Risk stratification in patients with uns
Thrombosis Research (2004) 114, 251 — 257
intl.elsevierhealth.com/journals/thre
Regular Article
Risk stratification in patients with unstable angina
and/or non-ST-elevation myocardial infarction by
Troponin T and plasminogen-activator-inhibitor-1
(PAI-1)
Andreja Sinkovic*, Vojko Pogacar
Department for Medical Intensive Care, Teaching Hospital Maribor, Ljubljanska 5, 2000, Maribor, Slovenia
Received 22 February 2004; received in revised form 23 June 2004; accepted 23 June 2004
Available online 12 August 2004
KEYWORDS
Unstable angina;
Myocardial infarction;
Mortality;
Reinfarction;
Troponin T;
PAI-1
Abstract
Background: Increased Troponin T (TnT) and PAI-1 levels are markers of poor
outcome in acute coronary syndromes (ACS). In order to stratify the risk for 30-day
combined endpoint of mortality and/or reinfarction in unstable angina and/or nonST-elevation myocardial infarction (UA/NSTEMI), TnT and PAI-1 levels were simultaneously assessed. Methods: The TnT and PAI-1 levels of 113 patients with UA/NSTEM
were estimated within the first 48 h. Initial therapy was medical. Percutaneous
coronary interventions were performed in case of recurrent ischemia and/or
hemodynamic and/or rhythmic instability. Results: Statistically significant differences in mean admission PAI-1 (4.2 F 3.4 vs. 2.8 F 2.4 U/ml, p b 0.05), mean peak
PAI-1 levels within the first 48 h (4.98 F 3.1 vs. 3.4 F 2.5 U/ml, p b 0.05), and no
significant difference in any TnT level were observed between patients with and
without 30-day mortality and/or reinfarction. The risk for 30-day mortality and/or
reinfarction significantly increased in patients with admission PAI-1 levels N 4.0 U/ml
(OR=4.44, 95%CI=1.47–13.4), peak PAI-1 levels N 4.0 U/ml (OR=5.78, 95%CI=1.838–
18.20) and with simultaneously increased peak PAI-1 N 3.5 U/ml and TnT N 0.1 Ag/l
within the first 48 h (OR=4.9, 95%CI=1.569–15.385). Conclusions: Simultaneous
assessment of TnT and PAI-1 would provide complementary prognostic information
and enable clinicians to stratify risk more effectively among patients with UA/
NSTEMI.
D 2004 Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: +386 2 3211656; fax: +386 2 3312393.
E-mail address: [email protected] (A. Sinkovic).
0049-3848/$ - see front matter D 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.thromres.2004.06.040
252
Introduction
Acute coronary syndromes (ACS), either with or
without persistent ST-segment elevation on ECG,
share the same athero-thrombotic mechanism and
involve different processes including thrombosis,
fibrinolysis, hemostasis and inflammation [1].
In ACS without persistent ST-segment elevation
on ECG, unstable angina (UA) and non-ST-elevation myocardial infarction (NSTEMI) are considered together as a clinical entity [2,3]. In UA/
NSTEMI, Troponin T (TnT) is the most important
biochemical marker of ischemic necrosis and of
prognosis including mortality, reinfarction and the
need for percutaneous coronary interventions
(PCI). Prognostic role of increased TnT levels in
UA/NSTEMI is more accurate when clinical risk
factors, such as increased age, character of chest
pain, changes in ECG during pain, hemodynamic
compromise and arrhythmias, are considered as
well [3—5].
Increased plasminogen-activator-inhibitor-1
(PAI-1) activity is a marker of impaired fibrinolysis.
It significantly stratifies the risk of adverse outcome
in ST-elevation ACS due to its resistance to fibrinolytic agents and progression of coronary atherothrombosis by decreasing endogenous fibrinolytic
plasma activity. It promotes pathogenesis of vulnerable plaques and inflammation and participates in
the genesis of acute coronary events [6—11].
Utilizing simultaneous assessment of TnT and
PAI-1 levels in patients with UA/NSTEMI has not yet
been defined. Our aim was to investigate the
predictive role of simultaneous assessments of
TnT and PAI-1 levels for the 30-day combined
endpoint of all-cause mortality and/or reinfarction
in patients with UA/NSTEMI.
Patients and methods
Of the 134 patients, consecutively admitted to the
Department of Medical Intensive Care over 24
months due to UA/NSTEMI, 113 were studied
prospectively after the patients’ informed consent
was obtained. The study was approved by the
National Ethical Commission.
Patients were included, if they had had chest
pain at rest within the last 48 h (Braunwald classes
IIIA, IIIB and IIIC), changes in standard ECG without
persistent ST-segment elevations (ST-segment
depression z0,1 mV and/or T wave inversion z0,1
mV and/or pathological Q wave suspective of
previous MI) and/or increased TnT level on admission [2—5]. PAI-1 levels were estimated in addition
A. Sinkovic, V. Pogacar
to admission TnT. Neither TnT, nor PAI-1 levels were
estimated in 21 excluded patients.
