Prognostic implications of elevated troponin in patients with suspected acute coronary syndrome but no critical epicardial coronary disease: a TACTICS-TIMI-18 substudy.

Abstract

The purpose of this study is to determine whether there is clinical significance to elevated troponin I in patients with suspected acute coronary syndromes (ACS) with non-critical angiographic coronary stenosis.
Elevation of troponin in patients admitted with ACS symptoms with non-critical coronary artery disease (CAD) may result from coronary atherothrombosis not evident using standard angiography or from other ischemic and non-ischemic causes that may confer increased risk for future events.
Patients with ACS enrolled in the Treat Angina With Aggrastat and Determine Cost of Therapy With Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction (TACTICS-TIMI)-18 were included. Of 2,220 patients enrolled in the trial, 895 were eligible. Patients were divided into four groups according to troponin status on admission and presence of significant angiographic stenosis. Baseline brain natriuretic peptide (BNP) and C-reactive protein (CRP) were obtained on all patients.
The median troponin I levels were 0.71 ng/ml in patients with CAD compared with 0.02 ng/ml in patients without CAD (p <0.0001). Troponin-positive patients with or without angiographic CAD had higher CRP and BNP levels compared with troponin-negative patients (p <0.01 for both). The rates of death or reinfarction at six months were 0% in troponin-negative patients with no CAD, 3.1% in troponin-positive patients with no CAD, 5.8% in troponin-negative patients with CAD, and 8.6% in troponin-positive patients with CAD (p=0.012).
Elevated troponin in ACS is associated with a higher risk for death or reinfarction, even among patients who do not have significant angiographic CAD. The mechanisms conferring this adverse prognosis merit further study.

Full text

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Acute Myocardial Infarction
Prognostic Implications of Elevated Troponin
in Patients With Suspected Acute Coronary
Syndrome But No Critical Epicardial Coronary Disease
A TACTICS-TIMI-18 Substudy
Hisham Dokainish, MD,* Manu Pillai, MD,* Sabina A. Murphy, MPH,† Peter M. DiBattiste, MD,§
Marc J. Schweiger, MD,‡ Amir Lotfi, MD,‡ David A. Morrow, MD, MPH,†
Christopher P. Cannon, MD,† Eugene Braunwald, MD,† Nasser Lakkis, MD,*
for the TACTICS-TIMI-18 Investigators
Houston, Texas; and Boston and Springfield, Massachusetts
OBJECTIVES
The purpose of this study is to determine whether there is clinical significance to elevated
troponin I in patients with suspected acute coronary syndromes (ACS) with non-critical
angiographic coronary stenosis.
Elevation of troponin in patients admitted with ACS symptoms with non-critical coronary
artery disease (CAD) may result from coronary atherothrombosis not evident using standard
angiography or from other ischemic and non-ischemic causes that may confer increased risk
for future events.
Patients with ACS enrolled in the Treat Angina With Aggrastat and Determine Cost of
Therapy With Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction
(TACTICS-TIMI)-18 were included. Of 2,220 patients enrolled in the trial, 895 were
eligible. Patients were divided into four groups according to troponin status on admission and
presence of significant angiographic stenosis. Baseline brain natriuretic peptide (BNP) and
C-reactive protein (CRP) were obtained on all patients.
The median troponin I levels were 0.71 ng/ml in patients with CAD compared with 0.02
ng/ml in patients without CAD (p ? 0.0001). Troponin-positive patients with or without
angiographic CAD had higher CRP and BNP levels compared with troponin-negative
patients (p ? 0.01 for both). The rates of death or reinfarction at six months were 0% in
troponin-negative patients with no CAD, 3.1% in troponin-positive patients with no CAD,
5.8% in troponin-negative patients with CAD, and 8.6% in troponin-positive patients with
CAD (p ? 0.012).
CONCLUSIONS Elevated troponin in ACS is associated with a higher risk for death or reinfarction, even
among patients who do not have significant angiographic CAD. The mechanisms
conferring this adverse prognosis merit further study.
