(Circulation. 1999;99:2720-2732.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
From Brigham and Women's Hospital (E.M.A., R.P.G., C.H.M., E.B.), Boston, Mass; Allegheny General Hospital (C.M.G.), Pittsburgh, Pa; Universitair Ziekenhuis Gasthuisberg (P.C., F.V.d.W.), Leuven, Belgium; Methodist Hospital (N.S.K.), Houston, Tex; Hopital Tenon (A.V.), Paris, France; Royal Victoria Hospital (A.A.J.A., I.M.), Belfast, United Kingdom; Medizinische Klinik II (H.-J.R.), Mainz, Germany; OLVG afdeling Cardiologie (R.V.d.W.), Amsterdam, Netherlands; University of Manitoba Health Sciences Centre (J.D.), Winnipeg, Canada; Eli Lilly, Inc (J.S.), Indianapolis, Ind; and Centocor (K.A.), Malvern, Pa.
Correspondence to Elliott M. Antman, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. E-mail eantman{at}bustoff.bwh.harvard.edu
| Abstract |
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Methods and ResultsPatients (n=888) with ST-elevation MI presenting <12 hours from onset of symptoms were treated with aspirin and randomized initially to either 100 mg of accelerated-dose alteplase (control) or abciximab (bolus 0.25 mg/kg and 12-hour infusion of 0.125 µg · kg-1 · min-1) alone or in combination with reduced doses of alteplase (20 to 65 mg) or streptokinase (500 000 U to 1.5 MU). Control patients received standard weight-adjusted heparin (70-U/kg bolus; infusion of 15 U · kg-1 · h-1), whereas those treated with a regimen including abciximab received low-dose heparin (60-U/kg bolus; infusion of 7 U · kg-1 · h-1). The rate of TIMI 3 flow at 90 minutes for patients treated with accelerated alteplase alone was 57% compared with 32% for abciximab alone and 34% to 46% for doses of streptokinase between 500 000 U and 1.25 MU with abciximab. Higher rates of TIMI 3 flow at both 60 and 90 minutes were observed with increasing duration of administration of alteplase, progressing from a bolus alone to a bolus followed by either a 30- or 60-minute infusion (P<0.02). The most promising regimen was 50 mg of alteplase (15-mg bolus; infusion of 35 mg over 60 minutes), which produced a 76% rate of TIMI 3 flow at 90 minutes and was tested subsequently in conjunction with either low-dose or very-low-dose (30-U/kg bolus; infusion of 4 U · kg-1 · h-1) heparin. TIMI 3 flow rates were significantly higher in the 50-mg alteplase plus abciximab group versus the alteplase-only group at both 60 minutes (72% versus 43%; P=0.0009) and 90 minutes (77% versus 62%; P=0.02). The rates of major hemorrhage were 6% in patients receiving alteplase alone (n=235), 3% with abciximab alone (n=32), 10% with streptokinase plus abciximab (n=143), 7% with 50 mg of alteplase plus abciximab and low-dose heparin (n=103), and 1% with 50 mg of alteplase plus abciximab with very-low-dose heparin (n=70).
ConclusionsAbciximab facilitates the rate and extent of thrombolysis, producing early, marked increases in TIMI 3 flow when combined with half the usual dose of alteplase. This improvement in reperfusion with alteplase occurred without an increase in the risk of major bleeding. Substantial reductions in heparin dosing may reduce the risk of bleeding even further. Modest improvements in TIMI 3 flow were seen when abciximab was combined with streptokinase, but there was an increased risk of bleeding.
Key Words: thrombolysis myocardial infarction platelet aggregation inhibitors platelets
| Introduction |
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5% to 10% of patients experience
reocclusion of the culprit coronary artery.1 2
When it occurs, reocclusion may be associated with recurrent
infarction and an increased risk of mortality and
morbidity.1 3 4 Obstructive arterial thrombi
that are platelet rich are resistant to
thrombolysis and have an increased tendency to produce
reocclusion after initial reperfusion.5 Although aspirin
acts synergistically with thrombolytics to reduce
mortality and may also be helpful in preventing reocclusion, it is a
relatively weak antiplatelet agent.6 7 Despite the
inhibition of cyclooxygenase by aspirin,
platelet activation continues to occur through
thromboxane A2-independent pathways,
leading to platelet aggregation and increased thrombin
formation.8 The activation of platelets by several agonists results in the expression of functional receptors for fibrinogen on the platelet surface, referred to as glycoprotein (GP) IIb/IIIa receptors. The GP IIb/IIIa inhibitor abciximab produces an antithrombotic effect by direct inhibition of the binding of natural ligands such as fibrinogen to the GP IIb/IIIa receptor, leading to a dose-dependent inhibition of platelet aggregation.9 Because abciximab is a much more potent inhibitor of platelet function than aspirin, it has the potential to promote a greater degree of thrombolysis and prevent rethrombosis in the short-term management of patients with ST-elevation MI.9 10 11
Preclinical studies have shown that GP IIb/IIIa inhibition accelerates thrombolysis and prevents reocclusion in several animal species with experimentally induced platelet-rich coronary thromboses that were treated with alteplase.5 12 13 14 15 Analyses from previous clinical trials16 17 18 suggested that administration of abciximab to support direct coronary intervention or rescue coronary intervention after failed thrombolysis for ST-elevation MI was helpful in reducing death and cardiac ischemic events. Pilot angiographic observations suggest that abciximab facilitates dissolution of intracoronary thrombi without a significant risk of distal embolization, no reflow, or abrupt closure.12 19
The Thrombolysis and Angioplasty in Myocardial Infarction
(TAMI) 8 study evaluated prospectively the safety of administering
murine Fab fragments of a monoclonal antibody against the GP IIb/IIIa
receptor (m7E3) after standard-dose alteplase in the treatment of acute
MI.20 m7E3 inhibited platelet aggregation in a
dose-dependent fashion, ultimately achieving
80% inhibition at a
dose of 0.25 mg/kg. There was no increase in bleeding events in
patients receiving m7E3, and no intracranial hemorrhages were
observed. TIMI grade 2 or 3 flow was seen in the infarct-related artery
at follow-up angiography at day 5 in 5 (56%) of 9 control patients and
34 (92%) of 37 patients receiving m7E3 (P=0.02).
