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(Circulation. 1999;100:1593-1601.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
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
From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital (E.M.A., C.H.M., E.B.) Boston, Mass; Fundacion Favaloro (E.P.G.), Buenos Aires, Argentina; McMaster University (A.G.G.T.), Hamilton, Ontario, Canada; Martini Hospital (P.J.L.M.B.), Groningen, Netherlands; Clinical Research Services (D.S.), Kelkheim, Germany; Hospital de la Santa Creu I Sant Pau (A.B.d.L.), Barcelona, Spain; Royal Brompton Hospital (K.F.), London, UK; Hopital Cardiologique (J.-M.L.), Lille, France; and Rhône-Poulenc Rorer (D.R., J.P.), Collegeville, Pa. Rhône-Poulenc Rorer manufactures Lovenox (enoxaparin).
Correspondence to Elliott M. Antman, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. E-mail eantman{at}rics.bwh.harvard.edu
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionAppendix 1References |
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Background—Low-molecular-weight heparins are attractive alternatives to unfractionated heparin (UFH) for management of unstable angina/non–Q-wave myocardial infarction (UA/NQMI).
Methods and Results—Patients (n=3910) with UA/NQMI were
randomized to intravenous UFH for 
3 days followed by
subcutaneous placebo injections or uninterrupted antithrombin therapy
with enoxaparin during both the acute phase (initial 30 mg
intravenous bolus followed by injections of 1.0 mg/kg every
12 hours) and outpatient phase (injections every 12 hours of 40 mg for
patients weighing <65 kg and 60 mg for those weighing 65 kg). The
primary end point (death, myocardial infarction, or urgent
revascularization) occurred by 8 days in 14.5% of
patients in the UFH group and 12.4% of patients in the enoxaparin
group (OR 0.83; 95% CI 0.69 to 1.00; P=0.048) and by 43
days in 19.7% of the UFH group and 17.3% of the enoxaparin group (OR
0.85; 95% CI 0.72 to 1.00; P=0.048). During the first
72 hours and also throughout the entire initial hospitalization, there
was no difference in the rate of major hemorrhage in the
treatment groups. During the outpatient phase, major hemorrhage
occurred in 1.5% of the group treated with placebo and 2.9% of the
group treated with enoxaparin (P=0.021).
Conclusions—Enoxaparin is superior to UFH for reducing a composite of death and serious cardiac ischemic events during the acute management of UA/NQMI patients without causing a significant increase in the rate of major hemorrhage. No further relative decrease in events occurred with outpatient enoxaparin treatment, but there was an increase in the rate of major hemorrhage.
Key Words: angina • heparin • anticoagulants • coronary disease
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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After rupture of a vulnerable atherosclerotic plaque in a coronary artery, tissue factor in the lipid-rich core is exposed and complexes with factor VIIa, and the tissue factor–factor VIIa complex then promotes generation of factor Xa.1 2 Owing to a multiplier effect in the coagulation cascade, relatively low concentrations of factor Xa lead to the downstream production of large quantities of thrombin, with ultimate deposition of fibrin strands, as well as activation of platelets.3 4 Clinical studies5 suggest that patients with an acute coronary syndrome who demonstrate biochemical evidence of activation of the coagulation cascade are at increased risk of clinical events. Also, as reported by Merlini et al,6 there is persistent activation of the coagulation cascade for several weeks to months after the index event, which has led investigators to design antithrombotic treatments that can be administered on a long-term basis. Antithrombotic strategies for the acute management of patients with unstable angina/non–Q-wave myocardial infarction (MI) include a combination of an antithrombin agent, usually an intravenous infusion of unfractionated heparin, and an antiplatelet agent, usually oral aspirin.7 8 9 10 11 12 Beyond aspirin, optimal outpatient-phase therapy for patients presenting with unstable angina/non–Q-wave MI remains to be defined.13
Low-molecular-weight heparin preparations are theoretically attractive alternatives to intravenous unfractionated heparin because of an enhanced anti–factor-Xa:anti–factor-IIa ratio, leading to reductions in both thrombin generation and thrombin activity, a reliable anticoagulant effect, without the need for monitoring of the activated partial thromboplastin time (aPTT), and they provide a simpler method of administration via the subcutaneous route, permitting both short- and long-term treatment.14 15 16 17 Previous studies have shown that dalteparin, when added to aspirin, was superior to placebo but similar to unfractionated heparin for prevention of death and MI in patients with unstable angina/non–Q-wave MI.18 19 The ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-wave Coronary Events) study reported that a brief course of therapy (median duration of treatment 2.6 days) of subcutaneous injections of enoxaparin 1.0 mg/kg every 12 hours was superior to intravenous unfractionated heparin in patients with unstable angina/non–Q-wave MI.20
The TIMI 11A trial, a dose-ranging study, demonstrated that an initial 30-mg intravenous bolus followed by subcutaneous injections of 1.0 mg/kg enoxaparin every 12 hours was associated with a major hemorrhage rate of 1.9%, whereas a higher dose of 1.25 mg/kg every 12 hours was associated with a major hemorrhage rate of 6.5%.21 Through 14 days, the incidence of death, recurrent MI, or recurrent myocardial ischemia requiring revascularization was 5.2% in the 1.0 mg/kg dose group and 5.6% in the 1.25 mg/kg dose group.21 Thus, an enoxaparin dose of 1.0 mg/kg was associated with a lower risk of major hemorrhage without an apparent loss of efficacy. Having identified a safe and effective dose of enoxaparin, we designed the TIMI 11B trial to test the benefits of a strategy of an extended course of uninterrupted antithrombotic therapy with enoxaparin compared with standard treatment with unfractionated heparin for prevention of death and cardiac ischemic events in patients with unstable angina/non–Q-wave MI.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Patient Population
Patient enrollment occurred between August 1996 and March 1998 in 200 centers across 10 countries in North America, South America, and Europe. All patients were required to have ischemic discomfort of
5 minutes' duration at rest within 24 hours before randomization
and additional evidence of ischemic heart disease as described
below. At the start of the trial, patients were eligible if they had
either a history of coronary artery disease (as evidenced by an
abnormal coronary angiogram, prior MI, CABG surgery, or PTCA),
ST deviation, or elevated serum cardiac markers. After 10 months and
enrollment of 
1800 patients, the Operations Committee performed a
blinded review of the aggregate event rate and made the decision to
modify the inclusion criteria to focus on higher-risk patients by
requiring that all patients have either ST deviation or positive serum
cardiac markers. Before the change in enrollment criteria, 731 patients
were enrolled solely on the basis of a prior history of
coronary artery disease. The major exclusion criteria were as
follows: planned revascularization within 24 hours,
a treatable cause of angina, an evolving Q-wave MI, a history of CABG
surgery within 2 months or PTCA within 6 months, treatment with a
continuous infusion of unfractionated heparin for >24 hours before
enrollment, history of heparin-associated thrombocytopenia with or
without thrombosis, and contraindications to anticoagulation. The
protocol was approved by the institutional review board at each
enrolling site, and written informed consent was obtained from patients
before randomization.
