The New England Journal of Medicine

Original Article
Volume 344:1879-1887

June 21, 2001

Number 25
Comparison of Early Invasive and Conservative Strategies in Patients with
Unstable Coronary Syndromes Treated with the Glycoprotein IIb/IIIa Inhibitor
Tirofiban
Christopher P. Cannon, M.D., William S. Weintraub, M.D., Laura A.
Demopoulos, M.D., Ralph Vicari, M.D., Martin J. Frey, M.D., Nasser Lakkis,
M.D., Franz-Josef Neumann, M.D., Debbie H. Robertson, R.D., M.S., Paul T.
DeLucca, Ph.D., Peter M. DiBattiste, M.D., C. Michael Gibson, M.D., Eugene
Braunwald, M.D. for the TACTICS–Thrombolysis in Myocardial Infarction 18
Investigators

ABSTRACT
Background There is continued debate as to whether a routine, early invasive
strategy is superior to a conservative strategy for the management of
unstable angina and myocardial infarction without ST-segment elevation.
Methods We enrolled 2220 patients with unstable angina and myocardial
infarction without ST-segment elevation who had electrocardiographic
evidence of changes in the ST segment or T wave, elevated levels of cardiac
markers, a history of coronary artery disease, or all three findings. All
patients were treated with aspirin, heparin, and the glycoprotein IIb/IIIa
inhibitor tirofiban. They were randomly assigned to an early invasive
strategy, which included routine catheterization within 4 to 48 hours and
revascularization as appropriate, or to a more conservative (selectively
invasive) strategy, in which catheterization was performed only if the
patient had objective evidence of recurrent ischemia or an abnormal stress
test. The primary end point was a composite of death, nonfatal myocardial
infarction, and rehospitalization for an acute coronary syndrome at six
months.
Results At six months, the rate of the primary end point was 15.9 percent
with use of the early invasive strategy and 19.4 percent with use of the
conservative strategy (odds ratio, 0.78; 95 percent confidence interval,
0.62 to 0.97; P=0.025). The rate of death or nonfatal myocardial infarction
at six months was similarly reduced (7.3 percent vs. 9.5 percent; odds
ratio, 0.74; 95 percent confidence interval, 0.54 to 1.00; P<0.05).
Conclusions In patients with unstable angina and myocardial infarction
without ST-segment elevation who were treated with the glycoprotein IIb/IIIa
inhibitor tirofiban, the use of an early invasive strategy significantly
reduced the incidence of major cardiac events. These data support a policy
involving broader use of the early inhibition of glycoprotein IIb/IIIa in
combination with an early invasive strategy in such patients.
  _____