On admission, standard ECG was recorded,
continuous monitoring of rhythm initiated and a
peripheral i.v. catheter inserted. TnT was estimated by the immunochemical method (Boehringer-Mannheim, Germany, normal levels up to
0.1 Ag/l) from blood samples drawn on admission
8—12 h later and in case of recurrent chest pain to
confirm reinfarctions. [12]. PAI-1 activity was
estimated by the chromogenic method (Berichrom
PAI by Dade Behring, Marburg, Germany, normal
range 0.3—3.5 U/ml) from blood samples on
admission and every 12 h within the first 48 h of
hospitalization [13]. Creatine kinase MB isoenzyme
(CK-MB mass) was estimated by the immunomethod
(Boehringer-Mannheim, normal levels up to 5 Ag/l)
at recurrence of chest pain to confirm reinfarction.
Standard ECG was recorded 12 h after admission
and afterwards every 24 h of hospitalization and at
recurrence of chest pain.
Treatment consisted of daily oral acetylsalycylic
acid (ASA; 100—300 mg tablet), i.v. infusion of
standard heparin or s.c. injection of the recommended dose of low molecular weight heparin for
at least 5 days. Heparin therapy was prolonged at
the discretion of the attending physician [3—5]. If
necessary, the patients were treated with nitroglycerin, clopidogrel, beta blockers, ACE inhibitors,
statins, diuretics, calcium-channel blockers, dobutamin, etc. [3—5].
NSTEMI was confirmed by an increase in TnT
level N 0.1 Ag/l either on admission and/or 8—12 h
later.
Arterial hypertension was defined, when with
chronic antihypertensive therapy normal arterial
blood pressure was achieved, or when during
hospitalization systolic blood pressure was N 160
mm Hg and/or diastolic N 100 mm Hg on several
occasions without chest pain and without prior
antihypertensive treatment.
For at least 2 days, the patients were continuously monitored for arrhythmias and conduction
disturbances. Noninvasive systemic arterial blood
pressure was measured hourly and clinical examination was carried out twice daily during the first
few days. Later on, the patients were examined
at least once daily and noninvasive systemic
arterial blood pressure was measured at least
once daily.
In case of recurrent chest pain and/or hemodynamic and/or rhythmic instability within the first
48—72 h, the patients were treated with glycoprotein receptor IIb/IIIa (GP) antagonists (tirofiban, integrillin, abciximab), followed by urgent
percutaneous coronary angiography and interven-
Risk stratification in patients with unstable angina and/or non-ST-elevation myocardial infarction
tion (PCI) or surgical revascularization [3—5]. PCI
was associated with inevitable clopidogrel therapy-loading dose 300 mg, followed by 75 mg daily
[14].
In patients without recurrent chest pain,
hemodynamic and/or rhythmic instability within
the first 48—72 h, coronary angiography was
performed within the next few days or weeks
and subsequent PCI or surgical revascularization,
if indicated [3—5].
The primary end-point was 30-day combined
endpoint of all-cause mortality and/or reinfarction
rate. Complications within 30 days were reinfarctions, mortality, heart failure, bleedings, conduction disturbances and arrhythmias.
Atrial arrhythmias were atrial tachycardias,
atrial fibrillation and/or flutter. Ventricular
arrhythmias, tachycardias and fibrillation were
classified according to Lown’s classification [15].
Conduction disturbances were bundle branch
blocks or atrioventricular blocks I, II, III, sinoatrial
block or asystole. Reinfarction or a new MI was
defined as recurrent chest pain, accompanied by
new changes in ECG, recurrent rise in TnT and/or
rise and fall in CK-MB mass, when TnT was
already high (2.3). Heart failure was diagnosed
when classes II, III and IV were identified,
according to the NYHA and Killip—Kimball classification [16].
Statistical analysis
Statistical analysis was performed by IBM PC, SPSS
for Windows. The values were expressed as
meansFstandard deviations, or percentages where
necessary. Differences between the two groups
were tested by the chi-squared test and two-sided
Student’s t-test. The p value b0.05 was statistically
significant. Odds ratios and 95% confidence interTable 1
253
vals (CI) were calculated to test the relative
importance of variables [17].
Results
Baseline characteristics and admission laboratory
data of patients are listed in Table 1. Complications of patients within 30 days are summarized in
Table 2.
Primary endpoint 30-day combined endpoint of
all-cause mortality and/or reinfarction rate was
14.2% (16/113). Thirty-day survival without reinfarction was observed in 97 patients. Between the
group with mortality and/or reinfarction (Group 1)
and the group of 97 survivors without reinfarction
(Group 2) within 30 days, we observed nonsignificant and significant differences (Tables 1 and 3).
We observed significant differences in mean admission PAI-1 levels (Table 1) and peak PAI-1 levels
(4.98F3.1 vs. 3.4F2.5, p=0.022).
We did not observe any significant difference
between the Group 1 and Group 2 in neither
mean TnT level 8—12 h after admission (1.1F1.4
vs. 0.83F1.3 Ag/l; p=NS) nor mean peak TnT
level within 48 h (1.4F1.4 vs. 0.9F1.3 Ag/l;
p=NS).