Study Protocol
There were 2 treatment phases during the trial: (1) an acute
phase designed to determine whether treatment with enoxaparin was
superior to unfractionated heparin for preventing events during the
initial hospitalization and for a short period thereafter, and (2) an
outpatient phase that sought to explore whether there was a potential
benefit to administration of enoxaparin for an additional 35 days after
hospital discharge.
All patients received aspirin (100 to 325 mg/d) and were randomized to
1 of 2 antithrombin strategies. All patients received both an
intravenous infusion (unfractionated heparin or matched
placebo) and subcutaneous injections (enoxaparin or matched placebo) in
a double-blind fashion. The standard antithrombin strategy was a
weight-adjusted regimen of unfractionated heparin for a minimum of 3
days (and maximum of 8 days at the treating physician's discretion)
beginning with a bolus of 70 U/kg and an initial infusion of 15 U
· kg-1 · h-1.
The requirement of 3 days of treatment with unfractionated heparin
was incorporated into the protocol to match the design of previously
reported trials demonstrating the benefit of intravenous
unfractionated heparin in similar patient populations.7 13
The aPTT was measured at baseline, 4 to 6 hours after initiation of
study drug, and then as indicated per a preapproved nomogram at each
institution designed to maintain a target aPTT of 1.5 to 2.5 times
control. To maintain the double-blind design, the aPTT results were
reported to an unblinded third party who was not involved in the
patient's care and who ordered adjustments to the
intravenous infusion based on the actual aPTT value for
patients receiving active unfractionated heparin or a mock value for
patients receiving placebo infusions. The investigational antithrombin
strategy was enoxaparin (supplied by Rhône-Poulenc Rorer,
Collegeville, Pa) given as an initial intravenous bolus of
30 mg followed by immediate initiation of subcutaneous injections of 1
mg/kg (100 anti–factor Xa units per kilogram) every 12 hours.
Double-blind subcutaneous injections were continued until hospital
discharge or day 8, whichever came first.
Patients could undergo diagnostic
catheterization at the treating physician's discretion
and receive either double-blind study drug, no anticoagulation, or
open-label intravenous unfractionated heparin. All
interventional coronary procedures were performed with
open-label, unfractionated heparin after an activated clotting
time of 350 seconds had been achieved. For patients scheduled for
CABG surgery, study therapy was discontinued 12 hours before the
operation.
Patients who completed the acute phase were eligible for enrollment in
the outpatient phase unless they underwent CABG surgery, had no
clinically significant coronary artery disease, sustained a
major hemorrhage, developed severe thrombocytopenia, had
another indication for chronic anticoagulation, or withdrew consent.
Patients who had originally been assigned to intravenous
unfractionated heparin received placebo subcutaneous injections twice
daily. Those patients originally assigned to enoxaparin received
subcutaneous injections every 12 hours of 40 mg of enoxaparin if they
weighed <65 kg and 60 mg of enoxaparin if they weighed 65 kg.
Double-blind outpatient-phase therapy continued through day 43.
Study End Points
The primary efficacy end point was a composite of all-cause
mortality, recurrent MI, or urgent
revascularization. Comparison of treatments
received during the acute phase was ascertained at 8 days, and
assessment of the incremental benefit of the outpatient phase was
ascertained at 43 days. Additional prespecified time points for
comparison of the 2 treatment groups were 48 hours and 14 days.
An MI was considered to be present at enrollment if any of the
following criteria were met: (1) creatine kinase–MB (CKMB) was greater
than normal (3% of total CK) at baseline and 8 hours after
enrollment; (2) CKMB was elevated at the 16-hour sample and no
ischemic discomfort of 30 minutes' duration occurred between
enrollment and the 16-hour sample; (3) in the absence of CKMB
measurements, total CK was elevated to >2 times the upper limit of
normal; and (4) ECGs obtained at 8 or 16 hours after enrollment
exhibited new significant (>0.03 second) Q waves in 2 contiguous
leads that were not present on the enrollment ECG.
The definition of an MI after enrollment required that either of the following criteria be met:
1. CKMB was elevated
above normal and increased by 50% over the previous value. In the
absence of CKMB data, total CK had to be reelevated to >2 times the
upper limit of normal and increased by 25% over the previous value;
if reelevated to <2 times the upper limit of normal, total CK had to
exceed the upper limit of normal by 50% and exceed the previous
value by 2-fold. For patients who had PTCA <24 hours previously, CKMB
(or total CK if MB not available) had to be 3 times the upper limit
of normal and increased by 50% of the previous value. For patients
who had CABG surgery <24 hours previously, CKMB (or CK if MB not
available) had to be 5 times the upper limit of normal and increased
by 50% of the previous value.
