Implications of Upstream Glycoprotein IIb/IIIa Inhibition and Coronary Artery Stenting

in the Invasive Management of Unstable Angina/Non ST-Elevation Myocardial

Infarction : A Comparison of the Thrombolysis In Myocardial Infarction (TIMI) IIIB
Trial and the Treat angina with Aggrastat and determine Cost of Therapy with Invasive
or Conservative Strategy (TACTICS)-TIMI 18 Trial
Marc S. Sabatine, David A. Morrow, Robert P. Giugliano, Sabina A. Murphy, Laura A.
Demopoulos, Peter M. DiBattiste, William S. Weintraub, Carolyn H. McCabe, Elliott M.
Antman, Christopher P. Cannon and Eugene Braunwald

Circulation. 2004;109:874-880; originally published online February 2, 2004;

doi: 10.1161/01.CIR.0000112604.74713.35
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2004 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539

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 Implications of Upstream Glycoprotein IIb/IIIa Inhibition
and Coronary Artery Stenting in the Invasive Management
of Unstable Angina/NonST-Elevation Myocardial Infarction
A Comparison of the Thrombolysis In Myocardial Infarction (TIMI) IIIB
Trial and the Treat angina with Aggrastat and determine Cost of Therapy
with Invasive or Conservative Strategy (TACTICS)-TIMI 18 Trial
Marc S. Sabatine, MD, MPH; David A. Morrow, MD, MPH; Robert P. Giugliano, MD, MS;
Sabina A. Murphy, MPH; Laura A. Demopoulos, MD; Peter M. DiBattiste, MD;
William S. Weintraub, MD; Carolyn H. McCabe, BS; Elliott M. Antman, MD;
Christopher P. Cannon, MD; Eugene Braunwald, MD

BackgroundTIMI IIIB and TACTICS-TIMI 18 were 2 trials of an early invasive strategy in unstable angina
(UA)/nonST-elevation myocardial infarction (NSTEMI) that were conducted nearly a decade apart but with virtually
identical enrollment criteria and designs, except that upstream glycoprotein IIb/IIIa inhibition was mandated and
coronary artery stenting was routinely used in TACTICS-TIMI 18. We sought to examine the effect of these advances
on clinical outcomes and the benefits of an early invasive strategy in UA/NSTEMI.
Methods and ResultsPatients were stratified on the basis of their TIMI risk score into low-, intermediate-, and high-risk
categories. Within each risk category, the rates of clinical outcomes and the benefit of an early invasive strategy were
compared. Compared with patients in TIMI IIIB and adjusting for baseline risk, patients in TACTICS-TIMI 18 had
lower rates of death, MI, or rehospitalization for acute coronary syndromes (OR, 0.62; P0.0001). Across both trials,
the benefit of an early invasive strategy was significantly greater with increasing baseline risk: OR, 1.39 in low-risk, 0.80
in intermediate-risk, and 0.57 in high-risk patients (P0.004 for interactions). After adjustment for baseline risk, an
early invasive strategy tended toward a more favorable result in TACTICS-TIMI 18 than in TIMI IIIB (OR, 0.79; 95%
CI, 0.56 to 1.11).
ConclusionsAdvances in the care of patients with UA/NSTEMI, including glycoprotein IIb/IIIa inhibition and stenting,
were associated with lower rates of death, MI, and rehospitalization for acute coronary syndromes and a trend toward
a greater benefit of an early invasive strategy. (Circulation. 2004;109:874-880.)
Key Words: angiography inhibitors risk factors angina