19–24) © 2005 by the American College of Cardiology Foundation
BACKGROUND
METHODS
RESULTS
(J Am Coll Cardiol 2005;45:
Cardiac troponins are independent predictors of death or
reinfarction in patients presenting with acute coronary
syndromes (ACS) (1–3). Moreover, troponin elevations in
ACS have been associated with a higher incidence of
multivessel disease, complex lesions, visible thrombus, and
impaired myocardial perfusion (4–7).
The finding of elevated cardiac troponin in patients who
are subsequently found not to have non-critical epicardial
coronary artery disease (CAD) at angiography has been a
source of confusion for clinicians, and led to concern over
“false-positive” results with this biomarker (8). In this study,
we address for the first time this important clinical issue by
evaluating the outcome of patients with suspected ACS
according to the presence or absence of significant CAD on
angiography and troponin status on admission.
METHODS
Study population. The data were drawn from an 895-
patient subset from the Treat Angina With Aggrastat and
Determine Cost of Therapy With Invasive or Conserva-
tive Strategy-Thrombolysis In Myocardial Infarction
(TACTICS-TIMI)-18 trial who were randomized to the
invasive strategy, had angiographic evaluation, and baseline
determination of troponin I. The design of TACTICS-
TIMI-18 has been previously described (9).
Troponin testing. Cardiac troponin I (cTnI) was mea-
sured using the ACS:180 Chemiluminescensce troponin I
Immunoassay (Bayer Diagnostics, Tarrytown, New York).
This assay is an automated system using a two-site sandwich
immunoassay and direct chemoilluminescence technology.
From the *Section of Cardiology, Baylor College of Medicine, Houston, Texas;
†Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts;
‡Division of Cardiology, Baystate Medical Center, Springfield, Massachusetts; and
§Merck and Co., West Point, Pennsylvania. For a complete listing of the TACTICS-
TIMI-18 Investigators see reference 9.
Manuscript received June 10, 2004; revised manuscript received September 15,
2004, accepted September 19, 2004.
Journal of the American College of Cardiology
© 2005 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 45, No. 1, 2005
ISSN 0735-1097/05/$30.00
doi:10.1016/j.jacc.2004.09.056

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The manufacturer reports a lower limit of detection of 0.03
ng/ml. The total imprecision determined in the core labo-
ratory was characterized by a coefficient of variation of
10% at 0.4 ng/ml, 15% at 0.2 ng/ml, and 20% at 0.1
ng/ml. On the basis of our prior work with this assay, the
threshold used to define a positive cTnI test was 0.1
ng/ml (10,11).
B-type natriuretic peptide (BNP) and C-reactive protein
testing (CRP). Blood samples for BNP and CRP were
obtained at enrollment in citrated tubes, and plasma was
isolated within 60 min of acquisition. Aliquots for BNP
testing were shipped frozen to Biosite Inc. (San Diego,
California), where they were thawed and analyzed using an
established immunoassay by personnel blinded to clinical
outcomes. The decision limit of 80 pg/ml was prespecified
based on previous work with this assay (12); CRP levels
were measured with the BN II Nephelometer (Dade-
Behring, Deerfield, Illinois), and a prespecified decision
limit of 15 mg/l was used (13).
Angiographic analysis. Only patients who were assigned
to the invasive arm with early coronary angiography (be-
tween 4 and 48 h after randomization) are included in this
analysis. Patients were determined to have significant an-
giographic CAD if they had ?50% stenosis in any of their
coronary arteries as assessed by the local study investigators.
There were five patients who had no stenoses ?50% but
underwent percutaneous coronary intervention during the
index hospitalization and were excluded from the present
analysis. Investigators were not made aware of the patients’
troponin status.
Statistical analysis. Baseline demographics and electro-
cardiographic characteristics were compared between
groups using Pearsons’ chi-square test or Fisher exact test
(if n ?5) for categorical variables and Student t test or
analysis of variance for continuous variables. Continuous
biomarker data are described as both median and mean
values ? SD and were compared using the nonparametric
Wilcoxon rank-sum test (for two-way comparisons) or
Kruskal-Wallis test (for four-way comparisons). A p
value of ?0.05 was considered statistically significant. All
analyses were performed using STATA v8.0 (STATA
Corp., College Station, Texas).