The syndrome of unstable angina and myocardial infarction without ST-segment
elevation accounts for approximately 1.4 million hospital admissions
annually in the United States and 2 million to 2.5 million worldwide. 1
<http://content.nejm.org/cgi/content/full/344/25/#R1>  Until fairly
recently, initial treatment focused on medical stabilization through the use
of antianginal and antithrombotic agents, including aspirin and
unfractionated or low-molecular-weight heparin. 2
<http://content.nejm.org/cgi/content/full/344/25/#R2> , 3
<http://content.nejm.org/cgi/content/full/344/25/#R3> , 4
<http://content.nejm.org/cgi/content/full/344/25/#R4> , 5
<http://content.nejm.org/cgi/content/full/344/25/#R5>  The next step is to
decide whether to refer the patient for cardiac catheterization and
revascularization, if appropriate (a routine invasive approach), or to
follow a conservative strategy, in which cardiac procedures are performed
only if the patient has spontaneous or provoked recurrent ischemia. There is
considerable debate about which strategy is optimal, in part because the
results of previous randomized trials have been mixed. 6
<http://content.nejm.org/cgi/content/full/344/25/#R6> , 7
<http://content.nejm.org/cgi/content/full/344/25/#R7> , 8
<http://content.nejm.org/cgi/content/full/344/25/#R8> , 9
<http://content.nejm.org/cgi/content/full/344/25/#R9> , 10
<http://content.nejm.org/cgi/content/full/344/25/#R10> , 11
<http://content.nejm.org/cgi/content/full/344/25/#R11>
These trials were conducted before two major advances occurred in the field:
inhibitors of platelet glycoprotein IIb/IIIa were found to reduce the risk
of death, myocardial infarction, or recurrent angina in patients with
unstable angina and myocardial infarction without ST-segment elevation,
especially those who were undergoing percutaneous coronary
revascularization, 12 <http://content.nejm.org/cgi/content/full/344/25/#R12>
, 13 <http://content.nejm.org/cgi/content/full/344/25/#R13> , 14
<http://content.nejm.org/cgi/content/full/344/25/#R14>  and intracoronary
stents were found to reduce the rate of angiographically and clinically
evident restenosis. 15
<http://content.nejm.org/cgi/content/full/344/25/#R15> , 16
<http://content.nejm.org/cgi/content/full/344/25/#R16>  Given these
advances, we hypothesized that an early invasive strategy would be superior
to a more conservative approach.
Methods
Study Population
Between December 18, 1997, and December 22, 1999, a total of 2220 patients
underwent randomization. The protocol was approved by the relevant
institutional review boards, and written informed consent was obtained from
all patients. The study design has been described previously. 17
<http://content.nejm.org/cgi/content/full/344/25/#R17>  Briefly, men and
women who were at least 18 years old were eligible for inclusion if they had
had an episode of angina (with an accelerating pattern or prolonged [>20
minutes] or recurrent episodes at rest or with minimal effort) within the
preceding 24 hours, were candidates for coronary revascularization, and had
at least one of the following: a new finding of ST-segment depression of at
least 0.05 mV, transient (<20 minutes) ST-segment elevation of at least 0.1
mV, or T-wave inversion of at least 0.3 mV in at least two leads; elevated
levels of cardiac markers; or coronary disease, as documented by a history
of catheterization, revascularization, or myocardial infarction.
Patients were excluded from the study if they met any of the following
criteria: persistent ST-segment elevation, secondary angina, 18
<http://content.nejm.org/cgi/content/full/344/25/#R18>  a history of
percutaneous coronary revascularization or coronary-artery bypass grafting
within the preceding six months, factors associated with an increased risk
of bleeding, 17 <http://content.nejm.org/cgi/content/full/344/25/#R17>  left
bundle-branch block or paced rhythm, severe congestive heart failure or
cardiogenic shock, serious systemic disease, a serum creatinine level of
more than 2.5 mg per deciliter (221 µmol per liter), or current
participation in another study of an investigational drug or device.
Patients were also excluded if they were taking warfarin or had received
ticlopidine or clopidogrel for more than three days before enrollment.
Medical Management
The protocol specified that patients receive 325 mg of aspirin daily (unless
contraindicated); intravenous unfractionated heparin at an initial dose of
5000 U (as a bolus), followed by an infusion at a rate of 1000 U per hour
for 48 hours 17 <http://content.nejm.org/cgi/content/full/344/25/#R17> ; and
tirofiban (Aggrastat, Merck, West Point, Pa.), administered intravenously in
a loading dose of 0.4 µg per kilogram of body weight per minute for a period
of 30 minutes followed by a maintenance infusion of 0.1 µg per kilogram per
minute 13 <http://content.nejm.org/cgi/content/full/344/25/#R13>  for 48
hours or until revascularization, with tirofiban administered for at least
12 hours after percutaneous coronary revascularization procedures. Tirofiban
was available for all percutaneous coronary revascularizations performed
during follow-up. Aspirin, heparin, and tirofiban were administered to 98
percent, more than 99 percent, and more than 99 percent of patients,
respectively. Recommended medical therapy with beta-blockers, nitrates, and
lipid-lowering agents was administered to 82 percent, 94 percent, and 52
percent of patients, respectively. A blood sample was obtained at base line,
