Correlation between the TIMI risk score and high-risk

angiographic findings in non–ST-elevation acute

coronary syndromes: Observations from the Platelet
Receptor Inhibition in Ischemic Syndrome Management
in Patients Limited by Unstable Signs and Symptoms
(PRISM-PLUS) trial
Jessica L. Mega, MD,a David A. Morrow, MD, MPH,a,b Marc S. Sabatine, MD, MPH,a,b Xue-Qiao Zhao, MD,c
Steven M. Snapinn, PhD,d Peter M. DiBattiste, MD,d C. Michael Gibson, MS, MD,a Elliott M. Antman, MD,a,b
Eugene Braunwald, MD,a,b and Pierre Théroux, MDe Boston, Mass, Seattle, Wash, West Point, Pa, and
Montreal, Quebec, Canada

Background The TIMI risk score for unstable angina and non-ST elevation myocardial infarction is an effective tool for
predicting the risk of death and ischemic events among patients with non-ST elevation acute coronary syndromes, as well as
for identifying those who are likely to benefit most from low-molecular-weight heparin and glycoprotein IIb/IIIa inhibition.
Methods To explore the pathobiologic basis for this interaction, we evaluated the relationship between the risk score,
assessed at presentation, and angiographic findings among patients with non-ST elevation acute coronary syndromes.
Angiographic data regarding thrombus, epicardial flow, and lesion severity were available for 1491 patients from the
angiographic substudy of PRISM-PLUS.
Results Patients with risk scores of 5 to 7 (N = 435) were more likely to have a severe culprit stenosis (81% vs 58%,
P b .001) and multivessel disease (80% vs 43%, P b .001) compared to those with scores of 0 to 2 (N = 220). The probability
of left main disease ( P = .01), visible thrombus, and impaired flow in the culprit lesion also increased progressively with rising
risk scores ( P b .001). Of the risk indicators that comprise the score, history of coronary disease, advanced age, and ST
changes showed the strongest association with severe epicardial disease. Positive biomarkers of necrosis, ST changes, and
prior aspirin use emerged as stronger correlates of visible thrombus and/or impaired culprit artery flow.
Conclusions The TIMI risk score identifies patients who are more likely to have intracoronary thrombus, impaired flow,
and increased burden of coronary atherosclerosis. These findings likely explain in part the particular benefit of potent
antithrombin and antiplatelet agents among patients with higher risk scores. (Am Heart J 2005;149:846-50.)