When the patients were stratified into subgroups
according to different TnT levels, elevated TnT
levels were not associated with significant 30-day
combined endpoint of mortality and/or reinfarction
(Table 4). When stratifying patients into subgroups,
according to different PAI-1 levels and according to
simultaneous increase of PAI-1 and TnT, we
observed that admission and peak PAI-1 levels N 4.0
4.0 U/ml as well as simultaneous increase of peak
PAI-1 and peak TnT were associated with significant
30-day combined all-cause mortality and/or rein-
Baseline characteristics and admission laboratory data of patients
Baseline characteristics
and admission laboratory data
All patients (n=113)
Group 1 (n=16)
Group 2 (n=97)
p
Men (%)
Age (meanFS.D. years)
BMI (meanFS.D. years, kg/m2)
Arterial hypertension (%)
Diabetes (%)
Previous infarction (%)
Smoking (%)
Braunwald class IIIA/IIIB/IIIC (%)
ST-segment depression in ECG (%)
T-wave inversion (%)
TnT (meanFS.D. Ag/l)
PAI-1 activity (meanFS.D. U/ml)
65.5
62.2F10.3
26.5F3.6
61.9
24.8
39.8
20.4
1.8/88.5/9.7
66.4
49.6
0.4F0.68
2.99F2.5
50
66.4F7.9
26.7F3.7
62.5
31.3
56.3
12.5
0/93.8/6.3
87.5
25
0.40F0.6
4.2F3.4
68
61.5F10.5
26.5F3.6
61.8
23.7
37.1
21.6
2/87.6/10.3
62.9
53.6
0.4F0.68
2.8F2.4
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
0.042
Group 1: Patients with mortality and/or reinfarctions. Group 2: Survivors without reinfarctions. TnT: Troponin T. PAI-1:
Plasminogen-activator-inhibitor-1.
254
Table 2
A. Sinkovic, V. Pogacar
Complications within 30 days
Complications
All patients (n=113)
Heart failure Killip II (%)
Pulmonary edema (%)
Cardiogenic shock (%)
Ventricular arrhythmias (%)
Ventricular fibrillation (%)
Atrial arrythmias (%)
Conduction disturbances (%)
In-hospital mortality (%)
30-day Mortality (%)
30-day Reinfarctions (%)
30-day Mortality and/or
reinfarctions (%)
47.8
15
13.3
28.3
4.4
17.7
18.6
9.7
10.6
9.7
14.2
Troponin T,
Ag/l
All
(n=113), %
Group 1
(n=16), %
Group 2
(n=98), %
p
50
37.5
40.2
12.5
58.8
47.4
39.8
8.2
NS
NS
NS
NS
Troponin T 8—12 h after admission
N0.1
76.1
81.3
N0.2
66.4
75
N0.3
59.3
62.5
N1.0
27.4
31.2
75.3
64.9
58.8
26.8
NS
NS
NS
NS
Peak Troponin T
N0.1
77.9
N0.2
73.4
N0.3
64.6
N1.0
31.9
76.3
71.1
61.8
29.9
NS
NS
NS
NS
Admission Troponin T
N0.1
57.5
N0.2
46
N0.3
39.8
N1.0
8.8
farction rate of our patients (Table 5). Further
analysis demonstrated that the risk of combined 30day mortality and/or reinfarction rate of patients
with UA/NSTEMI significantly increased with PAI1 N 4.0 U/ml and with the simultaneous increase of
PAI-1 N 3.5 U/ml and TnT N 0.1 Ag/l within the first
48 h of hospitalization (Fig. 1).
Discussion
According to the results of several registries,
including ENACT, Euroheart Survey, GRACE and
NRMI, the incidence and prevalence of UA/NSTEMI
Table 3
Table 4 Stratification of patients according to Troponin T levels
Treatment and interventions within 30 days
Treatment and
interventions
All
patients
(n=113)
Group 1
(n=16)
Group 2
(n=97)
p
ASA (%)
Beta blocking
agents (%)
Diuretics (%)
ACE
inhibitors (%)
Statins (%)
Clopidogrel (%)
IABC (%)
Calcium-chanell
blockers (%)
Ticlopidin (%)
Inotropes (%)
Nitrates (%)
Urgent PCI (%)
Elective PCI (%)
GP IIb/IIIa
inhibitors (%)
CABG (%)
98.2
58.4
100
37.5
97.9
61.8
NS
NS
51.3
60.2
81.3
43.8
46.4
62.9
0.014
NS
59.3
15
3.5
7.9
43.8
6.3
18.8
6.3
61.9
16.5
1
8.2
NS
NS
0.007
NS
6.2
10.6
92
8.8
31.8
18.6
6.3
43.8
100
9.3
32.9
31.3
6.2
5.2
90.7
6.3
25
16.5
NS
0.0001
NS
NS
NS
NS
11.6
18.8
16.5
NS
Group 1: Patients with mortality and/or reinfarctions.
Group 2: Survivors without reinfarctions. PCI: Percutaneous
coronary interventions.GP IIb/IIIa inhibitors: Glycoprotein
IIb/IIIa inhibitors. CABG: Coronary artery bypass grafting.IABC: Intra-aortic balloon counterpulsation.
87.5
87.5
81.3
43.8
Group 1: Patients with mortality and/or reinfarctions.