and levels of troponin T (Roche Diagnostics, Indianapolis) and troponin I
(Bayer, Tarrytown, N.Y.) were analyzed later in the Thrombolysis in
Myocardial Infarction (TIMI) core laboratory. Creatine kinase and the MB
isoform of creatine kinase were measured on site every 8 hours for 24 hours
at the time of randomization, for episodes of recurrent angina suggestive of
myocardial infarction, and after all revascularization procedures. The TIMI
risk score for unstable angina and myocardial infarction without ST-segment
elevation 19 <http://content.nejm.org/cgi/content/full/344/25/#R19>  was
determined at base line. The test evaluates patients for the presence or
absence of seven risk factors for death and ischemic events. Patients with a
score of 0, 1, or 2 are considered to be at low risk; patients with a score
of 3 or 4 are considered to be at intermediate risk; and patients with a
score of 5, 6, or 7 are considered to be at high risk.
Treatment Strategy
Patients were randomly assigned to an early invasive strategy or an early
conservative strategy by means of a centralized system. Patients assigned to
the early invasive strategy were to undergo coronary angiography between 4
and 48 hours after randomization and revascularization when appropriate on
the basis of coronary anatomical findings. Patients assigned to the early
conservative strategy were treated medically and, if their condition was
stable, underwent an exercise-tolerance test (83 percent of such tests
included nuclear perfusion imaging or echocardiography performed according
to the protocol of the institution) before being discharged. These patients
were to undergo coronary angiography and revascularization as appropriate
only if they had one of the following: prolonged or recurrent angina at rest
that was associated with electrocardiographic evidence of ischemia or
changes in cardiac-enzyme levels sufficient to meet the inclusion criteria,
hemodynamic instability, documented ischemia before the end of stage 2 of
the standard Bruce protocol of a treadmill exercise test or at any time
during a pharmacologic stress test (angina accompanied by ST-segment
depression of at least 0.1 mV, ST-segment depression of at least 0.2 mV
alone, a fall in blood pressure of at least 10 mm Hg, one large region or
two smaller regions of reversible hypoperfusion on nuclear imaging, or a new
abnormality in wall motion on stress echocardiography), unstable angina
requiring rehospitalization, Canadian Cardiovascular Society class III or IV
angina with an abnormal exercise-tolerance test, or a new myocardial
infarction. Follow-up was conducted by telephone at 30 days and 6 months,
and medical records were examined to verify all end points. A total of 27
patients (1.2 percent) had been lost to follow-up by six months.
Statistical Analysis
The primary end point was the combined incidence of death, nonfatal
myocardial infarction, and rehospitalization for an acute coronary syndrome
at six months. End points were defined with the use of standard TIMI
definitions. 20 <http://content.nejm.org/cgi/content/full/344/25/#R20>
Patients were monitored for bleeding for 24 hours after the study medication
was stopped, and major bleeding was defined as a decrease in the blood
hemoglobin level of at least 5.0 g per deciliter, the need for the
transfusion of 2 or more units of blood, the need for corrective surgery,
the occurrence of an intracranial or retroperitoneal hemorrhage or cardiac
tamponade, or any combination of these events. 12
<http://content.nejm.org/cgi/content/full/344/25/#R12>  All primary end
points were adjudicated by members of an independent clinical end-points
committee who were unaware of patients' treatment assignments.
The prospectively defined analysis of the primary end point was a
logistic-regression analysis that included terms for prior aspirin use and
an age of at least 65 years. Data on patients who were lost to follow-up
were censored at the time of the last documented contact. We estimated that,
given a 22 percent rate of the primary end point in the
conservative-strategy group, 1720 patients would be needed to provide the
study with 80 percent power to detect a relative difference of 25 percent
between the two groups. A prespecified adjustment in the sample size to 2220
was carried out on the basis of blinded data after 50 percent of patients
had been followed for 30 days. One interim efficacy analysis was carried out
by the data and safety monitoring board. 17
<http://content.nejm.org/cgi/content/full/344/25/#R17>  Data coordination
was performed by Quintiles (see the Appendix), where the data were held for
analysis. Both TIMI investigators and Merck statisticians verified all
analyses.
Results
The two groups of patients were well matched; more than 40 percent of the
patients in each group were at least 65 years of age, and one third of the
patients were women ( Table 1
<http://content.nejm.org/cgi/content/full/344/25/#T1> ).
Electrocardiographic evidence of changes in the ST segment or T wave was
present in 48 percent of the patients, and levels of troponin T were
elevated (>0.01 ng per milliliter) in 54 percent of the 1826 patients in
whom they were measured, whereas 27 percent had evidence of prior coronary
artery disease as the sole criterion for enrollment. Base-line angiographic
data in the group assigned to the early invasive strategy revealed stenosis
of the left main coronary artery in 9 percent, three-vessel disease in 34
percent, and normal vessels in 13 percent.