RESULTS
Baseline characteristics. Baseline clinical characteristics of
the study patients are shown in Table 1. Of the 895 patients
who underwent angiography, 542 (61%) had elevated tro-
ponin values, and 510 (94%) of the patients with elevated
troponin had evidence of significant angiographic CAD. Of
the remaining 353 patients with negative troponin, 278
(79%) had evidence of significant CAD, whereas 75 (21%)
did not. As shown in Table 1, there were no differences in
smoking status, congestive heart failure, or renal function
among the four groups.
When comparing TnI-positive patients with angio-
graphic CAD to those without CAD, patients with elevated
troponin and CAD were more likely to have a history of
diabetes (p ? 0.034), hypertension (p ? 0.062), and
hypercholesterolemia (p ? 0.001). Similarly, TnI-positive
patients with CAD were more likely to be white (p ?
0.001) and have ST-segment depression on the initial
electrocardiogram (p ? 0.009). The TnI-positive patients
without angiographic CAD were more likely to be females
than males (p ? 0.017).
Troponin, BNP, and CRP. The median TnI level in
patients with CAD (n ? 788) was 0.71 ng/ml (interquartile
range 0.02 to 5.7 ng/ml), compared with 0.02 ng/ml
(interquartile range 0 to 0.24 ng/ml) in patients without
CAD (n ? 107, p ? 0.0001).
Table 2 shows baseline BNP and CRP levels in the four
groups of patients. There were statistically significant dif-
ferences in the median BNP and CRP levels between the
four groups, and in the percentage of patients with BNP
levels ?80 pg/ml and CRP ?1.5 mg/dl. Troponin-positive
patients with and without angiographic stenosis had similar
BNP and CRP measurements. Both BNP and CRP levels
were significantly higher in TnI-positive patients without
CAD compared with TnI-negative patients without CAD
(p ? 0.0001).
Six-month outcome by TnI status and CAD. As shown
in Table 3, the rate of death, reinfarction, or readmission for
ACS was 15.5% for troponin-positive patients with CAD,
20.1% in troponin-negative patients with CAD, 6.3% in
troponin-positive patients without CAD, and 2.7% in
troponin-negative patients without CAD (p ? 0.001).
There was no significant difference in outcome between
troponin-positive patients with CAD compared with those
without CAD (p ? 0.20). We then tested for interaction
between troponin level and CAD for the composite out-
come at six months. There was no significant interaction
(odds ratio 3.35, p ? 0.246). Figure 1 shows the Kaplan-
Meier death or reinfarction-free survival curve at six months
for the four study groups. The rate of death or reinfarction
was 8.6% in patients with positive troponin and CAD
compared with 5.8% in troponin-negative patients with
CAD, 3.1% in troponin-positive patients without CAD,
and 0% in troponin-negative patients without CAD (p ?
0.012). Troponin I positivity without CAD (odds ratio
Abbreviations and Acronyms
ACS
BNP
CAD
CRP
cTnI
TACTICS-TIMI ? Treat Angina With Aggrastat and
Determine Cost of Therapy With
Invasive or Conservative Strategy-
Thrombolysis In Myocardial
Infarction
? acute coronary syndromes
? B-type natriuretic peptide
? coronary artery disease
? C-reactive protein
? cardiac troponin I
20 Dokainish et al.
Troponin Positivity Without CAD in ACS
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15.7, 95% confidence interval 2.05 to 120.7, p ? 0.008),
troponin I positivity with CAD (odds ratio 11.6, 95%
confidence interval 1.48 to 90.2, p ? 0.019), and gender
(odds ratio 0.51, 95% confidence interval 0.32 to 0.81, p ?
0.005) were all independently associated with outcome on
multivariate analysis for the triple composite end point. A
multivariate analysis could not be done for death or rein-
farction alone because there were no events in the troponin-
negative no CAD group.