The observations noted above served as the foundation for testing the hypothesis that abciximab is a potent and safe addition to thrombolytic regimens for ST-elevation MI. To accomplish this, TIMI 14, a phase II, multicenter angiographic study, had as its primary objective an evaluation of the rate of TIMI 3 flow at 90 minutes for reperfusion regimens of abciximab alone and in combination with reduced doses of alteplase or streptokinase. Secondary objectives were to evaluate the safety of the new reperfusion regimens, make efficacy observations with a variety of angiographic criteria (including TIMI flow grade at 60 minutes and TIMI frame counts at 60 and 90 minutes), and make pilot observations on the rate of clinical events such as mortality, recurrent MI, recurrent ischemia, and development of severe pump dysfunction.
| Methods |
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Eligibility Criteria
Patients were eligible for inclusion if they were between 18 and
75 years of age, had a qualifying episode of ischemic
discomfort of
30 minutes' duration within the prior 12 hours, and,
as reported by the enrolling clinical center, exhibited
0.1-mV
ST-segment elevation in 2 contiguous leads. Patients were excluded if
they had any of the following findings:
6000 U heparin in the hour before randomization.
Study Protocol
The study consisted of randomized, open-label dose-finding and
dose-confirmation phases. During both phases, all patients were given
aspirin (150 to 325 mg PO or 250 to 500 mg IV) and were then randomized
into the treatment groups described below (Figure 1
).
|
Dose-Finding Phase
Randomization occurred at an equal rate for all treatment groups
by use of a centralized telephone system. The control group did not
receive abciximab but was treated with 100 mg of alteplase with a
front-loaded regimen (15-mg bolus, initial infusion of 0.75 mg/kg up to
50 mg over 30 minutes, followed by infusion of 0.50 mg/kg up to 35 mg
over 60 minutes) and standard-dose heparin consisting of a bolus of 70
U/kg (maximum 4000 U) and initial infusion of 15 U ·
kg-1 · h-1
(maximum 1200 U/h). The 3 experimental groups all received an initial
bolus of abciximab 0.25 mg/kg followed by a 12-hour infusion of 0.125
µg · kg-1 ·
min-1 and either received no lytic (abciximab
alone), reduced-dose streptokinase, or reduced-dose alteplase (Table 1![]()
). Abciximab was
to be administered before or concurrent with the
thrombolytic in the reduced-dose streptokinase and
reduced-dose alteplase groups. Abciximab-treated patients received
low-dose heparin with a bolus of 60 U/kg (maximum 4000 U) and infusion
of 7 U · kg-1 ·
h-1 (maximum 800 U/h). For all groups, heparin
infusions were adjusted according to a nomogram to a target
activated partial thromboplastin time (aPTT) of 50 to 70
seconds.
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Fourteen different reperfusion regimens were evaluated during the
dose-finding phase. These included the alteplase-alone and
abciximab-alone arms and the 12 reduced-dose lytic regimens combined
with abciximab shown in Table 1
. For each lytic, testing
proceeded in an ascending doseranging fashion. The 4 streptokinase
regimens were infusions of 500 000 U, 750 000 U, 1.25 MU, and 1.5 MU
over the times shown in Table 1
. To minimize the risk of
bleeding, heparin was eliminated at the 1.5-MU dose of streptokinase.
Eight alteplase regimens were tested that represented total
doses of 20, 35, 50, and 65 mg. For the 35- and 50-mg doses, regimens
that used a bolus and bolus plus infusion were evaluated. We evaluated
the impact of varying the duration of the infusion in the 50-mg dose
tier by comparing infusions of alteplase over 30 or 60 minutes. To test
the benefit of a higher abciximab dose, in 1 group receiving 50 mg of
alteplase over 60 minutes, the abciximab bolus dose was increased to
0.3 mg/kg and heparin reduced to a very-low-dose regimen of a bolus of
30 U/kg (maximum 2000 U) and initial infusion of 4 U ·
kg-1 · h-1
(maximum 400 U/h).
Dose-Confirmation Phase
After evaluation of the angiographic findings and safety
observations from the dose-finding phase, a regimen of 50 mg of
alteplase administered as a bolus of 15 mg and infusion of 35 mg over
60 minutes was selected for testing in the dose-confirmation phase.