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Table 1. Base-Line Characteristics of the Patients.

In the invasive-strategy group, 97 percent of the patients underwent cardiac
catheterization during the initial hospitalization a median of 22 hours
after randomization, and 60 percent underwent percutaneous coronary
revascularization or coronary-artery bypass grafting a median of 25 and 89
hours, respectively, after randomization ( Table 2
<http://content.nejm.org/cgi/content/full/344/25/#T2> ). In the
conservative-strategy group, 478 patients (43 percent) met the protocol
criteria for failure of medical therapy during the initial hospitalization:
56 percent of these patients had an abnormal stress test, 37 percent had
recurrent angina at rest with electrocardiographic changes, 4 percent had
hemodynamic instability, and 4 percent had recurrent myocardial infarction.
In an additional 8 percent, medical therapy failed during follow-up, and the
patients were rehospitalized for unstable angina or myocardial infarction.


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Table 2. Cardiac Procedures Conducted during the Initial Hospitalization and
during the First Six Months.

Of the patients who were randomly assigned to the conservative strategy, 51
percent underwent catheterization and 36 percent underwent revascularization
during the initial hospitalization. By six months the total rates of
revascularization had increased by 1 percentage point in the
invasive-strategy group and by 8 percentage points in the
conservative-strategy group. During the initial hospitalization, coronary
stents were used in 83 percent of the percutaneous coronary
revascularization procedures in the invasive-strategy group and in 86
percent of such procedures in the conservative-strategy group. Despite being
available for all percutaneous coronary revascularization procedures
conducted in both strategies, tirofiban was used during 94 percent of
procedures in the invasive-strategy group and 59 percent of procedures in
the conservative-strategy group. The median duration of tirofiban
administration was 48 and 50 hours, respectively.
Primary End Point
The rate of primary end point — death, nonfatal myocardial infarction, or
rehospitalization for an acute coronary syndrome at six months — was 15.9
percent with use of the early invasive strategy and 19.4 percent with use of
the conservative strategy (odds ratio, 0.78; 95 percent confidence interval,
0.62 to 0.97; P=0.025) ( Figure 1
<http://content.nejm.org/cgi/content/full/344/25/#F1>  and Table 3
<http://content.nejm.org/cgi/content/full/344/25/#T3> ). The results of the
unadjusted analysis were almost identical: the odds ratio was 0.78 (95
percent confidence interval, 0.63 to 0.98; P=0.028). This reduction was seen
after the first week ( Figure 1
<http://content.nejm.org/cgi/content/full/344/25/#F1> ) and at 30 days
(P=0.009) ( Table 3 <http://content.nejm.org/cgi/content/full/344/25/#T3> ).
Similarly, the likelihood of death or nonfatal myocardial infarction was
significantly lower in the invasive-strategy group than in the
conservative-strategy group at 30 days (4.7 percent vs. 7.0 percent; odds
ratio, 0.65; 95 percent confidence interval, 0.45 to 0.93; P=0.02) and at 6
months (7.3 percent vs. 9.5 percent; odds ratio, 0.74; 95 percent confidence
interval, 0.54 to 1.00; P<0.05). The benefit of the early invasive strategy
was consistent among the major subgroups, with a significantly greater
benefit in the patients with ST-segment changes at base line (P for
interaction=0.006) and in those without prior aspirin use at base line (P
for interaction=0.02) ( Figure 2
<http://content.nejm.org/cgi/content/full/344/25/#F2> ). The clinical
significance of the latter observation is unclear.


  <http://content.nejm.org/cgi/content/full/344/25/1879/F1>
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Figure 1. Cumulative Incidence of the Primary End Point of Death, Nonfatal
Myocardial Infarction, or Rehospitalization for an Acute Coronary Syndrome
during the Six-Month Follow-up Period.
The rate of the primary end point was lower in the invasive-strategy group
than in the conservative-strategy group (15.9 percent vs. 19.4 percent; odds
ratio, 0.78; 95 percent confidence interval, 0.62 to 0.97; P=0.025).



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Table 3. Clinical Outcomes Associated with the Invasive Strategy, as
Compared with the Conservative Strategy.



  <http://content.nejm.org/cgi/content/full/344/25/1879/F2>
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Figure 2. Rates of the Primary End Point of Death, Nonfatal Myocardial
Infarction, or Rehospitalization for an Acute Coronary Syndrome at Six
Months, According to Base-Line Characteristics.
Odds ratios and 95 percent confidence intervals were determined by
logistic-regression analysis. P values for the interaction were significant
only for prior aspirin use (P=0.02) and ST-segment changes (P=0.006). For
the analysis of the TIMI risk score, which assesses the risk of death and
ischemic events in patients with unstable angina and myocardial infarction
without ST-segment elevation, the upper bound of the confidence interval for
a score of 3 to 4 was 0.999 (P=0.048; P for the interaction among the three
risk groups=0.15). Troponin T was measured at base line in a total of 1826
patients. MI denotes myocardial infarction.

Risk Stratification
The benefit of the early invasive strategy was significantly greater in
patients with troponin T levels of more than 0.01 ng per milliliter than in
patients with levels of 0.01 ng per milliliter or less ( Table 4
<http://content.nejm.org/cgi/content/full/344/25/#T4>  and Figure 2
<http://content.nejm.org/cgi/content/full/344/25/#F2> ). In patients with a
troponin T level of more than 0.01 ng per milliliter, there was a relative
reduction in the risk of the primary end point of 39 percent with the use of
the invasive strategy rather than the conservative strategy (P<0.001),
whereas patients with a troponin T level of 0.01 ng per milliliter or less
had similar outcomes with either strategy. Similar results were observed
with the use of a troponin T cutoff point of 0.1 ng per milliliter ( Figure
2 <http://content.nejm.org/cgi/content/full/344/25/#F2> ). When patients
were stratified according to the TIMI risk score, intermediate-risk and
high-risk patients derived a significant benefit from the use of the early
invasive strategy, whereas low-risk patients had similar outcomes with the
use of either strategy ( Figure 2
<http://content.nejm.org/cgi/content/full/344/25/#F2> ).