Given the wide spectrum of risk for death and
recurrent ischemic events among patients presenting
with non-ST elevation acute coronary syndromes
(NSTEACS), effective risk assessment has become a
focus of contemporary management of these syn-
From the aTIMI Study Group, and bCardiovascular Division, Brigham and Women’s
Hospital, Boston, Mass, cDepartment of Medicine, University of Washington School of
Medicine, Seattle, Wash, dMerck & Co., West Point, Pa, and eMontreal Heart Institute,
Quebec, Canada.
Submitted January 30, 2004; accepted August 11, 2004.
Reprint requests. David A. Morrow, MD, MPH, TIMI Study Group, Cardiovascular
Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115.
E-mail: dmorrow@rics.bwh.harvard.edu
0002-8703/$ - see front matter
n 2005, Mosby, Inc. All rights reserved.
doi:10.1016/j.ahj.2004.08.042
dromes. The TIMI risk score for unstable angina/non-ST
elevation myocardial infarction (UA/NSTEMI) is a
practical bedside tool that was created to assist
clinicians with initial risk stratification and targeting of
therapy.1 The TIMI risk score has been validated in
multiple clinical trials,1-5 as well as in a community-
based registry in which the risk score showed a robust
graded association with risk of death and recurrent
ischemic events.6 In addition, the risk score has been
shown to identify patients who derive greater relative
benefit from treatment with low-molecular-weight
heparin and glycoprotein IIb/IIIa inhibition, as well as
early invasive management.1,3,4 To explore the patho-
biologic basis for these findings,7 we evaluated the
relationship between the TIMI risk score and angio-
American Heart Journal
Volume 149, Number 5
Figure 1
Extent and severity of epicardial disease stratified by TIMI risk score.
Multivessel disease is defined as N50% stenosis in z2 vessels.
graphic findings among patients with NSTEACS en-
rolled in the PRISM-PLUS trial.
Methods
Study population
PRISM-PLUS was a multicenter, randomized trial performed
in 72 hospitals in 14 countries. The design and results of
PRISM-PLUS have been described.8 Briefly, 1915 patients with
NSTEACS were enrolled within 12 hours of presentation with
severe rest angina (prolonged pain or repetitive episodes),
given aspirin, and randomized to 1 of 3 treatment groups:
tirofiban plus heparin, tirofiban placebo plus heparin, or
tirofiban plus heparin placebo. The protocol required infusion
of the study medication for at least 48 hours; coronary
interventions were discouraged until after this period unless a
patient had recurrent refractory ischemia. Angiography was
recommended but not required in all patients between 48
and 96 hours after randomization.
Coronary angiography
Of the 1915 patients in the study, 1719 (90%) underwent
angiography during the initial hospitalization and 1538 (80%)
had angiography during the first 97 hours; 1491 (78%) had a
readable angiogram and were included in the analysis by the
Angiographic Core Laboratory.9 Core Laboratory personnel,
who were unaware of treatment allocation or outcomes,
interpreted the anatomic location, perfusion characteristics,
and morphologic features of the coronary lesions. Multivessel
disease was defined as angiographic evidence of disease in z2
vessels. A lesion was termed severe if z70% stenosis was
present. Impaired flow was defined as less than TIMI grade
3 flow.
TIMI risk score
The TIMI risk score for UA/NSTEMI is calculated as the sum
of the number of risk indicators that are present: (1) age z65
years; (2) z3 risk factors for coronary artery disease (CAD);
Mega et al 847
Figure 2
Coronary artery flow and thrombus stratified by TIMI risk score.
Impaired flow is defined as TIMI flow grade 0/1/2.
(3) known significant coronary stenosis; (4) ST deviation N0.5
mm; (5) elevated cardiac markers of necrosis; (6) severe
anginal symptoms; and (7) use of aspirin in the prior 7 days.1
The TIMI risk score was applied to patients from the
PRISM-PLUS trial using baseline clinical data collected
before randomization. All patients, based on enrollment
criteria, were given 1 point for severe anginal symptoms. A
point for significant coronary stenoses was assigned for
documented CAD, including prior myocardial infarction,
coronary artery bypass grafting, or percutaneous coronary
intervention. ST-segment deviation of z1 mm was recorded
in PRISM-PLUS.4
Statistical analysis
The association between the risk score with specific
angiographic findings was assessed with a global nonpara-
metric test for correlation for continuous variables and the m2
test for dichotomous variables. The associations between
individual elements of the risk score and angiographic
findings were evaluated using logistic regression. Testing for
an effect of tirofiban on flow in the culprit vessel and for an
interaction with the TIMI risk score was performed using
logistic regression including the main effects as well as an
interaction term. P values b.05 were considered to indicate
statistical significance. All analyses were performed using SAS
version 6.12 (SAS Institute, Cary, NC).
Results
Patients
Core Laboratory interpretation of angiographic data
was available for 1491 patients. Angiography was
performed a mean of 65 hours after randomization. The
baseline risk profile of the population in this substudy
was similar to the overall population enrolled in PRISM-
PLUS, as assessed using the TIMI risk score4; 15% (n =
220) of patients were in the low-risk (0-2), 56% (n =
836) in the intermediate-risk (3-4), and 29% (n = 435)
 American Heart Journal
848 Mega et al
May 2005

Table I. Frequency of impaired flow stratified by TIMI risk score Table II. Association (OR) between TIMI risk score variables
and treatment group and extent of disease
TIMI risk score 0-2 3-4 5-7 P* 3-Vessel Left main Visible Impaired
CAD disease thrombus flow
Tirofiban + heparin 8.9 17.8 23.4 .025
Heparin 18.5 24.2 32.4 .025 Age z 65 y 1.77* 2.38* 0.91 0.95
z3 Risk factors 1.31y 1.38 1.06 1.01
Data are shown as the percentage of patients with impaired flow in the culprit vessel. History of CAD 2.09* 1.07 1.36z 1.21
*Association between the risk score and impaired flow in each of the treatment ST deviation 1.87* 1.46 1.42z 1.21
groups.
Aspirin 1.54* 0.98 0.98 1.37y
Biomarkers 1.09 1.34 1.46z 1.82*

Data are shown as ORs from multivariable analysis including all 6 variables.
in the high-risk (5-7) groups. The allocation to each *P b .001.
yP b .05.
treatment group was well balanced across each TIMI zP b .01.
risk score category.