T he TIMI IIIB and TACTICS-TIMI 18 trials were con-

ducted nearly a decade apart but had virtually identical
enrollment criteria and designs.1,2 Both trials examined the
role of an early invasive strategy in unstable angina/nonST-
elevation myocardial infarction (UA/NSTEMI). The major
differences were that in TACTICS-TIMI 18, all patients
received upstream glycoprotein (GP) IIb/IIIa inhibition with
tirofiban, and most patients who underwent percutaneous
coronary revascularization (PCI) received intracoronary
stents. The similarity of the 2 trials created the unique
opportunity to estimate the impact of the aforementioned
differences on overall event rates and the benefits of an early
invasive strategy.
Of concern, however, was the need to account for potential
differences in baseline risk between the 2 trial populations,
despite the nearly identical enrollment criteria. To address
this issue, we used the TIMI risk score for UA/NSTEMI to
perform analyses stratified by baseline risk. The score is an
integrated risk assessment tool that was developed by Ant-
man and colleagues in TIMI 11B3 and has subsequently been
validated in multiple clinical trials.25 The TIMI risk score
has a c statistic of 0.65 and a Hosmer-Lemeshow statistic of

Received June 17, 2003; de novo received August 28, 2003; revision received November 20, 2003; accepted November 21, 2003.
From the TIMI Study Group, Cardiovascular Division, Brigham and Womens Hospital (M.S.S., D.A.M., R.P.G., S.A.M., C.H.M., E.M.A., C.P.C.,
E.B.), Boston, Mass; Merck & Co, West Point, Pa (L.A.D., P.M.D.); and Emory University, Atlanta, Ga (W.S.W.).
Drs Demopoulos and DiBattiste are Merck & Co, Inc, employees and potentially own stock and/or hold stock options in the company.
Correspondence to Marc S. Sabatine, MD, MPH, Cardiovascular Division, Brigham and Womens Hospital, 75 Francis St, Boston, MA 02115. E-mail
msabatine@partners.org
2004 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org DOI: 10.1161/01.CIR.0000112604.74713.35

874
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 Sabatine et al GP IIb/IIIa Inhibition and Stenting in UA/NSTEMI 875