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Table 4. Outcomes Associated with the Invasive Strategy as Compared with the
Conservative Strategy, According to the Base-Line Level of Troponin T.

In an attempt to determine the cause of the beneficial effect of the early
invasive strategy, we examined the outcomes among patients who were
ultimately treated with revascularization procedures and those who received
medical therapy alone ( Table 5
<http://content.nejm.org/cgi/content/full/344/25/#T5> ). The benefits of the
early invasive strategy were apparent at 30 days among those who ultimately
underwent revascularization, whereas those who received medical therapy
alone in each strategy group had similar outcomes.


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Table 5. Clinical Outcomes at 30 Days and 6 Months, According to the
Revascularization Status.

Additional Outcomes
The rates of recurrent ischemia at rest were lower in the invasive-strategy
group than in the conservative-strategy group, both ischemia with
demonstrable electrocardiographic changes (6.3 percent vs. 10.3 percent;
odds ratio, 0.58; P=0.001) and ischemic pain without electrocardiographic
changes (32.3 percent vs. 49.4 percent; odds ratio, 0.49; P<0.001). Stroke
occurred in 0.5 percent of the patients in each group. The 30-day mortality
rates after coronary-artery bypass grafting and percutaneous coronary
revascularization were 3.6 percent and 1.9 percent, respectively, and were
similar in the two strategy groups. Protocol-defined bleeding 12
<http://content.nejm.org/cgi/content/full/344/25/#R12>  occurred in 5.5
percent of the patients in the invasive-strategy group, as compared with 3.3
percent of those in the conservative-strategy group (P<0.01), but the rates
of major bleeding according to the standard TIMI definition 20
<http://content.nejm.org/cgi/content/full/344/25/#R20>  were not
significantly different (1.9 percent vs. 1.3 percent, P=0.24). The median
length of hospitalization was one day shorter in the invasive-strategy group
than in the conservative-strategy group (5 days vs. 6 days, P<0.001).
Discussion
This study demonstrates that among patients with unstable angina and
myocardial infarction without ST-segment elevation who were treated with the
glycoprotein IIb/IIIa inhibitor tirofiban, an early invasive strategy was
superior to a conservative strategy in reducing the incidence of major
cardiac events at 30 days and at 6 months. The benefit observed was
consistent in nearly every subgroup tested, and in a prespecified analysis
that used the TIMI risk score, 19
<http://content.nejm.org/cgi/content/full/344/25/#R19>  the benefits were
observed in intermediate-risk and high-risk patients; such patients made up
75 percent of the population studied. For the 25 percent of patients who
were deemed to be at low risk for death and ischemic events, the outcomes
were similar with the use of either strategy. We also prospectively
demonstrated that in patients with an elevated troponin T level at base
line, the use of the early invasive strategy conferred added benefit and
reduced the rates of events to those of patients who did not have an
elevated troponin T level. In addition, the 4.7 percent rate of death or
nonfatal myocardial infarction at 30 days in the invasive-strategy group is
lower than the rates reported in previous trials of patients with unstable
angina and myocardial infarction without ST-segment elevation. 12
<http://content.nejm.org/cgi/content/full/344/25/#R12> , 14
<http://content.nejm.org/cgi/content/full/344/25/#R14> , 21
<http://content.nejm.org/cgi/content/full/344/25/#R21> , 22
<http://content.nejm.org/cgi/content/full/344/25/#R22>  Thus, we conclude
that this strategy of early inhibition of glycoprotein IIb/IIIa with
tirofiban in combination with an early invasive strategy leads to excellent
outcomes and could be considered the treatment of choice for the majority of
patients with unstable angina and myocardial infarction without ST-segment
elevation.
Two components of the early invasive strategy may explain the benefits we
observed: the early use of tirofiban and the early timing of
revascularization, the combination of which may have been needed to achieve
these benefits. In all four prior randomized trials, 6
<http://content.nejm.org/cgi/content/full/344/25/#R6> , 7
<http://content.nejm.org/cgi/content/full/344/25/#R7> , 8
<http://content.nejm.org/cgi/content/full/344/25/#R8> , 9
<http://content.nejm.org/cgi/content/full/344/25/#R9> , 10
<http://content.nejm.org/cgi/content/full/344/25/#R10> , 11
<http://content.nejm.org/cgi/content/full/344/25/#R11>  the rate of
myocardial infarction tended to be higher in the invasive-strategy group