Six-month outcome by CAD and positive markers. The
incidence of death, MI, or rehospitalization according to
the presence of positive markers or CAD is shown in
Table 4. There was an incremental worsening in outcome
among the four groups. The rate of death or reinfarction
was 0% in patients with all markers negative and no
CAD, 2.1% in patients with any marker positive and no
CAD, 5.4% in patients with all markers negative and
CAD, and 8.6% in patients with any marker positive
and CAD (p ? 0.023).
DISCUSSION
We have previously demonstrated the strong prognostic
value of cardiac troponin in patients with high clinical
suspicion for non–ST-segment elevation ACS (14). The
present study demonstrates that, in the important group of
patients presenting with symptoms of ACS who were later
found to not have angiographically significant CAD, the
presence of an elevated troponin is also associated with an
adverse prognosis. This finding challenges the idea that
these are “false-positive” troponin results and that these
patients may be regarded as low-risk for subsequent cardio-
vascular events. Elevation of troponin in these patients may
result from coronary atherothrombosis not evident using
Table 1. Baseline Characteristics of Study Patients
TnI Negative, No CAD
(n ? 75)
TnI Positive, No CAD
(n ? 32)
TnI Negative, CAD
(n ? 278)
TnI Positive, CAD
(n ? 510)p Value
Age, yrs (mean)
Gender (% male)
57.3 ? 11.6
45.3
34/75
69.3
52/75
16.0
12/75
49.3
37/75
73.3
55/75
25.3
19/75
28.0
21/75
8.0
6/75
20.0
15/75
6.7
5/75
30.7
23/75
1.3
1/75
40.0
20/75
2.7
2/75
4.0
3/75
2.7
2/75
0
0/75
0
0/75
60.5 ? 12.0
0.93 ? 0.56
60.6 ? 13.3
50.0
16/32
53.1
17/32
15.6
5/32
28.1
9/32
46.9
15/32
25.0
8/32
25.0
8/32
9.4
3/32
15.6
5/32
12.5
4/32
21.9
7/32
0
0/32
18.8
6/32
9.4
3/32
3.1
1/32
3.1
1/32
0
0/32
0
0/32
58.3 ? 9.5
1.46 ? 2.31
62.3 ? 10.4
61.5
171/278
80.9
225/278
23.4
65/278
74.1
206/278
67.3
187/278
27.3
76/278
26.3
73/278
7.6
21/278
20.5
57/278
20.5
57/278
53.2
148/278
29.1
81/278
44.6
124/278
8.3
23/278
11.2
31/278
1.4
4/278
43.2
120/278
12.6
35/278
54.2 ? 12.7
1.01 ? 0.25
62.5 ? 11.0
70.2
358/510
79.6
406/510
33.7
172/510
60.0
306/510
63.3
323/510
31.2
159/509
47.3
241/510
13.9
71/510
38.8
198/510
11.2
57/510
34.1
174/510
17.5
89/510
20.6
105/510
6.5
33/510
6.9
35/510
2.2
11/510
50.2
256/510
28.8
247/510
51.6 ? 12.5
1.01 ? 0.30
0.002
? 0.001
Race (% white)0.001
Diabetes (%)
? 0.001
Hypercholesterolemia (%)
? 0.001
Hypertension (%) 0.044
Smoker (%) 0.514
ST deviation (%)
? 0.001
ST elevation (%)0.040
ST depression (%)
? 0.001
Hx angina (%) 0.001
Prior MI (%)
? 0.001
Hx CABG (%)
? 0.001
Hx PTCA (%)
? 0.001
Hx CHF (%)0.336
PVD (%)0.060
Hx renal insufficiency (%)0.830
PCI during index
hospitalization (%)
CABG during index
hospitalization (%)
Ejection fraction (mean)
Creatinine (mean)
? 0.001
? 0.001
? 0.001
0.0281
CABG ? coronary artery bypass graft; CAD ? coronary artery disease; CHF ? congestive heart failure; Hx ? history; MI ? myocardial infarction; PCI ? percutaneous coronary
intervention; PTCA ? percutaneous transluminal; PVD ? peripheral vascular disease; TnI ? troponin I.