Group 2: Survivors without reinfarctions.
have increased over the last few years, while the
number of patients with STEMI is declining. Therefore, accurate early diagnosis, treatment and risk
stratification in patients with UA/NSTEMI are gaining importance [18—21].
Chest pain, changes in standard ECG and
increased TnT level are most important for early
recognition and prognosis in UA/NSTEMI patients
[3—5,22]. Classification of UA by Braunwald incorporated clinical circumstances as well as severity
of chest pain. Prognosis is worse with chest pain
within 14 days of an acute MI or in primary UA
Table 5 Risk stratification, according to increased
PAI-1 activity and simultaneous increase of PAI-1 and
TnT level
PAI-1/PAI-1+TnT
Group 1
(n=16)
Group 2
(n=97)
p
Admission PAI-1N3.5
U/ml
Admission PAI-1N4.0
U/ml
Peak PAI-1N3.5 U/ml
Peak PAI-1N4.0 U/ml
Admission PAI-1N3.5
U/ml+TnTN0.1 Ag/l
Admission PAI-1N4
U/ml+TnTN0.1 Ag/l
Peak PAI-1N3.5
U/ml+TnTN0.1 Ag/l
Peak PAI-1N4
U/ml+TnTN0.1 Ag/l
8 (50%)
25 (25.5%)
NS
8 (50%)
18 (18.4%)
0.014
11 (68%)
11 (68%)
4 (25%)
37 (37.7%)
27 (27.5%)
16 (16.5%)
0.04
0.0043
NS
4 (25%)
13 (13.4%)
NS
11 (68.8%)
30 (30.9%)
0.005
9 (56%)
23 (23.7%)
0.014
Group 1: Patients with mortality and/or reinfarctions.
Group 2: Survivors without reinfarctions.TnT: Troponin T. PAI1: Plasminogen-activator-inhibitor-1.
Risk stratification in patients with unstable angina and/or non-ST-elevation myocardial infarction
255
Figure 1 Odds ratios (boxes) and 95% confidence intervals (horizontal lines) for the combined 30-day endpoint of allcause mortality and/or reinfarction. Left of 1 indicates reduced risk and right of 1 indicates increased risk for the
combined 30-day endpoint of all-cause mortality and/or reinfarction rate.
without extracardiac causes. 88.5% of our patients
had primary UA (Braunwald class IIIB) and 9.7%
were within 14 days of an acute MI (Braunwald
class IIIC) [4,22]. Considering changes in standard
ECG, ST-segment depression, carrying worse prognosis, was present in 66.4% of our patients [4].
Increased TnT level, the most sensitive and
specific biochemical marker of ischemic necrosis
and prognosis, was present in 77.9% of our
patients, indicating the presence of NSTEMI in
majority of patients. When considering chest pain,
ECG changes and TnT levels, our patients were of
high-risk profile for subsequent events such as
mortality and reinfarctions. Indeed, 30-day combined all-cause mortality and/or reinfarction rate
was as high as 14.2%.
Heart failure, arrhythmias and recurrent chest
pain are well-known risk factors for subsequent
mortality or new MI in patients with UA/NSTEMI.
When they occurred within first 48 h in spite of
medical therapy, urgent PCI or surgical revascularization were performed [3—5]. However, neither
urgent PCI nor CABG within 30 days were associated
with 30-day combined endpoint of mortality and/or
reinfarction rate (Table 4).
Some clinical studies observed that in UA/
NSTEMI, risk stratification by multiple biomarkers
was more precise and earlier than by a single
marker, detecting multiple pathological processes
of coronary athero-thrombosis including inflammation, myocardial damage or dysfunction [23].
Increased PAI-1 activity is a marker of impaired
fibrinolysis, associated with severity, progression
and complications of atherosclerosis such as rupture, erosion or inflammation with subsequent
thrombosis [6—9]. Many clinical and experimental
studies suggest that thrombosis and inflammation
are closely linked, as markers of thrombosis are
often associated with inflammation and vice versa
[10,24]. PAI-1 is an acute phase reactant in
inflammation, where it stabilizes the chemoattractant form of Interleukin-8 [25]. The proinflammatory status associated with overexpression of TNF,
IL-6 and PAI-1, found in insulin resistant people,
provides a potential link between insulin resistance
and endothelial dysfunction, the early stage of
atherosclerosis in obese and type 2 diabetes
[26,27]. Our observations suggest that when PAI-1
assessment within the first 48 h was added to risk
stratification provided by clinical picture, ECG
256
changes and TnT estimation, prediction of 30-day
combined endpoint of mortality and/or reinfarction
was more accurate and earlier. The conclusion is
that simultaneously assessed TnT and PAI-1 could
provide complementary prognostic information and
allow clinicians to stratify risk more effectively
among patients with UA/NSTEMI.
There are several limitations of this small pilot
study. The population studied is relatively small in
size to allow any definite conclusions at present to
introduce our observations into everyday clinical
practice. Our observations should be validated in a
larger and better defined population, especially
regarding prior drug treatment, prior PCI or surgical
revascularization, etc.
Acknowledgments
The work was supported by the grant from Slovenian Ministry of Education, Science and Sports (L32159, 3411-00-232159). The authors wish to thank
Prof. Joze Nemec from the University of Maribor for
help with the statistical analysis and Marijana
Gajsek-Marchetti for help with the manuscript.