during the first several weeks, a finding that is consistent with the
initially increased risk of cardiac events associated with coronary
interventions. In contrast, we observed a significantly lower rate of
myocardial infarction during this period, an effect that may be attributable
to the well-documented protection afforded by the inhibition of glycoprotein
IIb/IIIa. 22 <http://content.nejm.org/cgi/content/full/344/25/#R22>
Cardiac procedures were carried out approximately two to three days earlier
in the invasive strategy than in the conservative strategy, which appears to
have averted events that would otherwise have occurred. Indeed, the
prevailing consensus little more than a decade ago, as recommended in the
1990 guidelines of the American College of Cardiology–American Heart
Association, 23 <http://content.nejm.org/cgi/content/full/344/25/#R23>  was
that patients with non–Q-wave myocardial infarction should undergo early
cardiac catheterization and revascularization to avert further events.
Although prior studies failed to demonstrate the benefit of this approach,
it now appears that with the use of early inhibition of glycoprotein
IIb/IIIa and current interventional techniques, early revascularization does
prevent major cardiac events in such patients. This further suggests that
the benefit of an early invasive strategy using inhibitors of glycoprotein
IIb/IIIa should be reevaluated in patients with myocardial infarction
involving acute ST-segment elevation.
Two types of conservative strategy were tested in earlier studies. In the
TIMI IIIB study 6 <http://content.nejm.org/cgi/content/full/344/25/#R6> , 7
<http://content.nejm.org/cgi/content/full/344/25/#R7>  and the Veterans
Affairs Non–Q-Wave Infarction Strategies in Hospital (VANQWISH) trial, 8
<http://content.nejm.org/cgi/content/full/344/25/#R8>  the conservative
strategy involved careful monitoring for ischemia with the use of stress
testing with radionuclide or echocardiographic imaging in nearly all
patients and an electrocardiographic criterion of the presence of ST-segment
depression of at least 0.1 mV for an abnormal test, which is consistent with
the 1994 and 2000 guidelines for the management of unstable angina and
myocardial infarction without ST-segment elevation. 1
<http://content.nejm.org/cgi/content/full/344/25/#R1> , 24
<http://content.nejm.org/cgi/content/full/344/25/#R24>  This approach led to
cardiac catheterization in approximately 50 percent of patients.
The conservative strategy in the Fragmin and Fast Revascularization during
Instability in Coronary Artery Disease (FRISC) II trial used more stringent
criteria for ischemia, in which an abnormal stress test and
electrocardiographic evidence of ST-segment depression of at least 0.3 mV
were required for a patient to undergo cardiac catheterization. 10
<http://content.nejm.org/cgi/content/full/344/25/#R10>  Consequently, only
10 percent of patients underwent cardiac catheterization during the initial
hospitalization. The study reported that, as compared with this very
conservative strategy, the invasive strategy was associated with a lower
rate of death or myocardial infarction and a lower one-year mortality rate.
10 <http://content.nejm.org/cgi/content/full/344/25/#R10>
Thus, because the conservative strategy they used 10
<http://content.nejm.org/cgi/content/full/344/25/#R10>  was more
conservative than the strategies recommended in both the 1994 and 2000
guidelines for the treatment of unstable angina and myocardial infarction
without ST-segment elevation, 1
<http://content.nejm.org/cgi/content/full/344/25/#R1> , 24
<http://content.nejm.org/cgi/content/full/344/25/#R24>  it was important to
determine the outcomes of a more selective invasive strategy. In addition,
the antithrombotic therapy used in FRISC II — dalteparin — has not been
shown to be more efficacious than unfractionated heparin. In our study, we
used both improved antithrombotic therapy and more sensitive monitoring for
ischemia, an approach that would also improve the outcomes of the
conservative strategy. In spite of this improved conservative strategy, we
found that the early invasive strategy, which included early inhibition of
glycoprotein IIb/IIIa and stenting, was superior in reducing the incidence
of major cardiac events.
We used immediate inhibition of glycoprotein IIb/IIIa as part of the medical
treatment of all patients. Early treatment with tirofiban, heparin, and
aspirin has been shown to reduce the incidence of coronary thrombus, 25
<http://content.nejm.org/cgi/content/full/344/25/#R25>  improve blood flow
(TIMI flow grade 3), 25
<http://content.nejm.org/cgi/content/full/344/25/#R25>  and lead to a
