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280 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
tion of left ventricular function in the infarct area. These findings are consistent with the
results of the ADMIRAL (Abciximab before Direct Angioplasty and Stenting in Myo-
cardial Infarction Regarding Acute and Long Term Follow-Up) trial (see the following
section), which found better TIMI flow grades after PCI in the abciximab-treated group
compared with the placebo group, as well as higher global LV function ejection fractions
(55). In CADILLAC (Controlled Abciximab and Device Investigation to Lower Late
Angioplasty) (6), another trial that assessed abciximab as an adjunct to PCI in acute myo-
cardial infarction (see the following section), LV ejection fractions and regional wall motions
at 7-mo follow-up showed no statistically significant difference, although the point esti-
mates favored abciximab. Detection of such long-term benefit is probably hampered by
considerable scatter caused by variations in restenosis, medication, and individual LV load-
ing conditions.
The improved recovery of contractile function in ISAR-2 and ADMIRAL provided cir-
cumstantial evidence for improved myocardial salvage by stents plus abciximab compared
with stents plus traditional antithrombotic treatment. The issue of myocardial salvage
was directly addressed in the two STOP-AMI (Stent versus Thrombolysis for Occluded
Coronary Arteries in Patients with Acute Myocardial Infarction) trials (56–58). Prior to
the STOP-AMI trials, it had never been shown that PCI confers larger myocardial salvage
than fibrinolysis (59). The prospective randomized STOP-AMI trials thus pursued the
question, of whether PCI optimized with stenting plus abciximab can improve myocar-
dial salvage over what can be achieved with thrombolysis. Both trials enrolled patients
with acute myocardial infarction who presented within 12 h of onset of symptoms and were
eligible for thrombolysis. The thrombolytic regimen was front-loaded alteplase in STOP-
AMI (56,57) and half-dose alteplase plus full-dose abciximab in STOP-AMI-2 (58). STOP-
AMI comprised 140 patients and STOP-AMI-2 162 patients. Technetium-99m sestamibi
scintigraphy was performed on admission to delineate the area at risk (initial perfusion
defect) and after a median of 10 (STOP-AMI) or 11 (STOP-AMI-2) d to assess the final
infarct size (late perfusion defect). In both studies, the primary endpoint was the salvage
index, reflecting the proportion of the area at risk that could be salvaged [(initial perfusion
defect−late perfusion defect)/initial perfusion defect].
In both STOP-AMI trials, the mechanical intervention optimized by abciximab yielded
a larger salvage index than the purely pharmacologic reperfusion strategies (Fig. 4). Cor-
roborating the primary endpoint, in both trials absolute infarct sizes were smaller after
PCI than after thrombolysis, and absolute myocardial salvages were larger. Although none
of the STOP-AMI trials was powered to look at clinical outcome, both suggest that better
salvage confers better clinical outcome. In STOP-AMI, 1-yr mortality in the PCI arm was
significantly lower than in the fibrinolysis arm (15.9% vs 4.2%, p = 0.02) (57), and in
STOP-AMI-2 the combined 6-mo rate of death, reinfarction, and stroke was 8.6% in the
PCI arm compared with 18.5% in the thrombolysis arm (p = 0.06) (58).
When comparing the two STOP-AMI trials, it is conspicuous that the benefit of opti-
mized PCI over fibrinolysis in STOP-AMI is diluted by addition of abciximab to fibino-
lysis in STOP-AMI-2 (Fig. 4). Hence, abciximab appears to exert a specific contribution
to the maximization of myocardial salvage by the optimized PCI. This interpretation is
supported by findings from the TIMI 14 study comparing thrombolytic regimens with
and without abciximab (60). In TIMI 14, ST-segment resolution as a surrogate for tissue
perfusion in patients with TIMI grade 3 reperfusion was better in the abciximab regimens
than in the fibrinolytic regimen without abciximab (60).