3.56df8 (P0.89), consistent with moderate discrimination TABLE 1. Baseline Characteristics of the 2 Trial Populations
and excellent calibration.
TIMI IIIB, % TACTICS-TIMI 18, %
Using the TIMI risk score, we stratified patients into low-, Characteristic (n1473) (n2220) P
intermediate-, and high-risk categories. Our objective was to
Age 65 y 32 43 0.001
use integrated risk stratification in the setting of 2 similar
clinical trials to gain insight into the effects of GP IIb/IIIa Male sex 66 66 0.82
inhibition and coronary artery stenting on clinical outcomes Hypertension 42 66 0.001
and the potential benefits of an early invasive strategy in Current smoker 37 28 0.001
UA/NSTEMI. Diabetes 15 28 0.001
Hyperlipidemia 21 61 0.001
Methods Family history of CAD 41 43 0.23
Patients Previous MI 41 39 0.36
The study designs and main results of TIMI IIIB and TACTICS-
TIMI 18 have been reported.1,2 In brief, TIMI IIIB enrolled 1473 Previous PCI 13 28 0.001
patients (from 1989 to 1992) and TACTICS-TIMI 18 enrolled 2220 Previous CABG 0 22 0.001
patients (from 1997 to 1999) with UA/NSTEMI. For both trials, Previous aspirin use 48 67 0.001
patients were required to have ischemic discomfort within the
previous 24 hours that was accompanied by objective evidence of ST deviation 40 36 0.28
ischemic heart disease. The latter consisted of ECG changes, Troponin I 0.1 41 59 0.001
elevated cardiac biomarkers of necrosis, or a documented history of ng/mL
coronary artery disease.
In both trials, patients were randomized to either an early invasive NSTEMI 25 37 0.001
arm (angiography within 48 hours) or a conservative arm (angiog- Blood samples were obtained at baseline, and levels of troponin I were
raphy only if the patient experienced spontaneous or significant assayed later at the TIMI Core Laboratory. The diagnosis of NSTEMI was
stress-testinduced ischemia). All patients received aspirin and determined by the individual treating physicians on the basis of local biomarker
unfractionated heparin. In TACTICS-TIMI 18 but not in TIMI IIIB, and ECG data.
all patients also received upstream GP IIb/IIIa inhibition with
tirofiban. For these analyses, the prespecified primary end point for
TACTICS-TIMI 18 was used, which was the composite of death, medications in Table 2. The distributions of risk scores (the
(re)infarction, or rehospitalization for acute coronary syndromes risk profile) of the 2 trials are shown in Figure 1. Despite
(ACS) through 6 months.
nearly identical eligibility criteria, patients enrolled in
Risk Stratification TACTICS-TIMI 18 had a markedly higher risk profile than
Patients were stratified on the basis of their TIMI risk score for those in TIMI IIIB (P0.0001 by 2 for trend).
UA/NSTEMI.3 In brief, patients are risk-stratified on the basis of 7
baseline characteristics: age 65 years, 3 risk factors for coronary Differences in Rates of Clinical End Points in
artery disease, known coronary artery disease, use of aspirin in the TIMI IIIB Versus TACTICS-TIMI 18
last 7 days, 2 episodes of angina in the previous 24 hours, ST
deviation 0.5 mm, and elevated cardiac biomarkers of necrosis. The rates of the composite end point in the 2 trials among
Patients are assigned 1 point for each risk factor that is present. On patients matched for similar degrees of baseline risk are
the basis of their TIMI risk score, patients were categorized as low
risk (0 to 2 points), intermediate risk (3 or 4 points), or high risk (5
TABLE 2. Procedures and Medications During the
to 7 points).
Initial Hospitalization
Statistical Analysis TIMI IIIB, % TACTICS-TIMI-18, % P
The TIMI risk score distribution in the 2 trials was compared by use
of the 2 test for trend. Within each risk stratification category, the Catheterization
proportions of patients experiencing an end point in TIMI IIIB and Invasive arm 98 97 0.32
TACTICS-TIMI 18 were compared by the 2 test. Heterogeneity of Days after randomization 2.5 2.2 0.001
the effect of trial (TIMI IIIB versus TACTICS-TIMI 18) among
different subgroups of patients was assessed by the Breslow-Day Conservative arm 57 51 0.006
test. If there was no significant heterogeneity, a stratified Mantel- Days after randomization 6.6 4.9 0.001
Haenszel odds ratio (OR) with 95% confidence intervals (CIs) was
computed. A multivariable logistic regression model was constructed PCI
to assess the independent effect of trial on the composite end point Invasive arm 37 41 0.055
after adjustment for baseline TIMI risk score, treatment strategy, Conservative arm 23 24 0.56