Extent and severity of epicardial coronary disease

The risk score showed a strong graded association
with the probability of multivessel CAD (80.2% in high
risk, 63.2% in intermediate risk, and 43.2% in low risk,
P b .001) (Figure 1). Similarly, high-risk patients were
more likely to have significant left main CAD compared
with those in the lowest risk score groups (10% vs
4.5%, P = .01). The risk score at presentation also
correlated with the frequency of severe (N70%) culprit
stenoses ( P b .001) (Figure 1). Although total occlu-
sion of the culprit artery was infrequent in this
population with NSTEACS, patients with the highest
TIMI risk scores (5-7) were more likely to have an
occluded vessel (12.2% in high risk, 8.6% in interme-
diate risk, and 5.2% in low risk, P = .008).
Coronary artery flow and thrombus
The proportion of patients with visible thrombus
and impaired flow in the culprit coronary artery
increased progressively with rising TIMI risk score
( P b .001) (Figure 2). High-risk patients were twice as
likely to have impaired flow (TIMI flow grade 0/1/2)
when compared to those with risk scores of 0 to 2.
Patients in PRISM-PLUS who were randomized to
heparin and tirofiban had better coronary flow across
each of the risk score groups compared with those
treated with heparin alone ( P = .002) (Table I).
There was no detectable interaction between the
risk score and the effect of tirofiban on coronary flow
( P-interaction = .83).
TIMI risk score variables and high-risk angiographic
findings
Comparative assessment of the association between
individual elements of the risk score with angio-
graphic findings revealed that a history of CAD,
advanced age, and ST changes showed the strongest
association with severe underlying epicardial disease
(Table II). Positive biomarkers of necrosis, ST changes,
and prior aspirin use emerged as the 3 stronger
correlates with visible thrombus and/or impaired flow
in the culprit artery.
Discussion
The TIMI risk score is a simple integer score that
integrates information from multiple clinical predictors
to aid in producing a quantitative estimate of the risk
of death and recurrent ischemic events.1 Our present
analysis demonstrates associations that may reflect the
pathobiologic underpinnings of the TIMI risk score.
Specifically, the risk score identified patients who
were more likely to have intracoronary thrombus,
impaired angiographic flow, and increased burden of
coronary atherosclerosis. In addition to providing
insight into the prognostic performance of the risk
score, these findings may also explain the particular
benefit of potent antithrombin and antiplatelet agents
among patients with higher risk scores.1,4
The findings in this study are plausible based on
prior observations. The TIMI risk score is composed
of 7 risk indicators, several of which have been
individually related to the degree of atherosclerosis
or the presence of thrombosis. Rising age, for
example, has been associated with increased clinical
as well as subclinical CAD.10,11 Resting electrocar-
diogram abnormalities and elevation of biomarkers of
necrosis have correlated with lesion severity, im-
paired flow, myocardium jeopardy score, and extent
of coronary disease.12-16 Likewise, patients with
refractory chest pain and multiple anginal events are
more likely to have complex lesions, intracoronary
thrombus, and decreased TIMI grade flow.17 Although
the specific mechanisms have not been elucidated,
individuals who develop unstable angina while taking
aspirin have been shown to be at particularly high
risk.18,19 As demonstrated in this study, by integrating
each of these indicators, the TIMI risk score captures
information related both to the underlying athero-
American Heart Journal
Volume 149, Number 5
sclerotic disease burden as well as plaque instability
and thrombosis.
At the same time, potent antiplatelet and antithrom-
bin agents are particularly useful in the setting of
increasing risk and burden of disease.20 In addition,
these agents have been shown to reduce the thrombus
size and improve coronary flow. For example, the
angiographic study in PRISM-PLUS showed that tirofi-
ban in addition to heparin reduced the burden of
thrombus at the culprit lesion and improved distal
perfusion in patients with UA/NSTEMI. Moreover, both
the presence of thrombus and impaired flow were
strongly associated with the risk of death or recurrent
ischemic events.9 Angiographic data have confirmed
that the addition of potent antiplatelet therapies
achieves greater reduction in thrombus burden in high-
risk patients, such as those patients with elevated
troponins.15 Our study adds further to understanding
the links between cardiac risk, extent of disease, and
effect of aggressive treatment regimens.
Study limitations
Several limitations to this analysis should be ac-
knowledged. The angiographic evaluation was per-
formed, at the discretion of the managing physician,
after the delivery of heparin and tirofiban and as such,
performance of angiography could have been influ-
enced by treatment. In addition, 22% of the patients did
not have an interpretable angiogram available for the
angiographic substudy. It is also possible that patient
selection, considering the overall high-risk profile of
patients in PRISM-PLUS, may have identified patients
with an increased prevalence of high-risk anatomy for
