Prognostic value of the Thrombolysis in Myocardial
Infarction risk score in a unselected population with chest
pain. Construction of a new predictive modeli
Francisco J. García-Almagro MDa,⁎, Juan R. Gimeno MDa, Manuel Villegas MDa,
Jose Hurtado MDa, Francisca Teruel MDa, Maria C. Cerdán MDa,
Josefa González-Carrillo MDa, Domingo Pascual MDa,
Miguel Rodríguez-Barranco PhDb, Mariano Valdés PhDa
aCardiac Department, University Hospital Virgen de la Arrixaca, 30120 El Palmar, Murcia, Spain
bEpidemiology Department, General Section of Public Health, Murcia, Spain
Received 4 June 2007; revised 20 July 2007; accepted 21 July 2007
and simple tool for risk stratification of patients with chest pain in intermediate- and high-risk populations.
There is little information on its applicability in daily clinical routine with unselected populations.
Aims: The aims of the study were to prospectively analyze the predictive value of the TRS in a
heterogeneous population admitted for chest pain and to construct where possible a new modified model
with a greater prognostic capacity.
score variables, relevant medical history variables, in-hospital examination results,and therapy information
were collected. Cardiac events at 1 and 6 months were recorded.
Results: Seventy-one (9.8%) patients had a compound event (myocardial infarction/revascularization/
cardiac death) at 6 months. On multivariate analysis, the variables associated with cardiac events were left
ventricular ejection fraction (EF)of b35% (hazard ratio [HR] = 2.9,P = .002), diabetes (HR = 1.8,P = .02),
and TRS (HR = 1.3, P = .007). Events at 6 months were 2.3% for a TRS of 0/1, 4.2% for 2, 10.2% for 3,
11.0%for 4,and18.7% fora scoreofmorethan5.AnewmodifiedscalewasconstructedtoincludeEFand
score unit increase (HR = 1.44,P = .001). The modified scale showed a greater predictive capacity than the
Conclusions: The TRS is an important short- and long-term prognostic predictor when applied to an
unselected population consulting for chest pain. The inclusion of diabetes and EF as variables in the model
increases predictive capacity at no expense to simplicity.
© 2008 Published by Elsevier Inc.
☆Dr Gimeno was supported by a grant from Merck Sharp and Dhome, Madrid, Spain.
⁎Corresponding author. Tel.: +34 629488658; fax: +34 868951279.
E-mail address: firstname.lastname@example.org (F.J. García-Almagro).
0735-6757/$ – see front matter © 2008 Published by Elsevier Inc.
American Journal of Emergency Medicine (2008) 26, 439–445
Chest pain is one of the most common reasons for
consultation in emergency units, accounting for between 5%
and 10% of the total [1-3]. Of these patients, between 10%
and 20% present with a high risk of complications and would
benefit from admission and aggressive treatment. The
association of different clinical variables, electrocardiogram
(ECG), and laboratory markers with an unfavorable evolu-
tion has been shown widely [4-6].
In this context, Antman et al  developed the
Thrombolysis in Myocardial Infarction (TIMI) risk score
(TRS), a scoring system with 7 risk variables in patients with
unstable angina or acute myocardial infarction (AMI)
without ST elevation. This scale was created by retro-
spectively applying multivariate statistic models to the
populations of 2 tests with heparins: TIMI 11B  and
Efficacy and Safety of Subcutaneous Enoxaparin in Unstable
Angina and Non–Q-wave Myocardial Infarction
(ESSENCE) . It has since been validated in various
studies such as CURE, PRISM-PLUS, and TACTICS-TIMI
18, among others [10,11], in which it has proved capable of
predicting both the prognosis and the response to new
therapies in both the short and long term.
However, there is little information on its applicability to
daily clinical practice beyond the trials in which it was
developed or to very selected populations . The presence
of ECG changes and the elevation of cardiac markers were
inclusion criteria in these studies; however, many of the
patients admitted to cardiology units with chest pain do not
present with such a homogeneous or high-risk profile .
