A. Morrow,
probability of ACS. Additional investigation will be neces- Cardiovascular Division, Brigham and Women’s Hospital, 75
sary to explore the utility of BNP in a broad spectrum of Francis Street, Boston, Massachusetts 02115. E-mail: dmorrow@
patients presenting with chest pain and low-to-intermediate [Link].
probability of ACS. B-type natriuretic peptide levels may be
elevated in a number of other cardiac and some non-cardiac
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 Evaluation of B-type natriuretic peptide for risk assessment in unstable
Angina/Non–ST-elevation myocardial infarction: B-type natriuretic peptide
and prognosis in TACTICS-TIMI 18
David A. Morrow, James A. de Lemos, Marc S. Sabatine, Sabina A. Murphy, Laura
A. Demopoulos, Peter M. DiBattiste, Carolyn H. McCabe, C. Michael Gibson,
Christopher P. Cannon, and Eugene Braunwald
J. Am. Coll. Cardiol. 2003;41;1264-1272
doi:10.1016/S0735-1097(03)00168-2
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Journal of the American College of Cardiology Vol. 41, No. 10, 2003
© 2003 by the American College of Cardiology Foundation ISSN 0735-1097/03/$30.00
Published by Elsevier Inc.

CORRECTIONS
Breithardt OA, Sinha AM, Schwammenthal E, Bidaoui N, Markus KU, Franke A, Stellbrink C. Acute Effects of Cardiac
Resynchronization Therapy on Functional Mitral Regurgitation in Advanced Systolic Heart Failure. J Am Coll Cardiol
2003;41:765–70. The first sentence of the Background section of the Abstract was printed incorrectly. The correct sentence is below.

BACKGROUND Both a decrease in left ventricular (LV) closing force and mitral valve tethering have been implicated as mechanisms for
functional mitral regurgitation (FMR) in dilated hearts.
doi:10.1016/S0735-1097(03)00552-7

Morrow DA, de Lemos JA, Sabatine MS, Murphy SA, Demopoulos LA, DBattiste PM, McCabe CH, Gibson CM, Cannon CP,
Braunwald E. Evaluation of B-Type Natriuretic Peptide for Risk Assessment in Unstable Angina/Non-ST-Elevation Myocardial
Infarction: B-Type Natriuretic Peptide Prognosis in TACTICS-TIMI 18. J Am Coll Cardiol 2003;41:1264-72. This paper had a
Guest Editor which was not noted in the article. The line below should have appeared in the opening footnote on page 1264:

Gottlieb C. Friesinger, II, MD, acted as Guest Editor for this paper.
doi:10.1016/S0735-1097(03)00571-0

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