During the dose-confirmation phase, patients were randomized into 3
groups consisting of the accelerated-dose alteplase control group, as
described for the dose-finding phase, and 2 experimental groups that
were treated with the 50-mg alteplase regimen described above and
abciximab (0.25 mg/kg bolus followed by a 12-hour infusion of 0.125
µg · kg-1 ·
min-1) and either a low-dose (60-U/kg bolus and
infusion of 7 U · kg-1 ·
h-1) or very-low-dose (30-U/kg bolus and
infusion of 4 U · kg-1 ·
h-1) heparin regimen (Figure 2
). During the dose-confirmation phase, 1
patient was randomized to the control group for every 2 patients
randomized to each of the experimental groups, and randomization into
the experimental groups proceeded in a sequential fashion.
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During both the dose-finding and dose-confirmation phases, use of ß-blockers, nitrates, calcium antagonists, and other medications was at the treating physician's discretion, as was the decision for referral for CABG surgery.
Angiographic Procedures
For timing the performance of coronary
angiograms, time 0 was considered to be the start of administration of
the first drug of the assigned reperfusion regimen. Coronary
angiography of the infarct-related artery was performed as soon as
possible after initiation of the reperfusion regimen but in no case
>90 minutes later. Standardized views and techniques of injection were
used by investigators. Except in cases of rapid and progressive
hemodynamic deterioration, coronary
interventional procedures were performed at the treating physician's
discretion after the 90-minute angiogram. When rescue interventional
procedures were performed, supplemental heparin dosing was administered
via a standardized nomogram, guided by measurements of
activated clotting time (ACT), with a target of 250 seconds in
the control group and 200 seconds in all groups receiving abciximab.
Arterial access sheaths were removed when the aPTT was
50
seconds or the ACT was
170 seconds.
Clinical Procedures
ECGs were obtained at admission, for any episodes of recurrent
ischemic discomfort
5 minutes during the index
hospitalization, 12 to 24 hours after any
revascularization procedure, and at the time of
hospital discharge. Creatine kinase (CK) and isoenzyme (CK-MB) levels
were measured on admission and at 6, 12, and 24 hours for the first 24
hours and were repeated for episodes of recurrent ischemic
discomfort
30 minutes in duration or after
revascularization procedures during the index
hospitalization. Platelet counts were measured at admission; 60
minutes and 3, 12, and 24 hours after administration of study drug; and
then daily until hospital discharge or day 3, whichever came first. In
the event of a platelet count <100 000/mL that
represented
25% decrease from baseline, platelet
counts were repeated. If true thrombocytopenia was confirmed, abciximab
was discontinued. Hemoglobin and hematocrit levels were obtained at
admission, 24 and 48 hours after administration of study drug, and at
hospital discharge.
All patients were followed up for clinical events during the index hospitalization and through 30 days.
Study End Points
Efficacy
The primary angiographic efficacy end point was the achievement
of TIMI grade 3 flow at 90 minutes in the infarct-related artery. All
angiograms were evaluated by the Angiographic Core Laboratory, which
was blinded to treatment assignment, using previously established
procedures for determination of TIMI flow grade21 and TIMI
frame count.22 Patients were considered angiographically
evaluable if they received the specified reperfusion regimen and had an
evaluable 90-minute angiogram. In patients receiving abciximab and a
thrombolytic drug, the angiographically evaluable
cohort was restricted to patients who received both abciximab and the
thrombolytic drug within 15 minutes of each other.
Prespecified secondary angiographic efficacy end points were TIMI grade
2 or 3 flow in the infarct-related artery at 60 and 90 minutes and TIMI
frame counts at 60 and 90 minutes.22
Clinical efficacy end points were analyzed for all randomized
patients (intention-to-treat cohort) by a Clinical Events Committee
using standardized definitions. These end points included all-cause
mortality, recurrent MI, recurrent ischemia
5 minutes, severe
recurrent ischemia requiring urgent
revascularization, severe pump failure, the
performance of rescue percutaneous
coronary interventions, and CABG. The definitions of recurrent
MI and severe pump failure were as previously
described.23 24 Severe recurrent ischemia
requiring urgent revascularization was considered
to be present if the patient experienced
1 episode of rest pain
of
5 minutes' duration or had Canadian Heart Association class III
or IV angina that resulted in either an urgent
percutaneous coronary intervention or CABG. In
the absence of pain, the following were considered evidence of severe
ischemia: new ST shifts
0.1 mV on 12-lead ECG or lasting >20
minutes on ambulatory ECG monitoring; acute pulmonary edema,
ventricular arrhythmias, or
hemodynamic instability presumed to be ischemic
in origin; TIMI 0 or 1 flow on the initial angiogram that was followed
by rescue angioplasty; or revascularization after a
recurrent MI.
Safety
The primary safety end point was major hemorrhage,
which was defined as any intracranial, retroperitoneal, or intraocular
hemorrhage or any clinically overt hemorrhage
associated with a drop in hemoglobin
5 g/dL. An additional end point
was thrombocytopenia (platelet count <100 000/mL and a decrease
of
25% from baseline) that was not due to interaction in the
blood-drawing tube with an anticoagulant such as EDTA, citrate, or
heparin (ie, pseudothrombocytopenia). Severe thrombocytopenia was
defined as a platelet count <50 000/mL. All patients who received
any element of the assigned reperfusion regimen were included in safety
analyses (safety-evaluable cohort); these events were also
reviewed and classified by the Clinical Events Committee.