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Chapter 12 / Adjunctive Therapy to PCI 281
EFFECT OF GPIIb/IIIa BLOCKADE ON CLINICAL OUTCOME
Subgroup analysis of the 55 patients with acute myocardial infarction in EPIC (Evalua-
tion of c7E3 for the Prevention of Ischemic Complications) suggested a major benefit
from abciximab with PCI for acute myocardial infarction (61). Subsequently, four major
studies investigated the effect of GPIIb/IIIa blockade on clinical outcome in this setting:
RAPPORT (62) (ReoPro and Primary PTCA Organization and Randomized Trial), ISAR-
2 (54), ADMIRAL (55), and CADILLAC (6) (Fig. 5).
The first of these studies, RAPPORT (62), randomized 483 patients with acute ST-ele-
vation myocardial infarction of <12-h duration on a double-blind basis, to placebo or abcix-
imab if they were deemed candidates for primary PTCA. Abciximab compared with placebo
significantly reduced the 30-d incidence of death, reinfarction, or urgent target vessel
revascularization (TVR) by 51% (Fig. 5). This benefit was maintained during 6-mo follow-
up. The rate of nonurgent TVR, however, was not significantly affected by abciximab
(17.4% at 6 mo with abciximab vs 13.6% with placebo). Thus, the primary efficacy end-
point of the study, the composite of death, reinfarction, or TVR at 6 mo showed no differ-
ence (28.2% vs 28.1%, p = 0.97). Because the heparin dosing was not reduced in the
abciximab arm, major bleeding occurred significantly more frequently in the abciximab
group, mostly at the arterial access site. It was concluded that abciximab during primary
PTCA for acute myocardial infarction yielded a substantial reduction in the acute cardiac
complications.
ISAR-2 (54) and ADMIRAL (55) specifically addressed the effect of abciximab on clin-
ical outcome with stenting in acute myocardial infarction. ISAR-2 included 401 patients
undergoing stenting within 48 h after onset of ST-elevation and non-ST-elevation acute
Fig. 4. Primary endpoint of the two STOP-AMI trials. The graph shows median salvage index and inter-
quartile range (56,58).
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282 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
myocardial infarction (54). In an open-label design, patients were randomized to abcixi-
mab plus reduced-dose heparin or to high-dose heparin. By 30 d, the composite clinical
endpoint of death, reinfarction, and target lesion revascularization was reached in 5.0% of
the abciximab group and in 10.5% of the control group (Fig. 5) (54). Abciximab thus achieved
a relative reduction of the early risk by 53% (Fig. 5) (54). At 1 yr, absolute reduction in
the composite clinical endpoint by abciximab was still 5.7% but had lost its statistical sig-
nificance. This was caused by a rate of TVR that was unaffected by abciximab (54). As in
ERASER (63) and EPISTENT (64), binary in-stent restenosis rates at angiographic fol-
low-up were not significantly different between abciximab and control in ISAR-2 (31.1
and 30.6%, p = 0.92) (54).
ADMIRAL tested abciximab in a double-blind, placebo-controlled design that included
300 patients with ST-elevation myocardial infarction within 24 h after onset of pain (55).
In this trial, the 30-d rates of death, reinfarction, and TVR were 6.0% in the abciximab group
but 14.6% in the placebo group ( p = 0.01) (Fig. 5) (55). At 6 mo, the risk reduction by abcixi-
mab compared with placebo was still statistically significant with respect to the composite
endpoint [relative risk (95% confidence interval) 0.68 (0.48–0.95); p = 0.035] (Fig. 5)
(55). An important new aspect of ADMIRAL, compared with other trials using abciximab
for PCI in acute myocardial infarction, is the upstream use of GPIIb/IIIa blockade. In
ADMIRAL, randomization and study drug administration were performed immediately
after the decision for catheter intervention in acute myocardial infarction. Thus, 26% of
the patients received their study medication upstream, that is, in the mobile intensive care
unit or the emergency room. These patients had substantially better 30-d and 6-mo out-
comes than those who received their study drug in the intensive cardiac care unit or the
catheterization laboratory (Fig. 6). ADMIRAL adds weight to the concept that abciximab,
in particular when administered upstream, improves the outcome of patients being stented
for acute myocardial infarction.