The aims of the present study were (1) to analyze the
prognostic value of the TRS in a heterogeneous population
admitted to a cardiology unit for chest pain; and (2) to
including other variables with independent prognostic value.
2. Population and methods
The study population was made of consecutive patients
with chest pain suggestive of an ischemic origin and
admitted to the cardiology unit between May 1, 2003, and
April 30, 2004. The only exclusion criterion was presenta-
tion of chest pain and persistent ST-segment elevation. After
clinical evaluation, the patients received serial ECGs and
determination of cardiac markers at the emergency depart-
ment (ED) (with at least 1 blood extraction more than 6 hours
after the onset of pain) and echocardiogram within 72 hours
of admission. An ischemia test (treadmill exercise test or
dobutamine stress echocardiogram, with or without single-
photon emission computed tomography imaging) was done
where appropriate. On admission, they were given antiag-
gregation and subcutaneous enoxaparin in anticoagulant
doses, in the absence of contraindications. All decisions
regarding management and treatment were made according
to the criteria of the responsible cardiologist.
The main epidemiological aspects of the population and
the variables of clinical manifestation, including character-
istics of pain, were collected. Pain was defined as typical
angina, suggestive or unspecific based on the score by
Geleinjse et al . Electrocardiograms were classed
according to the absence or presence of pain and ECG
changes—elevation or depression in the ST segment by
0.5 mm in any lead. Measurements of cardiac enzymes such
as total creatine kinase (CK), MB fraction (CK-MB), and
troponin I (TnI) level were determined. Normal values
were based on the center's biochemistry laboratory (CK,
ng/mL). Acute myocardial infarction was established as an
increase in CK and CK-MB levels to twice the reference
for redefining infarction [15,16]. We recorded the treatments
performed during admission and the results of the different
The appearance of complications such as death, infarction,
recurrent ischemia, and bleeding was recorded, the last one
defined according to criteria of the TIMI trials [12,17].
A prospective calculation of the TRS was made for each
patient. This yielded between 0 and 7 possible points
according to the simple mathematical sum of each of the
following characteristics: age of 65 years; existence of 3 or
more classical risk factors (hypertension, hypercholesterole-
mia, diabetes mellitus, smoking, or family history of
ischemic heart disease); previous significant coronariopathy
(stenosis of ≥50%); aspirin (acetylsalicylic acid [ASA])
consumption in the previous 7 days; at least 2 episodes of
angina in the previous 24 hours; elevation of cardiac necrosis
markers; and ST deviations of at least 0.5 mm .
Clinical follow-up was done at 1 and 6 months after
discharge by personal interview or telephone to record data
relating to the control of risk factors, adherence to treatment,
functional class, and appearance of symptoms or complica-
tions. The incidence of the combined event of cardiovascular
death, infarction, and need for revascularization was
recorded during follow-up.
2.2. Statistical analysis
Data are expressed as mean ± SD of the mean (range) or
frequency (percentage). Four possible events during follow-
up were defined: cardiovascular death (sudden death, death
from heart failure, or procedure-related death); revascular-
ization; AMI; and combined event, defined as the occurrence
of any of the 3 mentioned events. For each type of event, a
Cox univariate proportional risk model was constructed with
each of the following episode-related variables: age, sex,
F.J. García-Almagro et al.
previous revascularization, previous AMI, TRS items,
ejection fraction (EF; b35%, 35%-44%, 45%-54%, 55%-
89%), characteristics of pain (unspecific, angina/suggestive),
changes in ECG with pain, final diagnosis, revascularization
during admission, diabetes, and number of affected vessels in
the coronary angiogram. The assumption of proportional
risks was evaluated by graph. Cox multivariate regression
models were used to study the predictive variables for the
occurrence of events. A new indicator (modified TRS
[TRSm]), which included the variables associated with the
combined event at a significance level of α = .05, was
constructed. To study its predictive capacity, a Cox multi-
variate regression model was again constructed with
substitution of the TRS with the new TRSm indicator.