Statistical Considerations
Historical data suggest that
50% of angiographically
evaluable patients achieve TIMI grade 3 flow at 90 minutes after
receiving a front-loaded 100-mg alteplase regimen.25
Patients enrolled in the experimental reperfusion regimen groups were
compared with this historical rate. The protocol specified that in
order for abciximab without thrombolytics to be
considered a candidate for future study, the rate of TIMI 3 flow at 90
minutes should be comparable to 50%, whereas it needed to exceed 50%
in regimens that combined abciximab with a
thrombolytic. To guide the Operations Committee in
identifying promising new reperfusion regimens during the dose-finding
phase, the rates of TIMI 3 flow in each of the treatment groups were
monitored by use of a sequential probability ratio test
(SPRT).26 The prespecified SPRT boundaries were 30%
(H0) and 50% (Ha) TIMI 3
flow with types I and II error rates of 0.0001% and 10%,
respectively, for the abciximab-alone group and boundaries of 60%
(H0) and 80% (Ha) TIMI 3
flow with types I and II error rates of 1% and 2.5%, respectively,
for groups in which abciximab was combined with a
thrombolytic. On the basis of the operating
characteristics of the SPRT, it was estimated that 35 to 70 patients
per treatment group would provide sufficient information to determine
whether a given regimen was likely to be considered a candidate for
additional testing.
Statistical comparisons were made by
2
analysis for categorical variables and either Student's
t test or Wilcoxon signed rank test, as appropriate,
for continuous variables. Screening for any significant differences
in TIMI frame counts among the treatment groups was performed in a
protected fashion. This was accomplished first by performing a
generalized log-rank
2 procedure to test for
any difference between treatment groups. If significant, this was
followed by log-rank tests on pairwise comparisons between treatment
groups. Owing to the exploratory nature of the comparisons in the
trial, nominal probability values without adjustment for multiple
comparisons were taken as an indication of the statistical significance
of comparisons between groups or trends among groups.
| Results |
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Angiographic Observations
Of the 888 patients, 791 (89%) were considered angiographically
evaluable at 90 minutes. The reasons for exclusion from the
angiographically evaluable cohort at 90 minutes were failure to receive
the reperfusion regimen as specified in the protocol (n=38 [4.3%]),
lack of angiography for clinical reasons, performance of the
angiogram >15 minutes outside the 90-minute time frame (n=59
[6.6%]), and technically inadequate imaging (n=2 [0.2%]). A total
of 408 patients (45.9%) were considered angiographically evaluable at
60 minutes.
Dose-Finding Phase
Angiographic data for all groups during the dose-finding phase are
summarized in Table 2![]()
.
Patients treated with alteplase alone (n=152) achieved a 57% TIMI 3
flow rate at 90 minutes, whereas patients treated with abciximab alone
(n=31) achieved a 32% TIMI 3 flow rate. Doses of streptokinase between
500 000 U and 1.25 MU given with abciximab produced TIMI 3 flow rates
of 34% to 46%. The regimen of 1.5 MU of streptokinase plus abciximab
was terminated prematurely after only 5 angiographically evaluable
patients had been studied because of unacceptable bleeding (see
below).
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Reperfusion regimens consisting of total alteplase doses of 20, 35, 50,
or 65 mg produced 90-minute TIMI 3 flow rates that were at least
comparable to and in many cases exceeded those observed with full-dose
alteplase alone (Table 2
). An increase in the abciximab bolus to
0.3 mg/kg did not appear to offer any incremental benefit in
establishing TIMI 3 flow (Table 2
).
The most promising regimen appeared to be 50 mg of alteplase given as a 15-mg bolus and 35-mg infusion over 60 minutes. Compared with full-dose alteplase alone, the 50-mg alteplase regimen noted above produced substantial increases in the rates of both TIMI 3 flow (76% versus 57%; P=0.08) and infarct-related artery patency (TIMI 2/3 flow, 93% versus 78%; P=0.09) at 90 minutes.
Insight into the rate and extent of thrombolysis when
abciximab was combined with reduced-dose alteplase was gained by
comparing observations made at 60 and 90 minutes after the start of the
reperfusion regimens. The data shown in Figure 3
are plotted for patients in the
dose-finding phase who received varying total doses of alteplase
stratified by the administration schedule of the lytic. Increasingly
higher rates of TIMI 3 flow at both 60 and 90 minutes were observed
with more prolonged duration of administration of alteplase,
progressing from a bolus to a bolus followed by a 30-minute infusion
and then a bolus followed by a 60-minute infusion (P=0.02 by
2 for trend at 60 minutes and
P=0.0002 by
2 for trend at 90
minutes). Compared with a 45% TIMI 3 flow rate at 60 minutes in the
alteplase control arm, at the end of the 60-minute infusion schedule,
TIMI 3 flow was 63%. At 90 minutes, it reached 74% compared with 57%
in the alteplase control group.