reduction (by 66 percent) in the rate of death or myocardial infarction
within 48 hours as compared with treatment with aspirin and heparin alone.
12 <http://content.nejm.org/cgi/content/full/344/25/#R12> , 26
<http://content.nejm.org/cgi/content/full/344/25/#R26>  Furthermore, the
size of evolving myocardial infarctions without ST-segment elevation was
reduced with tirofiban (as measured on the basis of troponin I levels) 27
<http://content.nejm.org/cgi/content/full/344/25/#R27> ; this finding was
confirmed in another trial that used a different glycoprotein IIb/IIIa
inhibitor and measured creatine kinase MB levels. 28
<http://content.nejm.org/cgi/content/full/344/25/#R28> , 29
<http://content.nejm.org/cgi/content/full/344/25/#R29>  Finally, the
reduction in the rate of death or myocardial infarction 30 days after
treatment with tirofiban, heparin, and aspirin, as compared with heparin and
aspirin alone, was consistent among patients treated medically, with
percutaneous coronary revascularization, and with coronary-artery bypass
grafting. 12 <http://content.nejm.org/cgi/content/full/344/25/#R12> , 14
<http://content.nejm.org/cgi/content/full/344/25/#R14> , 30
<http://content.nejm.org/cgi/content/full/344/25/#R30> , 31
<http://content.nejm.org/cgi/content/full/344/25/#R31>
To provide patients with all these benefits, we administered tirofiban
immediately after randomization. The rate of death or nonfatal myocardial
infarction at 30 days in the invasive-strategy group was just 4.7 percent,
which compares favorably to the rates in prior studies of patients with
unstable angina and myocardial infarction without ST-segment elevation. 22
<http://content.nejm.org/cgi/content/full/344/25/#R22>  Whether similar
results could be achieved in this population if treatment with a
glycoprotein IIb/IIIa inhibitor was initiated in the catheterization
laboratory only in patients undergoing percutaneous coronary
revascularization should be tested in a prospective trial. For patients in
the invasive-strategy group who underwent percutaneous coronary
revascularization after having received tirofiban, the rate of death or
myocardial infarction at 30 days was 5.3 percent ( Table 5
<http://content.nejm.org/cgi/content/full/344/25/#T5> ), which also compares
favorably with the results of other recent trials of percutaneous coronary
revascularization with other inhibitors of glycoprotein IIb/IIIa.
The value of cardiac troponin levels as a means of identifying high-risk
patients has been well documented. 32
<http://content.nejm.org/cgi/content/full/344/25/#R32> , 33
<http://content.nejm.org/cgi/content/full/344/25/#R33> , 34
<http://content.nejm.org/cgi/content/full/344/25/#R34>  Furthermore,
elevations in troponin T and I levels have been found to identify the
patients who will benefit from more intensive antithrombotic therapy, which
includes low-molecular-weight heparin and inhibition of glycoprotein
IIb/IIIa. 35 <http://content.nejm.org/cgi/content/full/344/25/#R35> , 36
<http://content.nejm.org/cgi/content/full/344/25/#R36> , 37
<http://content.nejm.org/cgi/content/full/344/25/#R37> , 38
<http://content.nejm.org/cgi/content/full/344/25/#R38>  A major objective of
our study was to test prospectively the validity of the troponin
hypothesis — that the measurement of troponin T or I at the time of
presentation is useful in determining the optimal treatment strategy. We
observed that patients with elevated levels of troponin T at base line
derived a greater benefit from the early invasive strategy than did those
without elevated levels. Thus, the use of this marker could be incorporated
into management approaches for the triage of patients with respect to an
early invasive strategy.
We found that for patients with unstable angina and myocardial infarction
without ST-segment elevation, an early invasive strategy is superior to a
conservative or a selectively invasive strategy in reducing the incidence of
major cardiac events. This benefit applied to most patients studied,
especially those at intermediate or high risk, whereas the low-risk patients
had similar outcomes with the use of either strategy, indicating the
usefulness of early risk stratification. Our results provide evidence to
physicians of the value of broader use of a strategy of early inhibition of
glycoprotein IIb/IIIa in combination with an early invasive approach.
Supported by Merck.
Drs. Demopoulos, DiBattiste, and DeLucca and Ms. Robertson are employees of
Merck.
* The TACTICS (Treat Angina with Aggrastat and Determine Cost of Therapy
with an Invasive or Conservative Strategy)–Thrombolysis in Myocardial
Infarction 18 investigators are listed in the Appendix.
<http://content.nejm.org/cgi/content/full/344/25/#RFN1>