2. The ECG showed new significant (>0.03 seconds) Q waves in 2
contiguous leads or new left bundle-branch block not seen on enrollment
and not observed by 18 hours if the subject was classified as having an
MI at enrollment.
Severe recurrent ischemia requiring urgent revascularization was defined as an episode of recurrent angina prompting the performance of coronary revascularization on the index hospitalization or an episode of recurrent angina after discharge that resulted in rehospitalization during which coronary revascularization was performed.
Secondary efficacy end points of interest included the individual elements of the primary end point and the composite of death or nonfatal MI.
The main safety end point was major hemorrhage, defined as
overt bleeding resulting either in death; a bleed in a retroperitoneal,
intracranial, or intraocular location; a hemoglobin drop of 3 g/dL;
or the requirement of transfusion of 2 U of blood. Minor
hemorrhage was any clinically important bleeding that did not
qualify as major; for example, epistaxis, ecchymosis, hematoma, or
macroscopic hematuria.
An independent Clinical Events Committee blinded to treatment assignment reviewed relevant ECG tracings, laboratory data, and narrative summaries of clinical events for the purposes of adjudicating all primary efficacy and safety end points.
Statistical Analysis
Analysis of the primary efficacy end point was conducted
on all randomized patients by the intention-to-treat principle. To
adjust for country differences in treatment effect, a logistic
regression model was used that included terms for country, treatment
assignment, and their interaction. Significance of model terms was
assessed by likelihood ratio 
2 statistics with
2-sided probability values. ORs, 95% CIs, and relative risks were
constructed for the primary end point as well as its composite elements
arranged so that values <1 indicated a benefit of enoxaparin. A
secondary analysis was performed on the time to development of
the first element of the primary efficacy end point in the 2 treatment
groups by use of Kaplan-Meier methodology and a log-rank test.
Comparison of baseline characteristics was by
2 analysis for categorical
variables and either Student's t test or
Wilcoxon signed rank test as appropriate for continuous
variables.
The sample size of the trial was an event-based target such that a
total of 650 patients were to have experienced 1 element of the
primary efficacy end point through 43 days. No interim analyses
were conducted during the course of the trial. The chairman of an
independent Data Safety Monitoring Board (DSMB) received unblinded
safety reports after successive groups of 300 patients were enrolled.
No interim reports of efficacy were included with the above safety
reports. After review of each safety report, the Operations Committee
was notified whether any concerns had arisen. A meeting of the entire
DSMB could be convened at the chairman's discretion. Throughout the
course of the trial, enrollment continued without any safety concerns,
and the chairman did not convene any meetings of the full DSMB.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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A total of 3910 patients were enrolled, with 1957 patients assigned to unfractionated heparin and 1953 to enoxaparin. The 2 treatment groups were well matched for baseline characteristics (Table 1
). Of note, the profile of the
patients enrolled in the trial was typical of patients presenting
with a severe acute coronary syndrome in that 20% were
diabetic, nearly 33% had sustained a prior MI, ischemic
discomfort occurred despite previous treatment with aspirin in almost
85%, nearly 75% of the population presented with ST deviation
on the ECG, and 40% had elevated serum cardiac markers. Approximately
60% of patients were diagnosed as having unstable angina, 35% with a
non–Q-wave MI and 4% with an evolving Q-wave MI.
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Double-blind study-drug therapy was initiated in 99% of patients. The median (interquartile range) duration of acute-phase therapy in the group assigned to unfractionated heparin was 3.0 (2.99, 3.98) days and by protocol design was longer in the enoxaparin group at 4.6 (2.97,6.59) days. The median durations of treatment with the placebo intravenous and placebo subcutaneous therapies were 3.0 and 4.6 days, respectively, which were identical to those for the active therapies. In the group assigned to unfractionated heparin, the aPTT was between 55 and 85 seconds in 26% of patients within 6 to 12 hours and ranged between 42% and 47% of patients within 12 to 96 hours. Over the same time intervals, the aPTT was <60 seconds in 96% of patients assigned to enoxaparin.
Kaplan-Meier estimates of the composite primary end point of death, MI,
or urgent revascularization through the first 72
hours are shown in Figure 1. This
corresponds to the period when both study groups were receiving
antithrombin therapy. The curves began to separate by 8 hours. By 48
hours, the event rate was 7.3% in the unfractionated heparin group
versus 5.5% in the enoxaparin group (OR 0.75; 95% CI 0.58 to 0.97;
P=0.026). This corresponds to a 23.8% reduction in the
relative risk of the primary end point and was the largest treatment
effect observed during the course of the trial (Table 2).
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At 8 days, the incidence of the primary end point was 14.5% in the
unfractionated heparin group and 12.4% in the enoxaparin group (OR
0.83; 95% CI 0.69 to 1.00; P=0.048) (Figure 2). On the basis of the differences in
the composite end point, 21 events would be avoided per 1000 patients
treated with enoxaparin. For each element of the end point, there was a
reduction in events in the group assigned to enoxaparin (Table 2
). Similarly, the rate of the composite double end point of
death or MI was reduced from 5.9% in the unfractionated heparin group
to 4.6% in the enoxaparin group (OR 0.77; 95% CI 0.58 to 1.02;
P=0.073).