|
Dose-Confirmation Phase
On the basis of the angiographic observations noted above
and an acceptable safety profile (see below), a regimen of 50 mg of
alteplase administered as a bolus of 15 mg and infusion of 35 mg over
60 minutes in combination with abciximab was selected for the
dose-confirmation phase. TIMI 3 flow rates at 60 and 90 minutes in
patients collectively enrolled in the alteplase control arm from the
dose-finding and dose-confirmation phases are shown in Figure 4
. These are compared with the 50-mg
alteplase regimen from the dose-finding phase and during the
dose-confirmation phase, in conjunction with the low-dose and
very-low-dose heparin regimens. Rates of TIMI 3 flow similar to those
originally observed in the dose-finding phase were seen at both 60 and
90 minutes with the 50-mg alteplase regimen and low-dose heparin in the
dose-confirmation phase. The pooled data for the 50-mg alteplase
regimen with low-dose heparin showed a significant increase in the rate
of TIMI 3 flow at 60 minutes from 43% in the control arm to 72%
(P=0.0009), representing a relative 67%
increase. The very-low-dose heparin group had a 68% rate of TIMI 3
flow at 60 minutes. At 90 minutes, pooled data from the 50-mg alteplase
regimen with low-dose heparin showed a 77% rate of TIMI 3 flow, which
was significantly higher than the 62% rate observed in the alteplase
control group (P=0.01). In the very-low-dose heparin
regimen, the TIMI 3 flow rate at 90 minutes was 69%, a value
intermediate between alteplase without abciximab and the 50-mg
alteplase regimen with low-dose heparin.
|
TIMI frame counts at 60 and 90 minutes for 4
representative groups of reperfusion regimens are shown
in Figure 5
. The dashed vertical line at
28 frames is the upper 95% CI for normal flow, and the dashed line at
40 frames is the break point between TIMI 3 and TIMI 2 flow. It is in
the zone between these 2 values that some distinctions between groups
can be observed. The group receiving 50 mg of alteplase as a bolus of
15 mg and infusion of 35 mg over 60 minutes in combination with
abciximab and low-dose heparin was shifted up and to the left compared
with the full-dose alteplase control arm at both 60 and 90 minutes,
indicating a higher proportion of patients with lower frame counts.
These differences were statistically significant (P=0.001 at
60 minutes and P=0.005 at 90 minutes). At 90 minutes, the
median TIMI frame count in the 50-mg alteplase regimen was normal at 28
frames compared with 36 frames in the alteplase control arm. A
composite of all the streptokinase plus abciximab groups is shifted
below the alteplase control arm, indicating higher frame counts (median
frame count, 45 frames). This is followed by the abciximab-alone group,
which had the highest frame counts.
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Safety Observations and Other Clinical Events
Safety observations along with other clinical events from the
dose-finding phase are summarized in Table 3![]()
. The overall rate of
major hemorrhage was 7%. The rate of major hemorrhage
was 6% in the alteplase control group, 3% in the abciximab-alone
group, and 7% in all alteplase-plus-abciximab groups combined. The
rate of major hemorrhage was 10% for all
streptokinase-plus-abciximab groups combined. There was a dose-related
increase in the rate of major hemorrhage as ascending doses of
streptokinase were combined with abciximab, eventually culminating in a
substantially higher rate as full-dose streptokinase was combined with
abciximab even in the absence of heparin. Approximately two thirds of
hemorrhages were at instrumented sites. The overall rate of
intracerebral hemorrhage was 1.1%; no
important differences in this complication were observed among
reperfusion regimens. The overall rates for mortality, recurrent MI,
and development of severe pump failure were 4%, 3%, and 1%,
respectively, with no major differences observed across groups.
Revascularization for severe recurrent
ischemia was performed in 31% of patients overall but was
highest in the abciximab-alone group at 59%. Similarly, the rate of
rescue PTCA, which was 19% overall, was highest in the abciximab-alone
group, at 41%. Thrombocytopenia occurred in 5 (3%) of the 163
patients in the alteplase-alone control group and in 30 (6%) of the
514 patients who received a reperfusion regimen containing abciximab
(P=NS). Severe thrombocytopenia (<50 000/mL) occurred in 1
(0.6%) of the 163 patients in the alteplase-alone control group and in
6 (1.2%) of the 514 patients who received a reperfusion regimen
containing abciximab (P=NS).
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Figure 6
depicts the safety experience in
the cohort of patients collectively enrolled in the control alteplase
arm compared with the collective experience in the 50-mg alteplase plus
abciximab combined with low-dose and very-low-dose heparin regimens.
The rate of major hemorrhage was 6% in the alteplase-alone
control group, 7% in the low-dose heparin group, and 1% in the
very-low-dose heparin group; mortality rates were 3%, 5%, and 0%,
respectively.
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| Discussion |
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The evaluation in TIMI 14 of various reperfusion regimens to achieve TIMI 3 flow lends strong support to the hypothesis that GP IIb/IIIa inhibition with abciximab may play an important role in reperfusion of thrombotically occluded coronary arteries. It is now well established that the principal goal of reperfusion regimens is to achieve a high rate of TIMI 3 flow, which maximizes the mortality reduction achieved in patients with ST-elevation MI.31 Abciximab alone produced TIMI 3 flow rates that exceeded previously reported rates for patients receiving aspirin and heparin either before administration of thrombolytics or in preparation for primary angioplasty.21 32 The TIMI 3 flow rates with abciximab alone were similar to those previously reported for full-dose streptokinase alone.1 21 When abciximab was combined with doses of streptokinase that did not result in unacceptable bleeding risks, modest increases in TIMI 3 flow were observed compared with full-dose streptokinase alone in previous studies.1 21
Of particular importance is the observation that abciximab augmented the rate and extent of thrombolysis with reduced doses of alteplase. The increase in TIMI 3 flow at 60 minutes from 43% with alteplase alone to 72% using a 50-mg regimen of alteplase over 60 minutes combined with abciximab represents a 67% relative increase and a 29% absolute difference in TIMI 3 flow rates.