Fig. 5. Meta-analysis of studies on abciximab during percutaneous coronary intervention for acute
myocardial infarction (MI). PTCA, percutaneous transluminal coronary angioplasty; TVR, target vessel
revascularization. (From ref. 70, with permission.)
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Chapter 12 / Adjunctive Therapy to PCI 283
CADILLAC investigated stent versus PTCA and abciximab vs heparin alone in a
2-by-2 factorial design (6). CADILLAC, thus far, is the largest trial using abciximab for
PCI in AMI. It comprised 2082 patients with ST-elevation myocardial infarction within
the first 12 h after onset of pain (6). Abciximab compared with control reduced the com-
posite of death, myocardial infarction, and TVR by 30% (5.0% vs 7.1%, p = 0.04) at 30 d
and by 14% (13.0% vs 15.1%, p = 0.17) at 6 mo (Fig. 5) (6). Thus, the effect of abciximab
in CADILLAC was consistent with the other trials, although the risk reduction was some-
what lower than expected based on the earlier studies. This may be because CADILLAC
recruited a low-risk cohort with an unprecedented low overall mortality of 3.3% (6). Of
the 2681 patients who were screened for inclusion in CADILLAC, 599 (22.3%) were
excluded based on high-risk angiographic features or because noninterventional manage-
ment was the proper approach. Exclusion of these patients will have reduced the overall
risk in CADILLAC.
If CADILLAC is broken down into subgroups with and without stent, the benefit of
abciximab with respect to the composite endpoint at 6 mo was nearly significant in the
PTCA group (15.2% vs 19.3%, p = 0.07), whereas in the stent groups event rates were
almost identical (10.9% vs 10.8%). However, since an interaction of the effect of abciximab
with the type of percutaneous coronary intervention has not been shown in any previous
trial (see previous chapters), it is questionable whether the groups with and without stents
deserve separate analysis. Metaanalysis of all studies owing abciximab for PCI in acute
myocardial infarction reveals a significant reduction in 30-d and 6-mo event rates (Fig. 5).
FUTURE PROSPECTS
Confirming earlier smaller studies (65,66), the large randomized DANAMI-2 trial has
recently shown that transport to PCI in acute myocardial infarction gives a better outcome
than local thrombolysis, if the patient can be brought to the catheterization laboratory
Fig. 6. Relative risk of death, reinfarction, or urgent target vessel revascularization (TVR) according
to the timing of study drug administration (55). MI, recurrent myocardial infarction; MICU; mobile
intensive care unit; ER, emergency room; ICCU, intensive cardiac care unit; CL, catheterization
laboratory.
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284 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
within 3 h (67). In 1129 patients with acute myocardial infarction admitted to hospitals
without catheterization facilities and randomized to transport to PCI in a center, the 30-d
rate of death, reinfarction, and stroke was 8.5%, whereas it was 14.2% (p = 0.002) for
those randomized to local thrombolysis. DANAMI-2 suggests that, from a population
perspective, the prospects for patients with acute myocardial infarction can be substan-
tially improved by the implementation of networks that allow rapid allocation and trans-
port of patients to infarct centers that provide PCI.
With a treatment strategy of systematic transport to PCI in acute myocardial infarction,
the concept of upstream treatment will gain importance. Thus far, evidence from ADMIRAL
suggests that administration of abciximab well before the start of PCI improves acute and
long-term outcome. Subgroup analyses from both SPEED (68) and PACT (69) indicate that
the outcome in acute myocardial infarction can be improved, if prior to PCI at least partial
reperfusion is achieved by thrombolysis. In this respect, combination of full-dose abcixi-
mab with half-dose fibrinolytic agents (see Chapter 13) appears particularly attractive.