21
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Troponin Positivity Without CAD in ACS

Page 4

standard angiography or from other ischemic and non-
ischemic mechanisms.
In the current study, 6% of patients who satisfied clinical
criteria for ACS and had elevated troponin early after
presentation were found not to have significant angio-
graphic coronary stenosis. Despite the absence of significant
coronary stenosis, this group of patients had a 3.1% inci-
dence of death, reinfarction, or rehospitalization for ACS at
six months compared with 0% in troponin-negative patients
without angiographic CAD. The readmission rate at six
months for troponin-positive patients without CAD was
6.3% compared with 2.7% in troponin-negative patients
without CAD. Despite that this analysis is post hoc and
observational in nature, multiple in number, it is
hypothesis-generating and not definitive.
Several mechanisms can be suggested to explain our
findings. In this study, patients with significant CAD were
only classified if they had angiographic evidence of ?50%
diameter stenosis. It is likely that some patients who were
classified to not have significant CAD had clinically impor-
tant coronary atherothrombosis (15). It is now recognized
that angiography underestimates plaque burden. Other
patients may have presented late after the onset of symp-
toms, at a time where troponins were tracking down and the
degree of stenosis was less than expected. Finally, some
patients with ACS and positive troponin without significant
angiographic stenosis may have sustained myocardial isch-
emia secondary to coronary vasospasm.
In the current study, women comprised only 30% of the
troponin-positive patients with CAD compared with 50%
of the troponin-positive patients without CAD (p ? 0.017).
There has been much discussion in published reports about
coronary microvascular dysfunction and its prevalence in
women without significant obstructive CAD (16–18). Sim-
ilarly, coronary erosions on mild coronary plaques have been
described to occur more often in women (19). This phe-
nomenon may represent another potential explanation for
troponin release, increased CRP levels, and higher rate of
future events without significant coronary stenosis.
Another novel finding in this study is that both BNP and
CRP levels were increased in troponin-positive patients
independent of whether they had significant angiographic
disease or not. Several studies have shown that an elevated
CRP or BNP in the setting of ACS is associated with worse
prognosis (12,20). It is possible that the mechanisms leading
to increased CRP and BNP in troponin-positive patients
without significant angiographic CAD differ from those for
patients with epicardial CAD, but still carry adverse conse-
quences. It is conceivable that etiologies such pulmonary
embolism, left ventricular or diastolic dysfunction, myocar-
ditis, pericarditis, or arrhythmias may have led into elevated
troponin in these patients with subsequent bad outcomes on
Table 2. BNP and CRP by Presence of CAD on Catheterization and Troponin I Status on Admission
Troponin I
p Value
Negative, No CAD
on Cath
Negative, CAD
on Cath
Positive, No CAD
on Cath
Positive, CAD
on Cath
BNP (pg/ml), median and IQ range 15 (0, 37)
(n ? 65)
6.2
4/65
0.46
(0.21, 1.13)
(n ? 75)
16.0
12/75
16 (3, 39)
(n ? 252)
11.1
28/252
0.42
(0.17, 0.97)
(n ? 278)
18.4
51/278
19 (3, 57)
(n ? 29)
24.1
7/29
0.58
(0.24, 1.59)
(n ? 32)
25.0
8/32
38 (8, 81)
(n ? 454)
25.3
115/454
0.70
(0.28, 1,554)
(n ? 520)
25.5
130/510
0.0001
BNP ?80 pg/ml (%)
? 0.001
CRP (mg/l), median and IQ range 0.0001
CRP ?15 mg/l (%)0.063
BNP ? B-type natriuretic peptide; CAD ? coronary artery disease; Cath ? coronary angiography; CRP ? C-reactive protein; IQ ? interquartile.