On the basis of data from angiographic observations at 90 minutes, it may be estimated that a 20% absolute increment in TIMI 3 flow must be observed to translate into a 1% absolute mortality reduction mediated via enhanced reperfusion of the infarct-related artery and myocardial salvage.1 33 The absolute increment in TIMI 3 flow observed with the 50-mg alteplase-plus-abciximab regimen compared with the 100-mg accelerated-dose alteplase regimen exceeded the predicted 20% minimum at 60 minutes. Further evidence of the substantial improvement in flow in the infarct-related artery is the near normalization of the TIMI frame count in the 50-mg alteplase-plus-abciximab regimen by 60 minutes.
Insight into the mechanism of facilitation of
thrombolysis when abciximab is combined with alteplase
may be gained by considering the multiple effects of abciximab on clot
formation and structure. Inhibition of GP IIb/IIIa receptors prevents
aggregation of platelets, leading to reductions in both thrombus
mass and the platform for further thrombin generation.9
Evidence exists that abciximab inhibits the release reaction from
platelet-dense granules and
-granules, leading to a decrease in
the local concentration of inhibitors of
thrombolysis such as PAI-1 and
-2 plasma
inhibitor.34 Clot structure is weakened by the
ability of abciximab to block binding of activated factor XIII
to platelets, diminishing cross-linking of fibrin strands and of
-2 plasma inhibitor to fibrin.35
Platelet-mediated clot retraction and gel elastic modulus are also
reduced.36 37 38 By diminishing the tendency to thrombus
growth and increasing clot porosity, abciximab may promote penetration
of thrombolytic agents deeper into the clot, allowing
more rapid and more extensive
thrombolysis.9
The effects of abciximab on clot formation and structure noted above
likely contributed to the enhanced coronary blood flow observed
with reduced doses of alteplase (Table 2
). When combined with
abciximab, administration of only half the usual 100-mg dose of
alteplase produced significantly higher rates of TIMI 3 flow. Of note,
alteplase regimens of a bolus alone or a bolus and short infusion (30
minutes) did not appear to be as effective as regimens that used a
bolus and longer infusion (60 minutes). These data suggest that even in
the presence of abciximab, a sufficient concentration of a
thrombolytic agent must be maintained for a long-enough
period to enhance lytic efficiency. In the case of an agent with a
relatively short plasma half-life, such as alteplase, this requires a
more protracted infusion.
Safety Considerations
When used with low-dose heparin, abciximab and reduced-dose
alteplase were associated with a bleeding risk similar to standard
thrombolytic therapy. However, a larger sample size
from registries and phase III trials is needed for a more statistically
robust estimate of the risk of intracranial hemorrhage with the
new reperfusion regimen. Very-low-dose heparin regimens consisting of
an
50% reduction in the initial bolus and 75% reduction in the
initial infusion rate compared with standard weight-adjusted regimens
may decrease the risk of bleeding even further. The low rate of major
hemorrhage in the very-low-dose heparin group in TIMI 14
underscores the need for continued evaluation of the optimum dose of
heparin when new reperfusion regimens for ST-elevation MI are being
developed. On the other hand, streptokinase in combination with
abciximab showed dose-related bleeding, ultimately producing
unacceptable risks of bleeding when full-dose streptokinase was
administered, even when heparin was omitted from the reperfusion
regimen. The increased risk of major bleeding when streptokinase was
administered with abciximab in TIMI 14 and when streptokinase was
administered with eptifibatide by other investigators39
suggests that the combination of streptokinase with GP IIb/IIIa
inhibitors may be associated with increased risk of
bleeding. A likely explanation for this observation is the more
profound systemic disturbances of the hemostatic system and
generation of fibrinogen degradation products that occur with a
less fibrin-specific thrombolytic agent such as
streptokinase compared with alteplase.
Clinical Implications
The reperfusion era in the treatment of MI began with
streptokinase, and the next major advance was the introduction of
alteplase, first in the standard-dose regimen21 and later
in the accelerated-dose regimen.25 33 Newer
thrombolytics are clearly more convenient and can be
delivered either as a single40 41 or double
bolus42 but appear to be comparable to accelerated-dose
alteplase. The angiographic data from TIMI 14 strongly suggest that
abciximab in combination with a reduced dose of a
thrombolytic represents a further advance in
reperfusion therapy.
| Acknowledgments |
|---|
| Footnotes |
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| Appendix 1 |
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Leuven Coordinating Center
Leuven, Belgium. European Cochairman: Frans Van de Werf, MD,
PhD; Coinvestigator: Patrick Coussement, MD.
Angiographic Core Laboratory
West Roxbury, Mass. Principal Investigator: C. Michael Gibson,
MD, MS; Quantitative Angiography Technician: Kathryn Ryan, BS; Data
Manager: Sabina Murphy, MPH.
Sponsors
Centocor, Malvern, Pa: Keaven Anderson, PhD, Elliot Barnathan,
MD, Richard P. Schwarz, Jr, PhD, Ann Wang.
Eli Lilly, Inc, Indianapolis, Ind: Joel Scherer, MD, Shirley Paddock, RPh, Kimberly Hadley, BS.