Source Information
From the Cardiovascular Division, Brigham and Women's Hospital, Boston
(C.P.C., E.B.); Emory University, Atlanta (W.S.W.); Merck, West Point, Pa.
(L.A.D., D.H.R., P.T.D., P.M.D.); Holmes Regional Medical Center, Melbourne,
Fla. (R.V.); the Heart Center of Sarasota, Sarasota, Fla. (M.J.F.); Baylor
College of Medicine, Houston (N.L.); Medizinische Klinik der Technischen
Universität München, Munich, Germany (F.-J.N.); and Harvard Clinical
Research Institute, Boston (C.M.G.).
Address reprint requests to Dr. Cannon at the TIMI Study Group,
Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St.,
Boston, MA 02115, or at [log in to unmask] <mailto:[log in to unmask]>
.
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Appendix
The following investigators and research coordinators participated in the
study (the complete list of investigators and coordinators is available at
http://www.timi.org): Steering Committee — C. Cannon (chairman), E.
Braunwald (TIMI study chairman), J. Adgey, S. Ellis, M. Gibson, T. Henry, S.
King, N. Kleiman, R. Piana, J. Popma, P. Teirstein, W. Weintraub; Economics
Committee — W. Weintraub (chairman), S. Ellis, D. Feeny, H. Krumholtz, D.
Cohen, J. Spertus, S. Culler, A. Kosinski, E. Mahoney, C. Jurkovitz;
Clinical Events Committee — S. Borzak (chairman), M. Attabuto, N. Bernstein,
H. Cooper, R. Giugliano, A. Jacobs, G. Koren, P. McCullough, T. Palabrica,
C. Rogers, G. Tofler; TIMI Study Office — C.H. McCabe (project director), S.
McHale; TIMI Angiographic Core Laboratory (Harvard Clinical Research
Institute, Boston) — M. Gibson, S. Marble, S. Murphy; TIMI Serum Marker Core
Laboratory (Children's Hospital, Boston) — N. Rifai, J. Matsubara, J.
Barrow; Data and Safety Monitoring Board — W. Parmley (chairman), E.
Alderman, H. Anderson, S. Kelsey; Data Coordinating Center (Quintiles,
Research Triangle Park, N.C.) — D. Mackey, C. Kelly, D. Schneider, C. Tate,
J. Nelson, D. Sen, J. Davis; Merck — L. Demopoulos, P. DiBattiste, F. Sax,
G. Tarnesby, T. Bunt, D. Robertson, P. Dellea, A. Brinton, C. Polamalu, P.
DeLucca; the 25 clinical centers enrolling the most patients (in order of
enrollment) — Holmes Regional Medical Center, Melbourne, Fla.: R. Vicari, K.
Koteek; Heart Center of Sarasota and Doctor's Hospital of Sarasota,
Sarasota, Fla.: M. Frey, N. Fichter, T. McMullen; Ben Taub General Hospital,
Houston: N. Lakkis, S. Runchey; Heart Center Research Division, Huntsville,
Ala.: R. Hunter, N. Keenum, C. Cholewa; North Mississippi Medical Center,
Tupelo: B. Bertolet, C. Bond; German Heart Center, Munich, Germany: F.
Neumann, G. Pogatsa-Murray; East Carolina School of Medicine, Greenville,
N.C.: J. Babb, D. Bembridge; University of Oklahoma, Oklahoma City: A.
Kugelmass, J. Wells; United Hospital, St. John's Hospital, and St. Joseph's
Hospital, St. Paul, Minn.: K. Baran, C. Iacarella; Fundacion Cardio-Infantil
Santafe de Bogotá, Bogota, Colombia: M. Pineda, C. Ceballos; Cardiology of
Oklahoma, Tulsa: M. Carney, P. Flaugh; Garden City Hospital, Garden City,
Mich.: W. Back, L. Meharg, R. Morgan; Covenant Medical Center, Saginaw,
Mich.: P. Fattal, B. Garner; University of Regensburg, Regensburg, Germany:
E. Kromer, P. Schunkert, K. Kurzidim; Louisiana State University Medical
Center, Shreveport: F. Sheridan, C. Stephens; Veterans Affairs Medical
Center, Albuquerque, N.M.: S. Vernon, J. Collatz; Centre Hospitalier des
Vallees de l'Outaouais, Hull, Que., Canada: M. Nguyen, E. Phillipe; Suburban
Cardiologists, Drexel Hill, Pa.: E. LaPorta, M. Coll; Vassar Brothers
Hospital, Poughkeepsie, N.Y.: D. O'Dea, P. Soriano; San Diego Veterans
Affairs Medical Center, San Diego, Calif.: W. Penny, G. Poteat; University
of Michigan Medical Center, Ann Arbor: E. Bates, J. Fortino; Medical Clinic
I, University of Aachen, Aachen, Germany: P. Hanrath, K.-C. Koch; Montefiore
Medical Center, Bronx, N.Y.: H. Mueller, J. Kouns, J. Cosico; Grass Valley
Cardiology, Grass Valley, Calif.: P. Callaham, R. Schnabel-Petersen;
Harborview Medical Center and University of Washington Medical Center,
Seattle: M. Corson, C. Brown, R. Divine; Akron General Medical Center,
Akron, Ohio: J. Hodsden, D. Hudock.






Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.