our angiographic study population. However, it is likely
that the treatment with antiplatelet and antithrombin
agents intervening between assessment of the risk
score and angiography may have attenuated the
association between the score and impaired flow and
thrombus burden. In addition, only creatine kinase and
creatine kinase–MB levels were available in this study;
incorporation of cardiac troponin might strengthen the
relationship of the TIMI risk score and the disease
burden. Finally, coronary angiography is a specific but
insensitive tool used to detect intracoronary thrombus.
The use of angioscopy or intravascular ultrasound
might increase the detection of complex lesions.
Conclusion
This study revealed that patients with higher TIMI
risk scores were more likely to have increased burden
of epicardial disease and impaired coronary blood
flow. These findings provide insight into the patho-
biologic associations underlying the performance of
the TIMI risk score for risk assessment and therapeutic
decision making.
Mega et al 849
References
1. Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for
unstable angina/non-ST elevation MI: a method for prognostication
and therapeutic decision making. JAMA 2000;284:835 - 42.
2. Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents
death and cardiac ischemic events in unstable angina/non–Q-wave
myocardial infarction. Results of the Thrombolysis in Myocardial
Infarction (TIMI) 11B trial. Circulation 1999;100:1593 - 601.
3. Cannon CP, Weintraub WS, Demopoulos LA, et al. Comparison of
early invasive and conservative strategies in patients with unstable
coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor
tirofiban. N Engl J Med 2001;344:1879 - 87.
4. Morrow DA, Antman EM, Snapinn SM, et al. An integrated clinical
approach to predicting the benefit of tirofiban in non-ST elevation
acute coronary syndromes. Application of the TIMI risk score for
UA/NSTEMI in PRISM-PLUS. Eur Heart J 2002;23:223 - 9.
5. Budaj A, Yusuf S, Mehta SR, et al. Benefit of clopidogrel in patients
with acute coronary syndromes without ST-segment elevation in
various risk groups. Circulation 2002;106:1622 - 6.
6. Scirica BM, Cannon CP, Antman EM, et al. Validation of the
thrombolysis in myocardial infarction (TIMI) risk score for unstable
angina pectoris and non–ST-elevation myocardial infarction in the
TIMI III registry. Am J Cardiol 2002;90:303 - 5.
7. Morrow DA. New insight into clinical risk scores for patients with
acute coronary syndromes. Am Heart J 2003;146:754 - 6.
8. The PRISM-PLUS Investigators. Inhibition of the platelet glycoprotein
IIb/IIIa receptor with tirofiban in unstable angina and non–Q-wave
myocardial infarction. N Engl J Med 1998;338:1488 - 97.
9. Zhao XQ, Theroux P, Snapinn SM, et al. Intracoronary thrombus
and platelet glycoprotein IIb/IIIa receptor blockade with tirofiban in
unstable angina or non–Q-wave myocardial infarction. Angio-
graphic results from the PRISM-PLUS trial (platelet receptor inhibition
for ischemic syndrome management in patients limited by unstable
signs and symptoms). PRISM-PLUS Investigators. Circulation
1999;100:1609 - 15.
10. Jaffer FA, O’Donnell CJ, Larson MG, et al. Age and sex distribution
of subclinical aortic atherosclerosis: a magnetic resonance imaging
examination of the Framingham Heart Study. Arterioscler Thromb
Vasc Biol 2002;22:849 - 54.
11. Litovsky SH, Farb A, Burke AP, et al. Effect of age, race, body
surface area, heart weight and atherosclerosis on coronary artery
dimensions in young males. Atherosclerosis 1996;123:243 - 50.
12. Savonitto S, Ardissino D, Granger CB, et al. Prognostic value of the
admission electrocardiogram in acute coronary syndromes. JAMA
1999;281:707 - 13.
13. Cohen M, Hawkins L, Greenberg S, et al. Usefulness of ST-segment
changes in greater than or equal to 2 leads on the emergency room
electrocardiogram in either unstable angina pectoris or non–Q-
wave myocardial infarction in predicting outcome. Am J Cardiol
1991;67:1368 - 73.
14. Miranda CP, Lehmann KG, Froelicher VF. Correlation between
resting ST segment depression, exercise testing, coronary
angiography, and long-term prognosis. Am Heart J 1991;122:
1617 - 28.
15. Heeschen C, van Den Brand MJ, Hamm CW, et al. Angiographic
findings in patients with refractory unstable angina according to
troponin T status. Circulation 1999;100:1509 - 14.
16. Benamer H, Steg PG, Benessiano J, et al. Elevated cardiac troponin I
predicts a high-risk angiographic anatomy of the culprit lesion in
unstable angina. Am Heart J 1999;137:815 - 20.

850 Mega et al
17. Dangas G, Mehran R, Wallenstein S, et al. Correlation of
angiographic morphology and clinical presentation in unstable
angina. J Am Coll Cardiol 1997;29:519 - 25.
18. Santopinto J, Gurfinkel EP, Torres V, et al. Prior aspirin users with
acute non–ST-elevation coronary syndromes are at increased risk of
cardiac events and benefit from enoxaparin. Am Heart J
2001;141:566 - 72.
American Heart Journal
May 2005
19. Alexander JH, Harrington RA, Tuttle RH, et al. Prior aspirin use
predicts worse outcomes in patients with non–ST-elevation acute
coronary syndromes. PURSUIT Investigators. Platelet IIb/IIIa in
Unstable angina: Receptor Suppression Using Integrilin Therapy.
Am J Cardiol 1999;83:1147 - 451.
20. Cannon CP. Evidence-based risk stratification to target therapies in
acute coronary syndromes. Circulation 2002;106:1588 - 91.