Data Coordinating Center
COVANCE, Princeton, NJ. Global Program Director:
Lillian Dampman, PhD; Project Director: Kevin Vernarec; Project
ManagerEurope: Olive Fogarty; Director of StatisticsNashville:
Ramesh Amatya, PhD; Statistician: Steven Zweig; Site Coordinator: Patti
Sciarrotta; Clinical Research Associates: Dipali Nanavati,
CCRA; Kevin Dopke, MS; Senior Project Associate, Drug Management
Systems: Erik Hostert.
Drug Distribution CenterNorth America
COVANCE Pharmaceutical Packaging Services, Allentown, Pa. Senior
Clinical Coordinator: Margie Schneider; Distribution Coordinator:
Charles Rissmiller.
Drug Distribution CenterEurope
PENN Pharmaceuticals, Gwent, United Kingdom. Project
Manager: Debbie Williams.
Operations Committee
Chairman: Eugene Braunwald, MD. Other members: individuals from
the Study Chairman's Office, Leuven Coordinating Center, Sponsors, and
Data Coordinating Center.
Steering Committee
The members of the steering committee include the members of the
Operations Committee and the principal investigators from the TIMI 14
clinical centers and the Angiographic Core Laboratory.
Clinical Centers in Order of Number of Patients Enrolled (Principal
Investigator is First Individual Listed)
United States (372 patients)
Methodist Hospital and Ben Taub Hospital, Houston,
Tex: Neal S. Kleiman, MD; research coordinator, Kelly Maresh, RN.
Iowa Heart Center/Mercy Hospital Medical Center, Des Moines,
Iowa: Magdi G.H. Ghali, MD; research coordinator, Teresa Coulson.
Montefiore Medical Center, Bronx, NY: Coinvestigators, Mark
Greenberg, MD; Hiltrud Mueller, MD; research coordinators, Joseph
Cosico, RN; Kelly Schneider, RN. Baystate Medical Center,
Springfield, Mass: Marc J. Schweiger, MD; research coordinator,
Barbara Burkott, BSN, RN. Sarasota Memorial Hospital, Sarasota,
Fla: Martin J. Frey, MD; research coordinator, Holly Taylor, RN.
Rhode Island Hospital, Providence, RI: George McKendall, MD;
research coordinators, Mary Jane McDonald, RN; Janet Raymond; Mary
Grogan, RN. Alta Bates Medical Center, Berkeley, Calif:
Robert M. Greene; research coordinators, Eileen Healy, RN; Vickie
Perry, RN. Robert Wood Johnson Medical School, New Brunswick,
NJ: Sebastian T. Palmeri, MD; research coordinator, Laurie
Casazza, RN. Maine Medical Center, Portland, Me: Costas T.
Lambrew, MD; research coordinator, Susan Bosworth-Farrell, RN.
St. Luke's-Roosevelt Hospital Center, New York, NY:
Coinvestigators, Judith S. Hochman, MD; James Slater, MD; research
coordinators, Mary McAnulty, RN; Jeanine Libert, Dorothy Burch.
Massachusetts General Hospital, Boston, Mass: Ik-Kyung Jang,
MD; research coordinator: Jeanne Melley, RN. The Mount Sinai
Medical Center, New York, NY: Srinivas Duvvuri, MD; research
coordinators, Denise Ratner, Pauline Humphries, Eppie Brown,
Traci King. Columbia/JFK Medical Center, Atlantis, Fla:
Joshua Keival, MD; research coordinator, Jill Kinley, ARNP; Jamie
Kosik. Broward General Medical Center, Ft. Lauderdale, Fla:
Alan L. Niederman, MD; research coordinator, Terri Kellerman. LDS
Hospital, Salt Lake City, Utah: Principal investigators, Jeffrey
L. Anderson, MD; J. Brent Muhlestein, MD; research coordinators, Ann
Allen, RN; Staci Hall. Sacred Heart Health System, Pensacola,
Fla: Andrew Kees, MD; research coordinator, Elizabeth Steck, RN,
BSN. Utah Valley Regional Medical Center, Provo, Utah:
Charles F. Dahl, MD; research coordinator, Michelle LeBaron.
University of Vermont, Burlington, Vt: Matthew W. Watkins,
MD; research coordinator, Michaelanne Rowen, RN. John L.
McClellan Veteran's Memorial Hospital, Little Rock, Ark: J. David
Talley, MD; research coordinators, Millie Rawert, BSN; Mindy Dearen.
Sharp Memorial Hospital, San Diego, Calif: David G. Marsh,
MD; research coordinators, Beth Penny, RN; Sue Harte, CFNP. Saint
Francis Medical Center, Proctor Hospital, Peoria, Ill: Paul J.
Schmidt, MD; research coordinator, Cindy Ness, RN. Lancaster
General Hospital, St Joseph Hospital, Lancaster, Pa: Paul N.