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intl.elsevierhealth.com/journals/thre
Regular Article
Risk stratification in patients with unstable angina
and/or non-ST-elevation myocardial infarction by
Troponin T and plasminogen-activator-inhibitor-1
(PAI-1)
Andreja Sinkovic*, Vojko Pogacar
Department for Medical Intensive Care, Teaching Hospital Maribor, Ljubljanska 5, 2000, Maribor, Slovenia
Received 22 February 2004; received in revised form 23 June 2004; accepted 23 June 2004
Available online 12 August 2004
KEYWORDS
Unstable angina;
Myocardial infarction;
Mortality;
Reinfarction;
Troponin T;
PAI-1
Abstract
Background: Increased Troponin T (TnT) and PAI-1 levels are markers of poor
outcome in acute coronary syndromes (ACS). In order to stratify the risk for 30-day
combined endpoint of mortality and/or reinfarction in unstable angina and/or nonST-elevation myocardial infarction (UA/NSTEMI), TnT and PAI-1 levels were simultaneously assessed. Methods: The TnT and PAI-1 levels of 113 patients with UA/NSTEM
were estimated within the first 48 h. Initial therapy was medical. Percutaneous
coronary interventions were performed in case of recurrent ischemia and/or
hemodynamic and/or rhythmic instability. Results: Statistically significant differences in mean admission PAI-1 (4.2 F 3.4 vs. 2.8 F 2.4 U/ml, p b 0.05), mean peak
PAI-1 levels within the first 48 h (4.98 F 3.1 vs. 3.4 F 2.5 U/ml, p b 0.05), and no
significant difference in any TnT level were observed between patients with and
without 30-day mortality and/or reinfarction. The risk for 30-day mortality and/or
reinfarction significantly increased in patients with admission PAI-1 levels N 4.0 U/ml
(OR=4.44, 95%CI=1.47–13.4), peak PAI-1 levels N 4.0 U/ml (OR=5.78, 95%CI=1.838–
18.20) and with simultaneously increased peak PAI-1 N 3.5 U/ml and TnT N 0.1 Ag/l
within the first 48 h (OR=4.9, 95%CI=1.569–15.385). Conclusions: Simultaneous
assessment of TnT and PAI-1 would provide complementary prognostic information
and enable clinicians to stratify risk more effectively among patients with UA/
NSTEMI.
D 2004 Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: +386 2 3211656; fax: +386 2 3312393.
E-mail address: [email protected] (A. Sinkovic).
0049-3848/$ - see front matter D 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.thromres.2004.06.040
252
Introduction
Acute coronary syndromes (ACS), either with or
without persistent ST-segment elevation on ECG,
share the same athero-thrombotic mechanism and
involve different processes including thrombosis,
fibrinolysis, hemostasis and inflammation [1].
In ACS without persistent ST-segment elevation
on ECG, unstable angina (UA) and non-ST-elevation myocardial infarction (NSTEMI) are considered together as a clinical entity [2,3]. In UA/
NSTEMI, Troponin T (TnT) is the most important
biochemical marker of ischemic necrosis and of
prognosis including mortality, reinfarction and the
need for percutaneous coronary interventions
(PCI). Prognostic role of increased TnT levels in
UA/NSTEMI is more accurate when clinical risk
factors, such as increased age, character of chest
pain, changes in ECG during pain, hemodynamic
compromise and arrhythmias, are considered as
well [3—5].
Increased plasminogen-activator-inhibitor-1
(PAI-1) activity is a marker of impaired fibrinolysis.
It significantly stratifies the risk of adverse outcome
in ST-elevation ACS due to its resistance to fibrinolytic agents and progression of coronary atherothrombosis by decreasing endogenous fibrinolytic
plasma activity. It promotes pathogenesis of vulnerable plaques and inflammation and participates in
the genesis of acute coronary events [6—11].
Utilizing simultaneous assessment of TnT and
PAI-1 levels in patients with UA/NSTEMI has not yet
been defined. Our aim was to investigate the
predictive role of simultaneous assessments of
TnT and PAI-1 levels for the 30-day combined
endpoint of all-cause mortality and/or reinfarction
in patients with UA/NSTEMI.
Patients and methods
Of the 134 patients, consecutively admitted to the
Department of Medical Intensive Care over 24
months due to UA/NSTEMI, 113 were studied
prospectively after the patients’ informed consent
was obtained. The study was approved by the
National Ethical Commission.
Patients were included, if they had had chest
pain at rest within the last 48 h (Braunwald classes
IIIA, IIIB and IIIC), changes in standard ECG without
persistent ST-segment elevations (ST-segment
depression z0,1 mV and/or T wave inversion z0,1
mV and/or pathological Q wave suspective of
previous MI) and/or increased TnT level on admission [2—5]. PAI-1 levels were estimated in addition
A. Sinkovic, V. Pogacar
to admission TnT. Neither TnT, nor PAI-1 levels were
estimated in 21 excluded patients.