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A stable treatment benefit of enoxaparin was observed through 14 days,
at which time the incidence of the primary end point was 16.7% in the
unfractionated heparin group and 14.2% in the enoxaparin group (OR
0.82; 95% CI 0.69 to 0.98; P=0.029) (Figure 2). The
event rates for each element of the primary end point and for the
composite of death and MI also were lower in the enoxaparin group
through 14 days (Table 2). There was no evidence of an abrupt
increase in the rate of events (ie, "rebound") within 24 hours of
discontinuation of either study drug (Figure 2).
Differences in treatment effect with enoxaparin in several subgroups of
interest based on characteristics of the patient's presenting
illness are shown in Figure 3. With rare
exceptions, such as no ECG changes at presentation, all
subgroups had point estimates for the OR that favored enoxaparin.
Noteworthy subgroups in which there was a particularly strong treatment
benefit of enoxaparin were those patients who presented with
various ECG changes or aspirin treatment within the preceding 24
hours.
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The number of patients who progressed to the outpatient phase was 1185
(60.6%) in the unfractionated heparin group and 1179 (60.4%) in the
enoxaparin group. The major reasons patients did not enter the chronic
phase were performance of CABG surgery (n=344 [8.8%]),
informed consent withdrawal (n=349 [8.9%]), and an adverse event
(eg, bleeding) (n=168 [4.3%]). The baseline characteristics of the
cohorts from the 2 treatment groups that participated in the outpatient
phase were well matched and were similar those seen in the full cohort
at the original randomization (Table 1). As noted in Figure 2, the initial treatment benefit with enoxaparin observed
through day 14 was sustained, but during the outpatient phase, the 2
curves remained parallel to each other, which suggests that there was
no further relative treatment benefit of an additional 35 days of
enoxaparin therapy. By 43 days, the incidence of the primary end point
was 19.7% in the unfractionated heparin group and was reduced to
17.3% in the enoxaparin group (OR 0.85; 95% CI 0.72 to 1.00;
P=0.048). As was the case for observations at days 8 and 14,
the event rates for each element of the primary end point and for the
composite of death and MI also were lower in the enoxaparin group
(Table 2). Of note, the incidence of urgent
revascularization was reduced from 12.6% in the
unfractionated heparin group to 10.7% in the enoxaparin group (OR
0.82; 95% CI 0.67 to 1.00; P=0.050), which
represents a 15.6% reduction in the relative risk of that
event.
Patients who had not experienced a primary end point event up to day 8 were analyzed to assess the incidence of the primary end point between day 8 and day 43 (outpatient phase). Of 1673 such patients in the unfractionated heparin group, 101 (6.0%) experienced an end point by day 43 compared with 95 (5.6%) of 1711 patients in the enoxaparin group (OR 0.91; 95% CI 0.69 to 1.22; P=0.55).
Rates of major hemorrhage are summarized in Table 3 for the cohort of patients treated with
double-blind study drug. During the first 72 hours and also throughout
the entire initial hospitalization, there was no significant difference
in the rate of major hemorrhage in the 2 treatment groups.
During the outpatient phase, the rate of major hemorrhage was
1.5% in the group treated with placebo and 2.9% in the group treated
with enoxaparin (P=0.021). The excess of major
hemorrhage in the enoxaparin group was almost equally split
between spontaneous and instrumented events. At all time points, the
rate of minor hemorrhage, which in the majority of cases was
due to ecchymosis at the subcutaneous injection site or a hematoma at
the site of a sheath inserted for cardiac
catheterization, was significantly higher in the
enoxaparin group. There were no significant differences in the rates of
other adverse events such as stroke (unfractionated heparin 1.0%;
enoxaparin 1.2%), transient ischemic attack (unfractionated
heparin 0.3%; enoxaparin 0.3%), or thrombocytopenia
<100 000/mm3 (unfractionated heparin 2.1%;
enoxaparin 1.9%).
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There were 8 hemorrhagic deaths reported during the trial. Hemorrhage was considered the primary cause of death in 6 patients: 3 in the heparin group (2 intracranial, 1 procedure related) and 3 in the enoxaparin group (1 intracranial, 2 procedure related). Hemorrhage was considered the secondary cause of death in 2 patients: 1 in the heparin group (procedure related) and 1 in the enoxaparin group (retroperitoneal).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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The results of TIMI 11B indicate that for the acute management of unstable angina/non–Q-wave MI patients, enoxaparin is superior to unfractionated heparin for reducing a composite of death and serious cardiac ischemic events. This acute-phase superiority is achieved without a significant increase in the rate of either spontaneous or instrumented major hemorrhage. With respect to the outpatient phase, there was a durable treatment effect in that the initial treatment benefit with enoxaparin was sustained through day 43; however, no further relative decrease in events was observed. Although the absolute event rates were rather low, there was an increase in the rate of major hemorrhage (both spontaneous and instrumented) with outpatient enoxaparin treatment.
Despite receiving a weight-adjusted regimen, the patients assigned to
the unfractionated heparin group in TIMI 11B had a similar therapeutic
response to that treatment as seen in previous trials in which 40%
to 50% of patients had an aPTT value in the target range while
receiving unfractionated heparin infusions.20 22 Although
the protocol design led to a slightly longer median duration of
treatment with enoxaparin (4.6 days) than with unfractionated heparin
(3.0 days), it is unlikely that this difference in the duration of
treatment played an important role in the observed benefit of
enoxaparin, because a statistically significant treatment effect of
enoxaparin was already evident at 48 hours (Figure 1). The
benefits of enoxaparin were sustained in that relative risk reductions
of 15% to 20% in primary end point events were observed through 43
days. Internal consistency across each element of the
primary end point was also present. Although there was some
quantitative variation in the magnitude of the treatment effect, the
group assigned to enoxaparin experienced lower rates for each element
at virtually all the time points analyzed in Table 2,
which suggests that the composite end point was not driven primarily by
1 category of events. The trial was not powered to demonstrate
significant differences in individual subgroups, but the vast majority
of subgroups analyzed showed a trend in favor of enoxaparin,
with larger treatment benefits seen in higher-risk subgroups, such as
those with ECG changes or prior aspirin use. The acute-phase benefits
of enoxaparin were not achieved at the cost of a significant increase
in the rate of major hemorrhage, although there was a
significant increase in the rate of minor hemorrhage. The
increase in minor hemorrhage was due largely to ecchymoses at
the subcutaneous injection site and groin hematomas at sheath-insertion
sites, 2 problems that are potentially modifiable by improvements in
technique.