The concept of “facilitated PCI” by upstream use of GPIIb/IIIa blockade, either alone or
in combination with a half-dose fibrinolytic agent, needs to be tested in future randomized
trials, such as FINESSE (Facilitated Intervention with Enhanced Reperfusion Speed to
Stop Events).
SUMMARY
GPIIb/IIIa receptor blockade with abciximab interferes with several mechanism that
limit reperfusion in acute myocardial infarction. Clinical studies have shown that abciximab
improves recovery of microvascular and contractile function. Stenting in combination with
abciximab confers a substantially larger myocardial salvage than thrombolysis. Circum-
stantial evidence suggests that abciximab makes an important contribution to this benefi-
cial effect. Metaanalysis of the four randomized clinical trials using abciximab as an adjunct
to PCI in acute myocardial infarction, RAPPORT, ISAR-2, ADMIRAL, and CADILLAC,
reveals a reduction in the composite of death, reinfarction, and reintervention during
30-d and 6-mo follow-up. This benefit is particularly large if abciximab is administered
upstream, as suggested by ADMIRAL, and may be negligible in low-risk settings, as sug-
gested by analysis of the stent group in CADILLAC. The concept of facilitated PCI either
by upstream GPIIb/IIIa blockade alone or in combination with a half-dose fibrinolytic
agent awaits confirmation by future studies. Further studies are also needed to address the
efficacy of GPIIb/IIIa blockers other than abciximab in the setting of PCI in acute myo-
cardial infarction.
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288 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
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Chapter 13 / Adjunctive Therapy to Fibrinolysis 289
289
From: Contemporary Cardiology: Platelet Glycoprotein IIb/IIIa
Inhibitors in Cardiovascular Disease, 2nd Edition
Edited by: A. M. Lincoff © Humana Press Inc., Totowa, NJ
13 Glycoprotein IIb/IIIa
Receptor Blockade in Acute
Myocardial Infarction
Adjunctive Therapy to Fibrinolysis
CONTENTS
INTRODUCTION
EARLY EXPERIENCE WITH ADJUCTIVE PLATELET INHIBITION
REDUCED-DOSE FIBRINOLYSIS WITH GPIIb/IIIa ANTAGONISM:
P
HASE II ANGIOGRAPHIC STUDIES
REDUCED-DOSE FIBRINOLYSIS WITH GPIIb/IIIa ANTAGONISM:
P
HASE III STUDIES
SUMMARY AND RECOMMENDATIONS
REFERENCES
Sorin J. Brener, MD
INTRODUCTION
Pharmacologic reperfusion with fibrinolytic therapy remains the principal method of
infarct-artery recanalization for patients with acute myocardial infarction (AMI). Its uni-
versal availability, ease of administration, and effectiveness have been demonstrated in
an impressive array of clinical trials in the last two decades (1–3). Nevertheless, signifi-
cant limitations and unfulfilled expectations continue to render this therapy less than per-
fect. Three generations of fibrinolytic agents have not been able to solve three vexing
problems: restoration of normal flow [Thrombolysis in Myocardial Infarction (TIMI)
grade 3] in the infarct artery is achieved in fewer than half the patients at 60 min from drug
administration: one-fourth of those with epicardial reperfusion have impaired microvas-
cular perfusion (4,5); and finally, major bleeding [particularly intracranial hemorrhage
(ICH)] remains high and has a major impact on outcome. Three recent megatrials (6–8)
comparing the parent tissue plasminogen activator (t-PA) molecule with novel compounds,
specifically designed to address some of t-PA’s deficiencies, have failed to demonstrate,
in general, superior efficacy (mortality reduction) or safety (ICH reduction). Some progress
has been made with respect to major, nonintracranial, hemorrhage (9) and treatment of
patients presenting beyond 4 h from symptom onset (8).
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