On admission, standard ECG was recorded,
continuous monitoring of rhythm initiated and a
peripheral i.v. catheter inserted. TnT was estimated by the immunochemical method (Boehringer-Mannheim, Germany, normal levels up to
0.1 Ag/l) from blood samples drawn on admission
8—12 h later and in case of recurrent chest pain to
confirm reinfarctions. [12]. PAI-1 activity was
estimated by the chromogenic method (Berichrom
PAI by Dade Behring, Marburg, Germany, normal
range 0.3—3.5 U/ml) from blood samples on
admission and every 12 h within the first 48 h of
hospitalization [13]. Creatine kinase MB isoenzyme
(CK-MB mass) was estimated by the immunomethod
(Boehringer-Mannheim, normal levels up to 5 Ag/l)
at recurrence of chest pain to confirm reinfarction.
Standard ECG was recorded 12 h after admission
and afterwards every 24 h of hospitalization and at
recurrence of chest pain.
Treatment consisted of daily oral acetylsalycylic
acid (ASA; 100—300 mg tablet), i.v. infusion of
standard heparin or s.c. injection of the recommended dose of low molecular weight heparin for
at least 5 days. Heparin therapy was prolonged at
the discretion of the attending physician [3—5]. If
necessary, the patients were treated with nitroglycerin, clopidogrel, beta blockers, ACE inhibitors,
statins, diuretics, calcium-channel blockers, dobutamin, etc. [3—5].
NSTEMI was confirmed by an increase in TnT
level N 0.1 Ag/l either on admission and/or 8—12 h
later.
Arterial hypertension was defined, when with
chronic antihypertensive therapy normal arterial
blood pressure was achieved, or when during
hospitalization systolic blood pressure was N 160
mm Hg and/or diastolic N 100 mm Hg on several
occasions without chest pain and without prior
antihypertensive treatment.
For at least 2 days, the patients were continuously monitored for arrhythmias and conduction
disturbances. Noninvasive systemic arterial blood
pressure was measured hourly and clinical examination was carried out twice daily during the first
few days. Later on, the patients were examined
at least once daily and noninvasive systemic
arterial blood pressure was measured at least
once daily.
In case of recurrent chest pain and/or hemodynamic and/or rhythmic instability within the first
48—72 h, the patients were treated with glycoprotein receptor IIb/IIIa (GP) antagonists (tirofiban, integrillin, abciximab), followed by urgent
percutaneous coronary angiography and interven-
Risk stratification in patients with unstable angina and/or non-ST-elevation myocardial infarction
tion (PCI) or surgical revascularization [3—5]. PCI
was associated with inevitable clopidogrel therapy-loading dose 300 mg, followed by 75 mg daily
[14].
In patients without recurrent chest pain,
hemodynamic and/or rhythmic instability within
the first 48—72 h, coronary angiography was
performed within the next few days or weeks
and subsequent PCI or surgical revascularization,
if indicated [3—5].
The primary end-point was 30-day combined
endpoint of all-cause mortality and/or reinfarction
rate. Complications within 30 days were reinfarctions, mortality, heart failure, bleedings, conduction disturbances and arrhythmias.
Atrial arrhythmias were atrial tachycardias,
atrial fibrillation and/or flutter. Ventricular
arrhythmias, tachycardias and fibrillation were
classified according to Lown’s classification [15].
Conduction disturbances were bundle branch
blocks or atrioventricular blocks I, II, III, sinoatrial
block or asystole. Reinfarction or a new MI was
defined as recurrent chest pain, accompanied by
new changes in ECG, recurrent rise in TnT and/or
rise and fall in CK-MB mass, when TnT was
already high (2.3). Heart failure was diagnosed
when classes II, III and IV were identified,
according to the NYHA and Killip—Kimball classification [16].
Statistical analysis
Statistical analysis was performed by IBM PC, SPSS
for Windows. The values were expressed as
meansFstandard deviations, or percentages where
necessary. Differences between the two groups
were tested by the chi-squared test and two-sided
Student’s t-test. The p value b0.05 was statistically
significant. Odds ratios and 95% confidence interTable 1
253
vals (CI) were calculated to test the relative
importance of variables [17].
Results
Baseline characteristics and admission laboratory
data of patients are listed in Table 1. Complications of patients within 30 days are summarized in
Table 2.
Primary endpoint 30-day combined endpoint of
all-cause mortality and/or reinfarction rate was
14.2% (16/113). Thirty-day survival without reinfarction was observed in 97 patients. Between the
group with mortality and/or reinfarction (Group 1)
and the group of 97 survivors without reinfarction
(Group 2) within 30 days, we observed nonsignificant and significant differences (Tables 1 and 3).
We observed significant differences in mean admission PAI-1 levels (Table 1) and peak PAI-1 levels
(4.98F3.1 vs. 3.4F2.5, p=0.022).
We did not observe any significant difference
between the Group 1 and Group 2 in neither
mean TnT level 8—12 h after admission (1.1F1.4
vs. 0.83F1.3 Ag/l; p=NS) nor mean peak TnT
level within 48 h (1.4F1.4 vs. 0.9F1.3 Ag/l;
p=NS).