Given the lack of benefit of long-term administration of other
low-molecular-weight heparins in patients with unstable
angina/non–Q-wave MI, the outpatient-phase findings of TIMI 11B merit
additional scrutiny. Whereas there was a progressive convergence of the
event rates over time in trials comparing dalteparin with placebo, this
was not observed with enoxaparin, as evidenced by a comparison of the
ORs for the primary end point at days 8 and 43 in Table 2 (day
8=0.83, 95% CI 0.69 to 1.00 versus day 43=0.85, 95% CI 0.72 to 1.00).
A potential explanation is that enoxaparin achieved a greater
antithrombotic effect than dalteparin during the acute phase, with a
reduced thrombus burden being carried forth to the chronic phase. In
support of this hypothesis is the persistent separation of the
Kaplan-Meier event curves for the 2 treatment groups in the ESSENCE
trial at 1 year after enoxaparin therapy that was restricted to the
acute phase. 23
Clinical Implications
The results of TIMI 11B suggest that for the acute phase of
management of unstable angina/non–Q-wave MI, antithrombin therapy with
enoxaparin is superior to unfractionated heparin. Because the median
duration of acute treatment with enoxaparin in TIMI 11 B was 4.6 days,
it seems reasonable to continue its administration throughout the
initial hospitalization. However, no incremental benefit appears to be
achieved by continuing enoxaparin treatment beyond the initial
hospitalization, and there is an increased risk of major
hemorrhage in the outpatient setting.
Clinical perspective on the results of TIMI 11B can be gained by comparing it to those trials of glycoprotein IIb/IIIa receptor antagonists conducted in similar populations of patients.24 25 26 27 28 Background antithrombin therapy in the glycoprotein IIb/IIIa receptor trials was intravenous unfractionated heparin, a logical choice because it was the standard treatment available at the time they were conducted; the new glycoprotein IIb/IIIa receptor antagonists were tested against placebo. In contrast, TIMI 11B and ESSENCE compared enoxaparin with the active control of intravenous unfractionated heparin.20 When the data from TIMI 11B and ESSENCE were pooled in a meta-analysis, a stable 20% reduction in a composite of death and cardiac ischemic events was observed beginning at 48 hours and continuing through 43 day follow-up.29
Given the reduction in events reported with enoxaparin in TIMI 11B and ESSENCE, one may speculate that the reported quantitative benefits of the new glycoprotein IIb/IIIa receptor antagonists might have been modified if enoxaparin had been used as the antithrombin rather than unfractionated heparin, but the exact nature of its potential impact is unclear. Although it would be anticipated that the event rate would be lower in a control group receiving enoxaparin, thus tending to diminish the treatment effect of the glycoprotein IIb/IIIa receptor antagonist, it is also possible that a combination of the powerful, multifaceted antithrombin effects of enoxaparin and antiplatelet effects of a glycoprotein IIb/IIIa receptor antagonist would be synergistic, leading to a marked reduction in events in the active-treatment group. These issues, plus the need for additional data on its optimal use during percutaneous coronary interventional procedures and adjunctive use with thrombolytic agents, are likely to frame future trials of enoxaparin therapy in acute coronary syndromes.
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Acknowledgments |
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This work was supported by a grant from Rhône-Poulenc Rorer (Collegeville, Pa), the manufacturer of Lovenox (enoxaparin).
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Footnotes |
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1 Persons and institutions participating in TIMI 11B are listed in the Appendix.
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Appendix 1 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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TIMI 11B Participants
Study Chairman's Office
Harvard Medical School, Brigham & Women's Hospital, Boston, Mass. Study Chairman: Dr E. Braunwald; Principal Investigator: Dr E. Antman; Project Director: C. McCabe, BS; Study Coordinator: S. McHale.
Sponsor (Rhone-Poulenc Rorer)
In addition to the authors listed, the following individuals
contributed to the trial: Dr J. Rush, E. Genevois, MS, Dr G. Frommell,
J. Furst, and K. van Arsdale.
Data Coordination and Management
COVANCE, Princeton, NJ, Data Coordinating Center,
Clintrials Research Inc, Clinical Research Consulting Service.
Data Safety Monitoring Committee
Dr J. Loscalzo, Chairman; Dr J. Cairns, Dr R. Gorlin, Dr J.
Hirsh, Dr S. Kelsey. Statistical Consultant: Dr R. Makuch.
Clinical Events Committee
Dr J. Fang, Dr M. Gerhard, Dr R. Giugliano, Dr J. Hochman, Dr
I.K. Jang, Dr M. McConnell, Dr S. Reimold, Dr C. Rogers, Dr D.
Schneider, Dr D. Simon, Dr S. Solomon, Dr J. Topper.
Clinical Centers in Descending Order of Total Number of
Patients Enrolled
Argentina/Chile/Uruguay: Dr E. Gurfinkel
Instituto de Cardiologia y Cirugia–Fundacion Favaloro,
Buenos Aires, Argentina: Dr B. Mautner; Dr G. Bozovich.