index hospitalization procedures, and cardiac medication use. Strat-
ified analyses were performed to calculate the ORs and 95% CIs for Stent use 0 85 0.001
the effect of an early invasive strategy on the composite end point CABG
within each risk category and trial. Interaction terms were introduced
into a regression model to estimate the effects of TIMI risk score Invasive arm 24 20 0.04
category and of trial on the efficacy of an early invasive strategy. Conservative arm 18 13 0.005
Medications at discharge
Results Aspirin 87 79 0.001
Baseline Differences Between TIMI IIIB and -Blocker 62 62 0.96
TACTICS-TIMI 18 ACE inhibitor 8 17 0.001
The baseline characteristics of the 2 trial populations are
Statin 10 45 0.001
shown in Table 1 and index hospitalization procedures and
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876 Circulation February 24, 2004
Figure 1. Distribution of TIMI risk scores in TIMI IIIB (open bars)
vs in TACTICS-TIMI 18 (solid bars). TIMI risk score distribution
was significantly higher in TACTICS-TIMI 18 than in TIMI IIIB
(P0.0001 by 2).
shown in Figure 2. Compared with patients in TIMI IIIB,
patients in TACTICS-TIMI 18 had lower rates of death, MI,
or rehospitalization for ACS through 6 months in the low
(OR, 0.50; P0.0001), intermediate (OR, 0.72; P0.005),
and high (OR, 0.50; P0.003) risk groups. There was no
evidence for heterogeneity among the 3 different risk groups
in terms of the effect of trial on outcome (Breslow-Day test
P0.11), and the Mantel-Haenszel adjusted OR for the risk
of the composite end point in TACTICS-TIMI 18 versus
TIMI IIIB was 0.62 (95% CI, 0.52 to 0.73; P0.0001).
Directional consistency was seen with each of the individ-
ual components of the composite end point (Figure 3), with
the exception of death in the low-risk group, which was an
infrequent event and hence associated with wide CIs. For
each of the individual components of the composite end
point, there was no evidence of heterogeneity among the
different risk groups (Breslow-Day tests nonsignificant), and
the Mantel-Haenszel adjusted ORs and 95% CIs were as
follows: death, 0.87 (0.60 to 1.27); MI, 0.56 (0.43 to 0.74);
death/MI, 0.67 (0.53 to 0.85); and rehospitalization for ACS,
0.72 (0.59 to 0.88). Cumulative incidence curves are shown
in Figure 4 and suggest that the greatest difference between
the 2 trials in the occurrence of the composite end point was
in the first 30 days.
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Figure 2. Rate of composite end point of death (D), MI, or
rehospitalization for ACS at 6 months in TIMI IIIB (open bars) vs
in TACTICS-TIMI 18 (solid bars) among patients matched for
baseline TIMI risk score category (low, 0 to 2; intermediate; 3 to
4; or high, 5 to 7). Patients in TACTICS-TIMI 18 had significantly
lower event rates in low-risk (P0.0001), intermediate-risk
(P0.005), and high-risk (P0.003) categories.
Subgroup analyses (Table 3) revealed that the pattern of
lower rates of adverse cardiac events seen in TACTICS-TIMI
18 compared with TIMI IIIB in risk-matched patients was
observed both in patients randomized to an early invasive
strategy and in patients randomized to a conservative strat-
egy. Similar consistency was seen when patients were strat-
ified by actual revascularization status.
Multivariable Analyses
Although our analyses were stratified for baseline risk by use
of the TIMI risk score, it remained possible that other
baseline differences or nonrandomized treatments influenced
outcomes. Therefore, we first constructed a multivariable
logistic regression model that adjusted for baseline TIMI risk
score and treatment strategy. In this model, the OR for the
composite end point in patients in TACTICS-TIMI 18 com-
pared with patients in TIMI IIIB was 0.62 (95% CI, 0.52 to
0.73; P0.0001). We then adjusted for additional factors,
including previous PCI and previous CABG; in-hospital
revascularization; and use of aspirin, -blockers, ACE inhib-
itors, and statins. Patients in TACTICS-TIMI 18 still had
lower event rates, with an unchanged OR of 0.62 (95% CI,
0.49 to 0.79; P0.0001).
Figure 3. OR plots (point estimates and
95% CI) for risk of death (D), MI, rehospi-
talization for ACS, and their combinations
at 6 months among patients in TACTICS-
TIMI 18 (T18) vs in TIMI IIIB (T3B) among
patients matched for baseline TIMI risk
score category. Patients were categorized
as being low risk (score, 0 to 2; A), inter-
mediate risk (score, 3 to 4; B), or high risk
(score, 5 to 7; C).
 Sabatine et al