When the patients were stratified into subgroups
according to different TnT levels, elevated TnT
levels were not associated with significant 30-day
combined endpoint of mortality and/or reinfarction
(Table 4). When stratifying patients into subgroups,
according to different PAI-1 levels and according to
simultaneous increase of PAI-1 and TnT, we
observed that admission and peak PAI-1 levels N 4.0
4.0 U/ml as well as simultaneous increase of peak
PAI-1 and peak TnT were associated with significant
30-day combined all-cause mortality and/or rein-
Baseline characteristics and admission laboratory data of patients
Baseline characteristics
and admission laboratory data
All patients (n=113)
Group 1 (n=16)
Group 2 (n=97)
p
Men (%)
Age (meanFS.D. years)
BMI (meanFS.D. years, kg/m2)
Arterial hypertension (%)
Diabetes (%)
Previous infarction (%)
Smoking (%)
Braunwald class IIIA/IIIB/IIIC (%)
ST-segment depression in ECG (%)
T-wave inversion (%)
TnT (meanFS.D. Ag/l)
PAI-1 activity (meanFS.D. U/ml)
65.5
62.2F10.3
26.5F3.6
61.9
24.8
39.8
20.4
1.8/88.5/9.7
66.4
49.6
0.4F0.68
2.99F2.5
50
66.4F7.9
26.7F3.7
62.5
31.3
56.3
12.5
0/93.8/6.3
87.5
25
0.40F0.6
4.2F3.4
68
61.5F10.5
26.5F3.6
61.8
23.7
37.1
21.6
2/87.6/10.3
62.9
53.6
0.4F0.68
2.8F2.4
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
0.042
Group 1: Patients with mortality and/or reinfarctions. Group 2: Survivors without reinfarctions. TnT: Troponin T. PAI-1:
Plasminogen-activator-inhibitor-1.
254
Table 2
A. Sinkovic, V. Pogacar
Complications within 30 days
Complications
All patients (n=113)
Heart failure Killip II (%)
Pulmonary edema (%)
Cardiogenic shock (%)
Ventricular arrhythmias (%)
Ventricular fibrillation (%)
Atrial arrythmias (%)
Conduction disturbances (%)
In-hospital mortality (%)
30-day Mortality (%)
30-day Reinfarctions (%)
30-day Mortality and/or
reinfarctions (%)
47.8
15
13.3
28.3
4.4
17.7
18.6
9.7
10.6
9.7
14.2
Troponin T,
Ag/l
All
(n=113), %
Group 1
(n=16), %
Group 2
(n=98), %
p
50
37.5
40.2
12.5
58.8
47.4
39.8
8.2
NS
NS
NS
NS
Troponin T 8—12 h after admission
N0.1
76.1
81.3
N0.2
66.4
75
N0.3
59.3
62.5
N1.0
27.4
31.2
75.3
64.9
58.8
26.8
NS
NS
NS
NS
Peak Troponin T
N0.1
77.9
N0.2
73.4
N0.3
64.6
N1.0
31.9
76.3
71.1
61.8
29.9
NS
NS
NS
NS
Admission Troponin T
N0.1
57.5
N0.2
46
N0.3
39.8
N1.0
8.8
farction rate of our patients (Table 5). Further
analysis demonstrated that the risk of combined 30day mortality and/or reinfarction rate of patients
with UA/NSTEMI significantly increased with PAI1 N 4.0 U/ml and with the simultaneous increase of
PAI-1 N 3.5 U/ml and TnT N 0.1 Ag/l within the first
48 h of hospitalization (Fig. 1).
Discussion
According to the results of several registries,
including ENACT, Euroheart Survey, GRACE and
NRMI, the incidence and prevalence of UA/NSTEMI
Table 3
Table 4 Stratification of patients according to Troponin T levels
Treatment and interventions within 30 days
Treatment and
interventions
All
patients
(n=113)
Group 1
(n=16)
Group 2
(n=97)
p
ASA (%)
Beta blocking
agents (%)
Diuretics (%)
ACE
inhibitors (%)
Statins (%)
Clopidogrel (%)
IABC (%)
Calcium-chanell
blockers (%)
Ticlopidin (%)
Inotropes (%)
Nitrates (%)
Urgent PCI (%)
Elective PCI (%)
GP IIb/IIIa
inhibitors (%)
CABG (%)
98.2
58.4
100
37.5
97.9
61.8
NS
NS
51.3
60.2
81.3
43.8
46.4
62.9
0.014
NS
59.3
15
3.5
7.9
43.8
6.3
18.8
6.3
61.9
16.5
1
8.2
NS
NS
0.007
NS
6.2
10.6
92
8.8
31.8
18.6
6.3
43.8
100
9.3
32.9
31.3
6.2
5.2
90.7
6.3
25
16.5
NS
0.0001
NS
NS
NS
NS
11.6
18.8
16.5
NS
Group 1: Patients with mortality and/or reinfarctions.
Group 2: Survivors without reinfarctions. PCI: Percutaneous
coronary interventions.GP IIb/IIIa inhibitors: Glycoprotein
IIb/IIIa inhibitors. CABG: Coronary artery bypass grafting.IABC: Intra-aortic balloon counterpulsation.
87.5
87.5
81.3
43.8
Group 1: Patients with mortality and/or reinfarctions.
Group 2: Survivors without reinfarctions.
have increased over the last few years, while the
number of patients with STEMI is declining. Therefore, accurate early diagnosis, treatment and risk
stratification in patients with UA/NSTEMI are gaining importance [18—21].