Hospital Municipal Leonidas Lucero, Bahia Blanca, Argentina:
Dr J. Santopinto; E. Marcos. Hospital Fernandez, Buenos Aires,
Argentina: Dr S. Salzberg; Dr P. Gitelman. Universidad
Catolica, Santiago, Chile: Dr R. Corbalan; V. Bordes.
Sanatorio Mitre, Buenos Aires, Argentina: Dr A.S. Liprandi;
L. Blumetti. Hospital Italiano de Buenos Aires, Buenos
Aires, Argentina: Dr J.N. Estrada. Sanatorio de Casa De
Galicia, Montevideo, Uruguay: Dr F. Kuster. Hospital de
Urgencias Publica, Santiago, Chile: Dr E. Chavez. Clinica
Santa Maria, Santiago, Chile: Dr S. Kunstman. Hospital
Dipreca, Santiago, Chile: Dr M. Alcaino. Instituto
Cardiovascular de Buenos Aires, Buenos Aires,
Argentina: Dr M. Trivi; R. Henquin. Hospital Privado Del
Sur, Bahia Blanca, Argentina: Dr R. Cermesoni. Hospital
Aleman, Buenos Aires, Argentina: Dr G.J. Nau. Hospital Jose
Joaquin Aguirre, Santiago, Chile: Dr J.C. Prieto. Hospital
Frances, Buenos Aires, Argentina: Dr A. Campo. CEMIC, Buenos
Aires, Argentina: Dr J. Fuselli. Clinica Coronel Suarez,
Buenos Aires, Argentina: Dr A. Caccavo. Hospital Regional de
Temuco, Temuco, Chile: Dr F. Lanas. Sanatorio Otamendi,
Buenos Aires, Argentina: Dr B. Boskis. Sanatorio San Lucas,
Buenos Aires, Argentina: Dr R. Foye. Centro
Gallego, Buenos Aires, Argentina: Dr A. Marinesco.
Canada: Dr A.G.G. Turpie
Oshawa General Hospital, Oshawa, Ontario: Dr R.
Bhargava; A. McCallum. Centenary Health Center, Scarborough,
Ontario: Dr N. Singh; B. Bozek. Mississauga Hospital,
Mississauga, Ontario: Dr S. Tishler; H. Hink. CHUQ Pavillon
CHUL, Ste. Foy, Quebec: Dr L. Desjardins; L. St. Pierre.
Humber Memorial Hospital, Weston, Ontario: Dr M. Cheung; V.
Romaro. C.U.S.E. site Fleurimont, Sherbrooke, Quebec: Dr S.
LePage; Dr D. Soucy. C.H. Regional de Lanaudiere, Joliette,
Quebec: Dr S. Mouzayek-Kouz; M. Laforest. Montreal General
Hospital, Montreal, Quebec: Dr T. Huynh; B. St. Jacques/S.
Finkenbine. Royal Jubilee Hospital, Victoria, British
Columbia: Dr W.P. Klinke; N. Yaciuk. Pasqua Hospital,
Regina, Saskatchewan: Dr V. Gebhardt; J. Taylor. Vancouver
Hospital and Health Sciences, Vancouver, British Columbia: Dr K.
Gin; C. vanBeek. North York General Hospital, Willowdale,
Ontario: Dr B. Lubelsky; D. Burge. Thunder Bay Regional
Hospital–Port Arthur, Thunder Bay, Ontario: Dr C. Lai; D. Juskow,
K. Kwiatkowski. Gray Nuns Community Health Center, Edmonton,
Alberta: Dr L. Kasza; M. Goeres. St. Paul's Hospital,
Saskatoon, Saskatchewan: Dr M. Khouri; Dr P. Basaran. Royal
University Hospital, Saskatoon, Saskatchewan: Dr J. Lopez; P.
Kuny. Etobicoke General Hospital, Rexdale, Ontario: Dr K.
Kwok. St. Michael's Hospital, Toronto, Ontario: Dr
S. Goodman; B. Nolf. Royal Victoria Hospital, Barrie,
Ontario: Dr R. Haichin; V. Toyota, A. Serpa. Penticton
Regional Hospital, Penticton, British Columbia: Dr J.F. Hernandez;
D. Pethybridge. Surrey Memorial Hospital, Surrey, British
Columbia: Dr S. Pearce; L. Breakwell. Hopital St. Sacrement,
Quebec: Dr C. Demers; L. Dube, F. Menard. Hopital
Maisonneuve-Rosemont, Montreal, Quebec: Dr D. Gossard; H. Truchon.
University of Manitoba Health Sciences Center, Winnipeg,
Manitoba: Dr J. Ducas; U. Schick. St. John Regional Hospital
Facility, St. John, New Brunswick: Dr R. Bessoudo; C. Hume.
St. Paul's Hospital, Vancouver, British Columbia: Dr C.
Thompson; L. Buller. Misericordia Hospital, Edmonton,
Alberta: Dr P. Greenwood; A. Prosser.
Netherlands: Dr P.J.L.M. Bernink
Streek Ziekenhuis Zevenaar, Zevenaar: Dr J.A.F.M. van
der Vring. Martini Ziekenhuis, Groningen: Dr
P.J.L.M. Bernink; Dr M.Y. van der Heyden, St. Elisabeth
Ziekenhuis, Tilburg: Dr N.J. Holwerda; Dr P. Zijnen; Dr van
Rijswijk. Ziekenhuis Gelderse Vallei, Bennekom: Dr T.T. van
Loenhout. Ziekenhuis De Wever, Heerlen: Dr J.A. Kragten.
Canisius Wilhelmima Ziekenhuis, Nijmegen: Dr D. Hertzberger.