Figure 4. Kaplan-Meier curves of cumulative incidence of com-
posite end point of death (D), MI, or rehospitalization for ACS in
TIMI IIIB (solid lines) vs TACTICS-TIMI 18 (dashed lines) among
patients matched for baseline TIMI risk score category. Patients
were categorized as being low risk (score, 0 to 2; A), intermedi-
ate risk (score, 3 to 4; B), or high risk (score, 5 to 7; C).
Differences in Efficacy of an Early
Invasive Strategy
In the overall trial cohorts, the OR for the benefit of an
invasive strategy on death, MI, or rehospitalization for ACS
was 1.08 (95% CI, 0.85 to 1.38; P0.53) in TIMI IIIB and
0.78 (95% CI, 0.63 to 0.97; P0.028) in TACTICS-TIMI 18.
In Table 4, the ORs and 95% CI for the association between
an invasive strategy and the primary end point are listed for
patients grouped by baseline TIMI risk score and stratified by
trial. Two important trends are apparent.
First, across both trials combined, the benefit of an early
invasive strategy was greater with increasing baseline risk.
The OR for the composite end point at 6 months with an early
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GP IIb/IIIa Inhibition and Stenting in UA/NSTEMI 877
invasive versus a conservative strategy was 1.39 (95% CI,
1.02 to 1.88; P0.03) in low-risk patients, 0.80 (95% CI,
0.64 to 0.99; P0.04) in intermediate-risk patients, and 0.57
(95% CI, 0.38 to 0.87; P0.0083) in high-risk patients. In a
multivariable logistic regression model, these differences in
the efficacy of an invasive strategy based on risk group were
highly statistically significant (low versus intermediate,
P0.004 for interaction; low versus high, P0.001).
Second, within each risk stratum, an early invasive strategy
tended toward a more favorable result in TACTICS-TIMI 18
than in TIMI IIIB. In low-risk patients, the OR for the
composite end point at 6 months for patients randomized to
an early invasive strategy versus a conservative strategy was
1.55 (95% CI, 1.06 to 2.27) in TIMI IIIB and 1.10 (95% CI,
0.66 to 1.03) in TACTICS-TIMI 18. In intermediate-risk
patients, the ORs were 0.87 (95% CI, 0.61 to 1.24) and 0.75
(95% CI, 0.57 to 0.99) in the 2 trials. In high-risk patients, the
ORs were 0.71 (95% CI, 0.32 to 1.54) and 0.55 (95% CI, 0.33
to 0.91) in the 2 trials. Overall, by use of a multivariable
logistic regression model that included terms for TIMI risk
score group, trial, treatment strategy, and their interactions,
there was a trend for an early invasive strategy to be more
beneficial in TACTICS-TIMI 18 than in TIMI IIIB (OR,
0.79; 95% CI, 0.56 to 1.11). Qualitatively and quantitatively
similar results were obtained when the individual components
of the composite end point were examined.
Discussion
The first major, multicenter randomized trial of an early
invasive strategy versus a conservative strategy was TIMI
IIIB, which started enrollment in October 1989.1 The results
from that trial suggested that the 2 strategies yielded similar
outcomes. Two subsequent studies (Veterans Affairs NonQ-
Wave Infarction Strategies in Hospital [VANQWISH] and
Medicine versus Angiography in Thrombolytic Exclusion
[MATE]) also failed to show a clear benefit to an early
invasive strategy.6,7 However, since that time, new therapeu-
tic modalities were introduced that had the potential to shift
the balance between invasive and conservative treatment
strategies. In particular, intracoronary stents and GP IIb/IIIa
inhibitors rapidly gained clinical acceptance8,9 and were used
to varying degrees in Fragmin and fast Revascularisation
during InStability in Coronary artery disease (FRISC) II,10
TACTICS-TIMI 18,2 Randomized Intervention Treatment of
Angina (RITA)-3,11 and Intracoronary Stenting and Anti-
thrombotic Regimen COOLing-off (ISAR-COOL),11a all of
which showed an advantage to an early invasive strategy.
Although individual trials have demonstrated the efficacy of
these treatments, formal 22 factorial design trials have not
been performed to specifically assess the interaction between
these advances and an early invasive versus conservative
treatment strategy. Moreover, such trials are unlikely to be
conducted, given current practice patterns. Thus, we sought to
take advantage of the similarities in trial design between
TIMI IIIB and TACTICS-TIMI 18 to gain insight into the
impact of these advances on treatment strategy.
Using the TIMI risk score for UA/NSTEMI, we found that
despite the similar eligibility criteria, patients enrolled in
TACTICS-TIMI 18 had a more severe risk profile than did
878 Circulation February 24, 2004