A multivariate logistic regression model was adjusted for
the new indicator (TRSm) in which the variable response
was the occurrence of the combined event, and this was
compared with the same model including the TRS. The
Akaike information criterion and bayesian information
criterion (BIC) were used to compare the efficiency of
adjustment of the 2 models. All the multivariate regression
models were constructed using a backward selection
procedure. Included in the initial model were the variables
yielding P b .10 in the univariate analysis. The level of
confidence for the construction of confidence levels was set
at 95%. Statistical analysis was done with the Stata software
package (StataCorp 2001, Stata Statistical Software: Release
7.0; Stata Corporation, College Station, Tex).
The patients' baseline characteristics are summarized in
Table 1. Chest pain was typical or suggestive of anginal pain
in 598 (84.1%) cases and unspecific in the rest. There were
ECG recordings coinciding with pain in 506 (71.2%)
patients, and dynamic changes were observed in 158
(31.0%) of them. Serial TnI level was shown to be above
normal limit in 313 (44.0%) patients.
Twenty-eight (3.9%) patients underwent surgical revas-
cularization and 182 (25.6%) percutaneous coronary angio-
plasty. Details of treatment and complementary tests are
summarized in Table 2.
presented with recurrent ischemia, 14 (16.5%) of them with
ECG changes. Fourteen (2.0%) patients had an infarction
sudden deaths, 4 due to heart failure, 3 in the postsurgery
period, 1 during catheterization, and 3 not cardiac related.
There were 16 (2.2%) episodes of minor bleeding and 10
(1.4%) major episodes (Table 2). The final diagnoses at
discharge were AMI in 146 (20.5%) cases, unstable angina in
cardiac origin in 119 (16.7%), and noncardiological pain in
189 (26.6%) cases.
3.1. Follow-up and events
A complete clinical follow-up was achieved in 661
(93.0%) patients. At 6 months, 100 (15.1%) patients were
Baseline characteristics of the patients studied
NYHA functional class
Family history of IHD
ECG dynamic changes
66 ± 13
56.1 ± 11.6
NYHA indicates New York Heart Association; IHD, ischemic heart
and relevant events
Results of the in-hospital examinations, treatments,
Aspirin + clopidogrel
Aspirin + clopidogrel + tirofiban
Heart failure death
Death related to revascularization
aNonrelated to the episode that lead to admission.
441Prognostic value of the TIMI risk score
readmitted, 36 (5.1%) required coronary revascularization,
10 (1.4%) had AMI, and there were 25 (3.5%) deaths of a
cardiovascular origin. In total, 29 (4.1%) patients presented
with the combined death/AMI/revascularization event at
1 month and 71 (9.8%) at 6 months (Table 3).
In the multivariate analysis, the variables related to the
combined event were the TRS (hazard ratio [HR] = 1.3 [1.0-
1.6], P = .007), EF of less than 35% (HR = 2.9 [1.5-5.4], P =
.002), and diabetes (HR = 1.8 [1.0-3.1], P = .02). An
individual breakdown of the events is shown in Table 4.
In multivariate analysis, the combination of ASA and
clopidogrel was compared with the triple therapy with
the addition of tirofiban, and a protective effect for the
occurrence of the combined event was associated with
the triple therapy (HR = 0.47 [0.19-1.13], P = .09), although
it did not reach statistical significance.
3.2. Thrombolysis in Myocardial Infarction
Distribution of the TRS in the population is shown in
Fig. 1. The model proved to be an important predictor of risk.
Patients with higher scores presented more often with the
combined event: 0.6%, 2.1%, 4.8%, 6.1%, and 7% in the first
month, for a TRS of 0/1, 2, 3, 4, and more than 5,
respectively, and 2.3%, 4.2%, 10.2%, 11%, and 18.7% at 6
months (HR per unit increase = 1.3 [95% confidence
interval, 1.0-1.6], P = .007)] (Fig. 2).
Cardiac events at 1 and 6 months of follow-up
1 mo 6 mo
Excluded revascularization and AMI during first admission.