Table 3. Six-Month Outcomes by Presence or Absence of CAD and Troponin I Status
Troponin I
Negative, No CAD
(n ? 75)
Positive, No CAD
(n ? 32)
Negative, CAD
(n ? 278)
Positive, CAD
(n ? 510) p Value
Death (%)0 3.1
1/32
0
0/32
3.1
1/32
3.1
1/32
6.3
2/32
2.2
6/278
4.3
12/278
5.8
16/278
15.8
44/278
20.1
56/278
3.50.288
0/75
0
0/75
0
0/75
2.7
2/75
2.7
2/75
18/510
5.9
30/510
8.6
44/510
10.4
53/510
15.5
79/510
Re-MI (%) 0.064
Death/re-MI (%) 0.012
Rehospitalization for ACS (%)0.002
Death, re-MI, rehospitalization
? 0.001
ACS ? acute coronary syndromes; CAD ? coronary artery disease; MI ? myocardial infarction.
22 Dokainish et al.
Troponin Positivity Without CAD in ACS
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follow-up. It is possible that some troponin-positive pa-
tients without angiographic CAD, in particular those with
increased BNP, may have suffered from other conditions
resulting in acute increases in ventricular wall stress, such as
non-ischemic cardiomyopathy, worsening heart failure, or
pulmonary embolism (21,22).
A graded relationship between baseline troponin levels in
patients with ACS and death upon intermediate follow-up has
been established (23). We have now shown that ACS patients
withCADhavethegreatestriskforadverseoutcomes,whereas
patients with suspected ACS and elevated troponin but with-
outCADhaveanintermediateriskforrecurrentcardiovascular
events. As such, these findings underscore the notion that
elevated levels of troponin in patients with suspected ACS
without significant CAD (sometimes labeled as “false-
positives”) are the result of myocardial injury, and that these
patients are candidates for aggressive preventive therapies. The
interventions offered must be guided by a clinical assessment of
the probable cause of myocardial injury.
Study limitations. The analysis in the current study is
retrospective in nature, and the study population comes from a
clinical trial dataset that focused on lower-risk patients and
excluded patients with renal insufficiency and other high-risk
features. Troponin data were available at baseline only. The
number of patients with positive troponin without CAD was
small compared with the overall number of patients enrolled in
the study, and, therefore, the results should be interpreted with
caution. However, a similar analysis performed among patients
enrolled in the TIMI-IIIB study yielded similar outcomes.
Investigator-determined coronary stenosis is subjective and not
very reproducible. Angiographic CAD is not an accurate
assessment of underlying atherosclerosis, especially if including
up to 50% stenosis. Our study was not designed to provide
insight into the specific mechanisms resulting in myocardial
Table 4. Six-Month Outcomes by Presence or Absence of CAD and Marker Status (Troponin I, BNP, and CRP)
All Markers
Negative, No CAD
(n ? 53)
Any Marker
Positive, No CAD
(n ? 48)
All Marker
Negative, CAD
(n ? 185)
Any Marker
Positive, CAD
(n ? 590)p Value
Death (%)02.1
1/48
0
0/48
2.1
1/48
4.2
2/48
6.3
3/48
1.6
3/185
4.9
9/185
5.4
10/185
18.4
34/185
22.2
41/185
3.70.328
0/53
0
0/53
0
0/53
1.9
1/53
1.9
1/53
22/590
5.8
34/590
8.6
51/590
10.5
62/590
15.9
94/590
Re-MI (%)0.098
Death/Re-MI (%) 0.023
Rehospitalization for ACS (%) 0.001
Death, re-MI, rehospitalization
? 0.001
ACS ? acute coronary syndromes; BNP ? B-natriuretic peptide; CAD ? coronary artery disease; CRP ? C-reactive protein; MI ? myocardial in fraction.
Figure 1. Kaplan-Meier curves for death/myocardial infarction (MI) at 180 days by coronary artery disease (CAD) and troponin I status (p ? 0.029).
Groups: 1 ? troponin-negative/CAD-negative; 2 ? troponin-negative/CAD; 3 ? troponin-positive/CAD-negative; 4 ? troponin-positive/CAD.
23
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Dokainish et al.
Troponin Positivity Without CAD in ACS