TABLE 3. Subgroup Analyses of Odds Ratios for Death, MI, or Rehospitalization

for ACS in TACTICS-TIMI 18 vs TIMI IIIB Stratified by TIMI Risk Score
Odds Ratios (95% CI)

Low Intermediate High

Randomized treatment
strategy
Conservative 0.60 (0.380.95) 0.78 (0.571.06) 0.59 (0.311.11)
Invasive 0.43 (0.280.66) 0.67 (0.480.93) 0.46 (0.230.90)
Heterogeneity, P 0.29 0.53 0.59
Actual revascularization status
Medical 0.53 (0.340.84) 0.61 (0.440.85) 0.53 (0.241.18)
PCI 0.44 (0.270.73) 0.94 (0.641.39) 0.40 (0.190.83)
CABG 0.32 (0.110.90) 0.57 (0.330.99) 0.48 (0.171.33)
Heterogeneity, P 0.63 0.18 0.87

patients in TIMI IIIB. Even with 2 trials with nearly identical
enrollment criteria conducted by the same clinical trials study
group, significant differences in patient populations occurred.
Our approach illustrates how, in the appropriate setting, a
simple integrated risk tool such as the TIMI risk score can be
used to profile the risk distribution in a given cohort and
thereby facilitate more quantitative comparisons across
trials.5
After adjustment for differences in baseline risk, patients in
TACTICS-TIMI 18 were significantly less likely to experi-
ence the composite end point of death, MI, or rehospitaliza-
tion for ACS by 6 months. Directional consistency was seen
for the individual components of the composite end point,
with the magnitude of effect appearing to be greatest for MI
and somewhat less for rehospitalization for ACS and death.
The advantage in TACTICS-TIMI 18 was robust and was
observed regardless of randomized treatment strategy or
revascularization status and persisted even after adjustment
for differences in index hospitalization procedures and use of
cardiac medications. The explanations for this difference are
most likely multifactorial, and we speculate as to the contri-
butions below.
In TACTICS-TIMI 18, 85% of patients who underwent
PCI received an intracoronary stent, whereas no patient in
TIMI IIIB received a stent. Multiple interventional studies
have confirmed that stenting prevents restenosis and hence
the need for target vessel revascularization.12,13 Thus, the use
of stents might partially explain the lower rate of rehospital-
ization for ACS through 6 months, although restenosis
typically does not present as an ACS. However, stenting has
not been shown to decrease the rate of death or MI, and thus,
our observation of lower rates of these adverse events in
patients in TACTICS-TIMI 18 compared with patients in
TIMI IIIB is unlikely to be attributable to stenting. Of note,
patients in TACTICS-TIMI 18 who underwent stenting very
likely also received a thienopyridine for 2 to 4 weeks.
Although data show that thienopyridines reduce ischemic
complications in the setting of UA/NSTEMI,14 this cannot be
the sole explanation, because lower rates of death and
ischemic complications in TACTICS-TIMI 18 compared

TABLE 4. Rates of Death, MI, or Rehospitalization for ACS Stratified by TIMI

Risk Score, Trial, and Treatment Strategy
Event Rate, %
TIMI Risk
Score/Trial n INV CONS ARR, % OR 95% CI
Low (0 2)
TIMI IIIB 636 25.5 18.1 7.4 1.55 1.062.27
TIMI 18 555 12.8 11.8 1.0 1.10 0.661.83
Combined 1191 19.8 15.1 4.7 1.39 1.021.88
Intermediate (34)
TIMI IIIB 681 22.3 24.7 2.5 0.87 0.611.24
TIMI 18 1328 16.1 20.3 4.2 0.75 0.570.99
Combined 2009 18.2 21.8 3.6 0.80 0.640.99
High (57)
TIMI IIIB 108 34.6 42.9 8.2 0.71 0.321.54
TIMI 18 337 19.5 30.6 11.1 0.55 0.330.91
Combined 445 22.7 34.0 11.3 0.57 0.380.87
n indicates No. of subjects; INV, invasive strategy; CONS, conservative strategy; and ARR, absolute
risk reduction.