Variables associated with the occurrence of cardiac events
Univariate analysis Multivariate analysis
P HR (95% CI)P HR (95% CI)
CI indicates confidence interval.
aIncrease per unit of TRS.
bCompared with EF N35%.
cFinal diagnosis compared with noncardiac origin.
dPer year increase in age.
Distribution of patients according to TRS.
F.J. García-Almagro et al.
3.3. Modified TRS
In the univariate analysis, all but 1 of the TRS variables
showed a significant association with the occurrence of the
combined event, with the exception of “≥2 episodes of
angina in the previous 24 hours” (HR = 1.3 [0.8-2.1], P =
.185]. Thus, a new risk scale was constructed to exclude this
variable and include other independent risk factors such as
diabetes and EF. This TRSm was therefore made up of 8
variables, with a scoring system as follows:
1. one point if age is at least 65 years,
2. one point if with presence of 3 or more risk factors
for coronary disease (hypertension, hypercholester-
olemia, diabetes, smoking or family history of is-
chemic heart disease),
3. one point if with presence of known coronary disease
(stenosis ≥50% in previous coronary angiogram),
4. one point if with ASA consumption in the previous
5. one point if with ST-segment deviation of at least
0.5 mm in the presentation ECG,
6. one point if with elevation of cardiac markers,
7. one point if patient is diabetic—independent of b, and
8. two points if EF if less than 35% and 1 point if
EF ranges from 35% to less than 45%.
The total score was still a simple mathematical sum but
now ranging from 0 to 9. After adjusting the multivariate
logistic regression model for the TRSm, we noted a 44%
increase in occurrence of the combined event per unit
increase on the scale (HR = 1.44 [1.19-1.73], P b .001).
Comparison of the 2 indicators, TRS and TRSm, using the
Akaike information criterion and BIC (see “Statistical
analysis” in the methods section) showed that the latter
yielded a better predictive adjustment than the original TRS
(difference of 13.387 in the BIC between both). Moreover,
the simultaneous presence of the 2 scales in the multivariate
model yielded a significant association with the combined
event for the TRSm (HR = 1.69 [1.28-2.22], P b .001),
whereas the coefficient of the TRS did not reach significance
(HR = 0.87 [0.62-1.19], P = .389).
A third model adding only diabetes as an independent
variable to the traditional TRS, without considering EF, was
also tested. Predictive value of this model was significantly
better than traditional TRS (difference of 6.9 in the BIC
between TRS and TRS + diabetes, P b.001) but worse than
the proposed TRSm (difference of 6.5 in the BIC between
TRS + diabetes and TRSm, P b.001).
In this prospective study the TRS is confirmed as an
important short- and long-term prognostic predictor, even in
unselected populations with chest pain; it establishes a risk
curveranging from a low probability of events with the lower
scores (around 4% at 6 months with TRS b3) to almost 20%
atthe opposite extreme. Furthermore, a new modified scale is
obtained which, with the addition of presence of diabetes and
left ventricular EF to the other variables, increases prognostic
capacity at no expense to the simplicity of the model.
4.1. Risk stratification
Various methods of prognostic stratification have been
developed for the management of chest pain. Certain
algorithms of risk prediction such as that of Goldman or
Pozen et al  are complex and little used. In the context of
of the most widespread classifications is one proposed a
decade ago by Hamm and Braunwald  for unstable
angina, subsequently modified with the addition of enzyme
elevation as a clinical criterion. The PEPA study  was
developed in our midst and defined the risk of death or
with data from the Global Registry of Acute Coronary Events
(GRACE)  with prediction of overall mortality
at 6 months for any type of ACS, which is applied with
9 prognostic variables weighted by computer calculation.
4.2. Thrombolysis of Myocardial Infarction
The present study prospectively includes a very wide
spectrum of consultations for chest pain and confirms the
capacity of the TRS for discriminating the probability of
events in routine clinical practice. In fact, the 1-month
incidence of the combined event of death, infarction, and
need for revascularization ranges from less than 1% for a
score of 0/1 to 7% if more than 5 and furthermore maintains
and 6 months according to TRS.