St. Jansgasthuis, Weert: Dr H.C. Klomps. St. Gemini
Ziekenhuis, Den Helder: Dr J.G.M. Tans. Medisch Spectrum
Twente, Enschede: Dr J. C. Poortermans. St. Ignatius
Ziekenhuis, Breda: Dr P.H.J. Dunselman. Spaarne Hospital,
Heemstede: Dr E.J. Muller. Reinier de Graaf Gasthuis,
Delft: Dr A.J.A.M. Withagen. Ijsselland Ziekenhuis, Cappelle
A/D Ijssel: Dr W.M. Muis van de Moer. Oosterschelde
Ziekenhuis, Goes: Dr H.W.O. Roeters van Lennep. Onze Lieve
Vrouwe Gasthius, Amsterdam: Dr L.R. Van Der Wieken. St.
Joseph Ziekenhuis, Veldhoven: Dr L.C. Slegers. Leyenburg
Ziekenhuis, Den Haag: Dr R.M. Robles de Medina. Catharina
Ziekenhuis, Eindhoven: Dr H.R. Michels. Havenziekenhuis,
Rotterdam: Dr C.M. Leenders. Slingeland Ziekenhuis,
Doetinchem: Dr J.H.M. Deppenbroek. St. Antonius Ziekenhuis,
Nieuwegein: Dr W.J. Jaarsma.
United States: Dr E. Antman
Washington County Hospital, Hagerstown, Md: Dr G.
Papuchis; S. Etter. Baptist Medical Center, Montgomery, Ala:
Dr P. Moore; T. Garrett. Montefiore Medical Center, Bronx,
NY: Dr H. Mueller; K. Bassett. Allen Bennett
Hospital/MedQuest, Greer, SC: Dr J. Milas; R. Donze, D. Moore.
University of Louisville Hospital, Louisville, Ky: Dr M.
Leesar; J. Justice. SUNY/Downstate University Hospital, Brooklyn,
NY: Dr M. Alam; R. Julien. VAMC/Mountain Home, Mountain
Home, Tenn: Dr J. Whitaker; P. Canter. St. Luke's Hospital,
New York, NY: Dr J. Hochman; D. Burge. Winona Memorial
Hospital, Indianapolis, Ind: Dr J. Hall; D. Fausset P. Linden.
Brigham and Women's Hospital, Boston, Mass: Dr E. Antman;
E. Chao. Henry Ford Hospital, Detroit, Mich: Dr S. Borzak;
L. Douthat. George Washington University Hospital, Washington,
DC: Dr J. Reiner; A. Nys. University of Maryland Hospital,
Baltimore, Md: Dr W. Herzog; N. Calamunci. McKee Medical
Center, Loveland, Colo: Dr W. Voyles; A. Combs. University
of Alabama, Birmingham, Ala: Dr W. Rogers; N. Grady.
VAMC/St. Louis, St. Louis, Mo: Dr H. Stratmann; L. Conwill.
University of Vermont/Fletcher Allen HealthCare, Burlington,
Vt: Dr B. Sobel; M. Rowen. Munroe Regional Medical
Center/Mediquest, Ocala, Fla: Dr R. Feldman; B. Merchant.
Nassau County Medical Center, East Hempstead, NY: Dr I.
Freeman; L. Teplitz. St. Mary's Medical Center, Saginaw,
Mich: Dr L. Cannon; M. Harris. Danbury Hospital, Danbury,
Conn: Dr G. Lancaster; E. Hubina. Johns Hopkins University
School of Medicine, Baltimore, Md: Dr G. Gerstenblith; S.
Townsend. East Jefferson General Hospital, Matairie, La: Dr
G. Tilton; K. Sorensen. John Hopkins–Bayview, Baltimore,
Md: Dr G. Gerstenblith; S. Townsend. Winthrop-University
Hospital, Mineola, NY: Dr R. Steingart; S. Bilodeau.
Deaconess-Nashoba, Ayer, Mass: Dr T. Hack; S. Damitz.
Emerson Hospital, Concord, Mass: Dr L. Daley; G. Carey.
Anaheim Memorial Hospital, Anaheim, Calif: Dr M. Tonkin; C.
DiTommaso. St. Luke's Hospital, Saginaw, Mich: Dr P.
Fattal; M. Harris. Lutheran Medical Center/Rocky Mountain Heart
Associates, Wheat Ridge, Colo: Dr J. Miklin; C. Comeau.
Sioux Valley Hospital/North Central Heart Institute, Sioux Falls,
SD: Dr L. Solberg; K. Miller, R. Farley. Lutheran Medical
Center, Wheat Ridge, Colo: Dr J. Miklin; L. McFadden.
Oakwood Hospital and Medical Center, Dearborn, Mich: Dr A.
Riba; C. Draus. Barnes Hospital/Washington University, St. Louis,
Mo: Dr P. Eisenberg; J. Faszholz, Jr. University of
Minnesota Hospital and Clinics, Minneapolis, Minn: Dr D. Laxson;
J. Cartland. VAMC/West Roxbury, West Roxbury, Mass: Dr
C.M. Gibson; M. Rizzo. Sacred Heart Hospital, Pensacola,
Fla: Dr D. Doty; E. Steck. Hospital of the Good Samaritan,
Los Angeles, Calif: Dr T. Shook; B. Firth. Cedars-Sinai
Medical Center, Los Angeles, Calif: Dr P.K. Shah; Dr M. Gheorghiu.
Mount Sinai Medical Center, Miami Beach, Fla: Dr E.
Lieberman; S. Rubin. Loyola University Medical Center, Maywood,
Ill: Dr E. Grassman; E. Galbraith. Hunterdon Medical Center,
Flemington, NJ: Dr A. Kutscher, Jr.; J. McMahon. Wishard
Medical Center, Indianapolis, Ind: Dr V. Pompili; K. Crecelius.