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 Sabatine et al
with TIMI IIIB were seen even in the subset of patients who
did not undergo PCI and hence did not receive a
thienopyridine.
The use of GP IIb/IIIa inhibitors in UA/NSTEMI has been
shown to reduce the rate of death or MI. In the Platelet
Receptor Inhibition in Ischemic Syndrome Management in
Patients Limited by Unstable Signs and Symptoms (PRISM-
PLUS) trial, treatment with tirofiban was associated with a
20% reduction in the rate of death or MI through 6 months.15
Moreover, this benefit was seen as early as 48 hours. These
observations are in keeping with our findings of an early and
sustained difference between the event rates in TACTICS-
TIMI 18 and TIMI IIIB.
Using event rates stratified by the TIMI risk score, we were
able to dissect out the complex interrelationships between
baseline risk, clinical trial, and the benefits of an early
invasive strategy. We found that the efficacy of an early
invasive strategy was strongly related to a patients baseline
risk, with increasing benefits with higher levels of baseline
risk. This relationship was apparent in both TIMI IIIB and
TACTICS-TIMI 18. This observation underscores the impor-
tance of adjusting for baseline differences when attempting to
synthesize data across multiple trials. Such differences can be
particularly important if, as in this case, they interact with the
treatment being tested in the trials. For example, a meta-anal-
ysis of the results of TIMI IIIB and TACTICS-TIMI 18
would yield a statistically nonsignificant OR for the effect of
an early invasive strategy on the composite end point of 0.90
(95% CI, 0.77 to 1.06; P0.23). However, by performing
stratified analyses, we revealed a more complex picture and
demonstrated statistically significant and clinically important
heterogeneity with an early invasive strategy offering no
benefit in low-risk patients but 20% and 40% reductions
in death and ischemic complications in intermediate- and
high-risk patients, respectively. Moreover, after adjustment
for baseline risk, there was a trend toward an interaction
between an early invasive therapy and trial, with an early
invasive strategy being 20% more effective in TACTICS-
TIMI 18 than in TIMI IIIB. These data support the notion that
an early invasive approach may be even more efficacious in
reducing adverse cardiac events when used in the setting of
upstream GP IIb/IIIa inhibition and intracoronary stenting.
Study Limitations
Although we attempted to adjust for differences in baseline
risk between the 2 trial populations, any intertrial comparison
must be viewed with caution, and because multiple compar-
isons were made in these post hoc analyses, even those with
statistical significance must be viewed as exploratory. Un-
known and therefore uncontrolled-for confounding factors
may have led to the introduction of bias. It should also be
noted that although use of the TIMI risk score then permitted
stratified analyses, the score may not have fully captured a
patients risk. Although GP IIb/IIIa inhibition and stenting are
probably the predominant causes of the lower event rate and
greater benefit of an early invasive strategy in TACTICS-
TIMI 18, such attribution remains speculative, and other
interventions may have been responsible for the improved
outcome in TACTICS-TIMI 18. Nonetheless, using careful
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GP IIb/IIIa Inhibition and Stenting in UA/NSTEMI 879
multivariable analysis, we have attempted to estimate the
potential beneficial effects of GP IIb/IIIa inhibitors and
stenting in the absence of an opportunity for future random-
ized trials.
Conclusions
An integrated risk tool such as the TIMI risk score can be
used to allow stratified comparisons between patients of
similar risk in different trials. Using such an approach in
TIMI IIIB and TACTICS-TIMI 18, we found that among
patients matched for similar degrees of baseline risk, patients
in TACTICS-TIMI 18 had lower rates of death, MI, or
rehospitalization for ACS through 6 months. We also found
that the benefits of an early invasive strategy were signifi-
cantly greater with increasing baseline risk and that, within
each risk stratum, there was a trend toward the benefit of an
early invasive strategy being greater in TACTICS-TIMI 18
than in TIMI IIIB. Although the contribution of many factors
is possible, these differences most likely reflect the use of GP
IIb/IIIa inhibitors and coronary stents in TACTICS-TIMI 18
and thus support the most recent American College of
Cardiology/American Heart Association guidelines,16 which
call for GP IIb/IIIa inhibition and an early invasive approach
in patients with high-risk UA/NSTEMI.
Acknowledgments
Dr Sabatine was supported in part by National Heart, Lung, and
Blood Institute grant F32-HL68455-01. TACTICS-TIMI 18 was
supported by Merck & Co. The TIMI Study Group and Dr Weintraub
have received research grant support from Merck & Co.
References
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a comparison of early invasive and conservative strategies in unstable
angina and nonQ-wave myocardial infarction: results of the TIMI IIIB
trial. Circulation. 1994;89:15451556.
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