Cardiac events (AMI/revascularization/cardiac death) at 1
443 Prognostic value of the TIMI risk score
its prognostic value over the long term, with 2% of events at
6 months for the lowest TRS and 20% for the highest.
The fact that this is a more heterogeneous population
might explain the general prognosis being slightly better than
that published in the original study , although it is also true
that high-risk patients are included (mean age, 66 years;
more than 30% diabetic; 27% with former infarction, 22%
previously revascularized, and almost 45% with raised
troponin levels). This difference may also be justified by a
higher rate of invasive strategies (46% of the patient total
went to diagnostic catheterization, and 30% were revascu-
larized) and of the combination of antiplatelet therapies
(ASA and clopidogrel were associated in 63% of cases and
tirofiban in 14%), thus attenuating the risk of events. This
idea is reinforced when comparing the results with those
from medication trials such as CURE  (approximately
3% of events in 9 months for a TRS of 0/1 and 19% for 6/7 in
the treated arm).
4.3. Modified TRS
The inclusion of diabetes and EF as variables in the scale
improves prognostic capacity. It isshown that the presence of
diabetes alone yields a poorer prognosis in ACS. In the
OASIS Registry , the 2-year mortality rate was the same
in diabetic patients without previous disease and those with
established cardiovascular disease who were not diabetic.
The recent SYMPHONY study  revealed almost twice
the 1-year mortality rate among diabetic patients after an
ACS, and it also seems that these differences are maintained
despite more aggressive treatments . The predictive
contribution of diabetes in the TRS might be greater if it were
not integrated together with the other risk factors into a single
On the other hand, EF is strongly related to survival and
can also be obtained easily in the patient's initial evaluation.
Sabia et al  found up to 4 times more cardiac events in
2years in patients with chest pain and left ventricular systolic
dysfunction, evaluated by 2-dimensional echocardiogram in
the ED, than those with a preserved EF.
In the present study, the multivariate analysis showed that
EF also added prognostic value to the TRS (Fig. 3). The
excellent result of integrating these 2 variables lies possibly
in the fact that they predict different complications. The TRS
was developed to evaluate the risk of ischemic episodes
(including infarction and the need for revascularization in the
combined event), whereas the factors predicting mortality are
usually related to left ventricular dysfunction (worse Killip
index, severe hypotension, etc).
The study includes certain potential limitations such as
the fact that the distribution of the TRS is not entirely
homogeneous (b5% of individuals had a score of 6/7)
despite the size of the population (N = 711) and may have
influenced the frequency of events in this group. There are
some differences in definitions and populations with respect
to the TRS original article that could explain some of the
findings of the present work. The aim of the study was to
verify the predictive power of the TRS in a nonselected
population with chest pain. The small number of patients
enrolled led us to include revascularization together with
death and myocardial infarction. One- and 6-month event
periods were used, and, finally, a 6-month period was used
for the statistical analysis.
There are also differences in the determination of
enzymes with respect to the original and subsequent
validation tests. In the present study, TnI was determined
in all patients together with CK and CK-MB. The greater
sensitivity shown by the former [6,26] could have produced
differences in the risk score. It is also worth mentioning that
the analysis does not include quantitative data on the level
of these enzymes (as in the original study), nor does it
evaluate the contribution of other biologic markers such as
Finally, it must be remembered that this is a single-
center–based study, and results should be extrapolated
carefully to other environments with different populations
and clinical management schemes. Further studies would be
welcomed for verification of this new score.
The TRS is an important short- and long-term prognostic
predictor when applied to an unselected population consult-
ing for chest pain. The inclusion of diabetes and EF as
variables in the model shows an increase in predictive
capacity at no expense to the simplicity of the model. We
have, therefore, a simple and useful tool for risk stratification
6 months andTRS in3 groups ofEF(based on a multivariatemodel).
Probability of occurrence of combined cardiac event at
F.J. García-Almagro et al.
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