Via Christi Regional Medical Center–St. Francis Campus, Wichita,
KS: Dr K. Shah; P. Patterson-Midgley. Baptist Hospital,
Pensacola, Fla: Dr D. Doty; B. Lane.
Germany: Dr D. Salein
Ev. Krankenhaus Witten: Dr T. Horacek; Drs. M.
Iasevoli and J. Reifke. Ev. Krankenhaus Herne: Dr W.
Sehnert. Krankenhaus Bietigheim: Dr D. Hey; Dr E. Biechl.
Klinikum der Stadt Mannheim: Dr J. Harenberg; Dr U.
Hoffmann; Dr G. Huhle; Dr A. Scherhag. Krankenhaus Lichtenberg,
Berlin: Dr H.J. Schulz; Dr C. Axthelm. Klinikum
Bernburg: Dr F. Odemar; Dr F. Schmincke. Krankenhaus
Bruchsal: Drs. F. Heinrich and B. Kohler; Dr B. Kölmel.
Kreiskrankenhaus Rudolstadt: Dr F. Meier; Dr S. Segel.
St. Elisabeth Krankenhaus Herten: Dr N. Reike.
Krankenhaus am Urban, Berlin-Kreuzberg: Drs. Dissmann and D.
Andresen; Dr S. Hoffmann.
Spain: Dr A. Bayes de Luna, Dr J.L. Lopez-Sendon
Hospital Gregorio Maranon, Madrid: Dr J.L.
Lopez-Sendon; Dr E. Lopez de Sa. Hospital Puerta Hierro,
Madrid: Dr M.A. Alonso; Dr I. Antorrena, Dr A. Bautista.
Hospital La Paz, Madrid: Dr Roldan. Hospital
Torrecardenas, Almerio: Dr R. Martos. Hospital General Valle
Hebron, Barcelona: Dr J. F. Bellot; E. Nieto. Hospital
Son Dureta, Mallorca: Dr M. Fiol; Dr E. Busch. Hospital Sant
Pau, Barcelona: Dr J. Guindo; Dr A.M. Rubio. Hospital
General de Galicia, Santiago Compostela: Dr M. Pedreira; Dr G. de
la Pena. Hospital de Terrassa, Terrassa: Dr M.A. De Miguel
Diaz; Dr D. Martinez. H. General Asturias, Oviedo: Dr R.
Llorian. H. Juan Canalejo, Canalejo: Dr C. Beiras.
United Kingdom: Dr K. Fox
Royal Victoria Hospital, Belfast, Northern Ireland:
Dr A.A.J. Adgey; N. Irvine. Ealing Hospital, Middlesex, UK:
Dr J. Kooner; N. Smith. Leicester General, Leicester, UK: Dr
J.E.F. Pohl; P. Healey. St. Margaret's Hospital Epping, Epping
Essex, UK: Dr G. Ambepitiya; L. Ambepitiya. St. Luke's
Bradford, Bradford, UK: Dr C.A. Morley; T.J. Kurdziel. St.
George's Hospital London, Cranmer Terrace, UK: Dr J.C. Kaski; Dr
I. Cox. Royal Gloucester Hospital, Gloucester, UK: Dr D.
Lindsay. Old Church Hospital Romford, Romford, UK: Dr J.D.
Stephens; Dr H. Kadr.
France: Dr J. Lablanche
Center Hospitalier General (Abbeville), Abbeville: Dr
J. Poulard. Center Hospitalier d'Arras, Arras: Dr G.
Hannebicque. Center Hospitalier de Douai, Douai: Dr F.
Leroy. Groupe Hospitalier Pitie-Salpetriere, Paris: Dr G.
Montalescot. Hopital Chatiliez, Tourcoing: Dr E. Decoulx.
Center Hospitalier de Boulogne, Boulogne Sur Mer: Dr R.
Lallemant. Center Hospitalier Universitaire de Besancon,
Besancon: Dr J. Bassand. Hopital Victor Provo, Paris:
Dr Y. Haftel. Chu de Purpan, Toulouse,: Dr J. Puel, Dr M.
Jean. Center Hospitalier General "Antoine Gayraud,"
Carcassonne: Dr G. Baradat. Hopital Bichat, Paris:
Dr P.G. Steg. Hopital d'Adultes de la Timone, Marseille: Dr
J. Bonnet. Hopital Civil, Paris: Dr J. Mossard.
Center Hospitalier General, Vichy: Dr G. Amat.
Received April 14, 1999; revision received July 23, 1999; accepted July 26, 1999.
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E. J. Topol A guide to therapeutic decision-making in patients with non-ST-segment elevation acute coronary syndromes J. Am. Coll. Cardiol., February 19, 2003; 41(4_Suppl_S): 123S - 129S. [Abstract] [Full Text] [PDF]
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J. A. de Lemos, D. A. Morrow, M. S. Sabatine, S. A. Murphy, C. M. Gibson, E. M. Antman, C. H. McCabe, C. P. Cannon, and E. Braunwald Association Between Plasma Levels of Monocyte Chemoattractant Protein-1 and Long-Term Clinical Outcomes in Patients With Acute Coronary Syndromes Circulation, February 11, 2003; 107(5): 690 - 695. [Abstract] [Full Text] [PDF]
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S. G. Goodman, D. Fitchett, P. W. Armstrong, M. Tan, A. Langer, and for the Integrilin and Enoxaparin Randomized Asses Randomized Evaluation of the Safety and Efficacy of Enoxaparin Versus Unfractionated Heparin in High-Risk Patients With Non-ST-Segment Elevation Acute Coronary Syndromes Receiving the Glycoprotein IIb/IIIa Inhibitor Eptifibatide Circulation, January 21, 2003; 107(2): 238 - 244. [Abstract] [Full Text] [PDF]
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