Chest pain, changes in standard ECG and
increased TnT level are most important for early
recognition and prognosis in UA/NSTEMI patients
[3—5,22]. Classification of UA by Braunwald incorporated clinical circumstances as well as severity
of chest pain. Prognosis is worse with chest pain
within 14 days of an acute MI or in primary UA
Table 5 Risk stratification, according to increased
PAI-1 activity and simultaneous increase of PAI-1 and
TnT level
PAI-1/PAI-1+TnT
Group 1
(n=16)
Group 2
(n=97)
p
Admission PAI-1N3.5
U/ml
Admission PAI-1N4.0
U/ml
Peak PAI-1N3.5 U/ml
Peak PAI-1N4.0 U/ml
Admission PAI-1N3.5
U/ml+TnTN0.1 Ag/l
Admission PAI-1N4
U/ml+TnTN0.1 Ag/l
Peak PAI-1N3.5
U/ml+TnTN0.1 Ag/l
Peak PAI-1N4
U/ml+TnTN0.1 Ag/l
8 (50%)
25 (25.5%)
NS
8 (50%)
18 (18.4%)
0.014
11 (68%)
11 (68%)
4 (25%)
37 (37.7%)
27 (27.5%)
16 (16.5%)
0.04
0.0043
NS
4 (25%)
13 (13.4%)
NS
11 (68.8%)
30 (30.9%)
0.005
9 (56%)
23 (23.7%)
0.014
Group 1: Patients with mortality and/or reinfarctions.
Group 2: Survivors without reinfarctions.TnT: Troponin T. PAI1: Plasminogen-activator-inhibitor-1.
Risk stratification in patients with unstable angina and/or non-ST-elevation myocardial infarction
255
Figure 1 Odds ratios (boxes) and 95% confidence intervals (horizontal lines) for the combined 30-day endpoint of allcause mortality and/or reinfarction. Left of 1 indicates reduced risk and right of 1 indicates increased risk for the
combined 30-day endpoint of all-cause mortality and/or reinfarction rate.
without extracardiac causes. 88.5% of our patients
had primary UA (Braunwald class IIIB) and 9.7%
were within 14 days of an acute MI (Braunwald
class IIIC) [4,22]. Considering changes in standard
ECG, ST-segment depression, carrying worse prognosis, was present in 66.4% of our patients [4].
Increased TnT level, the most sensitive and
specific biochemical marker of ischemic necrosis
and prognosis, was present in 77.9% of our
patients, indicating the presence of NSTEMI in
majority of patients. When considering chest pain,
ECG changes and TnT levels, our patients were of
high-risk profile for subsequent events such as
mortality and reinfarctions. Indeed, 30-day combined all-cause mortality and/or reinfarction rate
was as high as 14.2%.
Heart failure, arrhythmias and recurrent chest
pain are well-known risk factors for subsequent
mortality or new MI in patients with UA/NSTEMI.
When they occurred within first 48 h in spite of
medical therapy, urgent PCI or surgical revascularization were performed [3—5]. However, neither
urgent PCI nor CABG within 30 days were associated
with 30-day combined endpoint of mortality and/or
reinfarction rate (Table 4).
Some clinical studies observed that in UA/
NSTEMI, risk stratification by multiple biomarkers
was more precise and earlier than by a single
marker, detecting multiple pathological processes
of coronary athero-thrombosis including inflammation, myocardial damage or dysfunction [23].
Increased PAI-1 activity is a marker of impaired
fibrinolysis, associated with severity, progression
and complications of atherosclerosis such as rupture, erosion or inflammation with subsequent
thrombosis [6—9]. Many clinical and experimental
studies suggest that thrombosis and inflammation
are closely linked, as markers of thrombosis are
often associated with inflammation and vice versa
[10,24]. PAI-1 is an acute phase reactant in
inflammation, where it stabilizes the chemoattractant form of Interleukin-8 [25]. The proinflammatory status associated with overexpression of TNF,
IL-6 and PAI-1, found in insulin resistant people,
provides a potential link between insulin resistance
and endothelial dysfunction, the early stage of
atherosclerosis in obese and type 2 diabetes
[26,27]. Our observations suggest that when PAI-1
assessment within the first 48 h was added to risk
stratification provided by clinical picture, ECG
256
changes and TnT estimation, prediction of 30-day
combined endpoint of mortality and/or reinfarction
was more accurate and earlier. The conclusion is
that simultaneously assessed TnT and PAI-1 could
provide complementary prognostic information and
allow clinicians to stratify risk more effectively
among patients with UA/NSTEMI.
There are several limitations of this small pilot
study. The population studied is relatively small in
size to allow any definite conclusions at present to
introduce our observations into everyday clinical
practice. Our observations should be validated in a
larger and better defined population, especially
regarding prior drug treatment, prior PCI or surgical
revascularization, etc.
Acknowledgments
The work was supported by the grant from Slovenian Ministry of Education, Science and Sports (L32159, 3411-00-232159). The authors wish to thank
Prof. Joze Nemec from the University of Maribor for
help with the statistical analysis and Marijana
Gajsek-Marchetti for help with the manuscript.
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