Casale, MD; research coordinator, Lisa Hollywood, RN. Brigham and
Women's Hospital, Boston, Mass: Robert Piana, MD; research
coordinators, Michele Po, Ed Chao. Medical College of Virginia
Hospitals of VCU, Richmond, Va: George W. Vetrovec, MD; research
coordinator, Roberta P. O'Brien. University of Alabama,
Birmingham, Ala: William Rogers, MD; research coordinators, Nancy
L. Grady, RN; Kerri Mulrooney, RN. University of Miami/Jackson
Memorial Hospital, Miami, Fla: R.F. Sequeira, MD; research
coordinators, Gayatri Girwar, MD; Sergio Medrano, MD. Lakeland
Regional Medical Center, Lakeland, Fla: Kevin F. Browne, MD;
research coordinators, Beth Evans, Mary Telatnik, RN. Munroe
Regional Medical Center, Ocala, Fla: Robert L. Feldman, MD;
research coordinator, Brandi Merchant, LPN. Winthrop University
Hospital, Mineola, NY: Richard M. Steingart, MD; research
coordinator, Suzanne Bilodeau-Parker, RN. The Ohio State
University Medical Center, Columbus, Ohio: Raymond D. Magorien,
MD; research coordinators, Laurie McCloud-Clouse, RN; Ann Marie
Nordgren, RN. Baptist Hospital, Pensacola, Fla: William
Pickens, MD; research coordinator, Elizabeth Steck, RN, BSN. Pitt
County Memorial Hospital, Greenville, NC: Joseph Babb, MD;
research coordinators, Carmen R. Corbitt, RN, BSN, CCRN; Doris R.
Francis, RN. Trinity Mother Frances Hospital, Tyler, Tex:
Frank Navetta, MD; research coordinator, Greg Murphy, RPh. St.
Elizabeth's Medical Center, Boston, Mass: Douglas, M. Losordo,
MD; research coordinators, Suzanne Farley-Keane, RN; Kathleen
Osborne. Geisinger Medical Center, Danville, Pa:
James C. Blankenship, MD; research coordinator, Saundra L.
Demko.
Belgium (120 patients)
Universitair Ziekenhuis Gasthuisberg, Leuven:
Coinvestigators, Frans Van de Werf, MD, PhD; Patrick Coussement, MD;
research coordinator, Patrick Coussement, MD. Dienst
Hartcatheterisatie, Ziekenhuis Oost-Limburg, Genk: Mathias Vrolix,
MD; research coordinator, LieveVan Dienst. Algemeen Ziekenhuis,
Brugge: Etienne Van der Stichele, MD; research
coordinator, Joerl Voet, MD. Onze Lieve Vrouwe Ziekenhuis,
Aalst: Guy Heyndrickx, MD; research coordinator, Frank Staelens.
Cliniques Universitaires St. Luc, Bruxelles: Jaques Col, MD;
research coordinator, Reine Lauwers. Imeldaziekenhuis,
Bonheiden: Guido Verstreken, MD; research coordinator, Marcel
Cuypers.
France (116 patients)
Hopital Tenon, Paris: Alec Vahanian, MD;
research coordinator, Reza Farnoud. Hopital St. Jacques,
Besancon: Jean Pierre Bassand, MD; research coordinator, Denis
Pales Espinosa. Center de Hospitalier Universitaire de Caen,
Caen: Giles Grollier, MD; Coinvestigator, Emmanuel Lecluse, MD;
research coordinator, Mireille Bourse. Center Hospitalier
Universitaire Pontchaillou, Rennes: Herve LeBreton, MD; research
coordinator, Heautot Herve Le Breton.
United Kingdom (107 patients)
Royal Victoria Hospital, Belfast: Coprincipal
investigators, A.A. Jennifer Adgey, Ian Menown; research coordinators,
Bernie Smith, Leslie Swailes. Western Infirmary, Glasgow: W.
Stuart Hillis, MD; coinvestigators, Douglas Muir, MD; Gerard McCann,
MD.
Germany (89 patients)
Medizinische Klinik II, Mainz: Hans-Jürgen
Rupprecht, MD; research coordinator, Felix Post, MD.
Universitats-Krankenhous Eppendorf, Hamburg:
Chrispoh A. Nienaber, MD; research coordinator, Tim Rehders,
MD. Klinikum der Stadt Ludwigshafen, Ludwigshafen: Ralph
Zahn, MD; research coordinator, Caroline Bergmeier, MD. Klinikum
Sud, Nurnberg: Martin Gottwik, MD; research coordinator, Riego,
MD. Medizinische Klinik, I, Aachen: Jürgen Vom Dahl,
MD; research coordinator, Christian Koch, MD. Klinik fur
Kardiologie, Munchen: Rainer Von Essen, MD; research coordinator,
Axel Reimer, MD.
Netherlands (58 patients)
OLVG afdeling Cardiologie, Amsterdam: R. Van der
Wieken, MD; Coinvestigator, Arthur Scholte, MD; research coordinator,
Gerde Kuiper. Afdeling Cardiologie, Eindhoven: Herman Rudolf
Michels, MD; research coordinators, Henricus Heymen, MD; Muriel Van
Tol, MD.
Canada (26 patients)
University of Manitoba Health Sciences Center,
Winnipeg, MB: John Ducas, MD; research coordinator, Usha Schick.
CUSE-Site Fleurimont, Sherbrooke, QC: Vincent Dangoisse, MD;
research coordinator, Jackie Dangoisse. Mount Sinai Hospital,
Toronto, ON: Allan G. Adelman, MD; research coordinator,
Susan Webber. Royal Columbian Hospital, New
Westminster, BC: Coinvestigator, Mark Henderson, MD; R.A.
Kuritzky, MD; research coordinators, Karen Stevens, Karen Wedding.
Received November 9, 1998; revision received March 22, 1999; accepted March 23, 1999.
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