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290 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
Intensive examination of the failure of fibrinolytic agents to produce a higher rate of
infarct-artery reperfusion has focused on the prothrombotic milieu engendered by these
agents upon lysis of fibrin and liberation of clot-bound thrombin. Furthermore, as platelets
are the initial element to accumulate at the site of plaque rupture and support rethrombosis,
potent inhibitors of this mechanism became a logical target of investigation (10,11). The
most profound blockade of platelet activation and subsequent aggregation can be achieved
by inhibitors of the final common pathway of platelet stimulation, glycoprotein (GP) IIb/
IIIa receptor (12). Their pharmacology and properties are discussed elsewhere in this text-
book. Experimental evidence in animals and humans pointed to the ability of these platelet
antagonists to cause “dethrombosis,” or reverse the process of fibrin deposition on a bio-
logic template provided by the cellular membrane of aggregating platelets (13).
Thus, application of these principles to reperfusion therapy using combination fibrin
and platelet lysis was expected to yield the following advantages:
1. Arrest and modify the process of coronary thrombosis, thus promoting faster and more com-
plete restoration of flow in a larger proportion of patients.
2. Improve tissue perfusion by minimizing the deleterious effects of thrombus embolization,
which are often related to platelet degranulation and activation.
3. Obviate the need for, or facilitate the performance of, immediate percutaneous revascu-
larization in patients who fail to reperfuse or are selected for immediate mechanical revas-
cularization on clinical grounds.
4. By employing a lower dose of fibrinolytics, reduce the most severe complications of full-
dose lytics, particularly intracranial hemorrhage.
This chapter will examine these expectations in light of the accumulated data and will
map the road for future research.
EARLY EXPERIENCE WITH ADJUCTIVE PLATELET INHIBITION
The initial efforts to combine fibrin and platelet lytics were directed mostly at prevent-
ing reocclusion following initial patency and revolved around a full dose of a plasmino-
gen activator-based regimen, to which GPIIb/IIIa inhibition was added in increasing doses.
This approach was based on the assumption that a large amount of plasminogen activator
is needed for clot lysis, while assigning lesser importance to the prothrombotic effect of
these agents.
The Thrombolysis and Angioplasty
in Myocardial Infarction (TAMI) 8 Trial
Kleiman et al. (14) conducted a pilot study in 60 patients treated with t-PA, aspirin, and
heparin (control group) and ascending doses of the monoclonal antibody 7E3 (abciximab
precursor) initiated at 3–15 h after fibrinolysis. Arterial patency (TIMI grade 2 or 3 flow)
was detected in 56% of the control group and 92% of the 7E3 patients without a significant
increase in major bleeding complications. Optimal platelet inhibition was obtained at a
bolus dose of 0.25 mg/kg, consistent with the current dosing of abciximab.
The Integrilin to Minimize Platelet Aggregation and Coronary
Thrombosis in Acute Myocardial Infarction (IMPACT-AMI) Trial
The IMPACT-AMI investigators (15) extended this concept to a dose-ranging trial in
which 180 patients with AMI were treated with accelerated full-dose t-PA and a peptide
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Chapter 13 / Adjunctive Therapy to Fibrinolysis 291
inhibitor of the GPIIb/IIIa receptor, eptifibatide, given in escalating doses. The primary
endpoint was the rate of TIMI grade 3 flow at 90 min. The highest dose of eptifibatide used
(180 µg/kg bolus and 0.75 µg/kg/min infusion for 24 h) achieved TIMI 3 grade flow in 66%,
compared with 39% in t-PA-alone patients (p = 0.006). There was a significant reduction
in the time to complete ST-segment deviation resolution in the optimal eptifibatide group,
from a median of 116 min for t-PA to 65 min (p = 0.05), indicating superior myocardial
reperfusion. Severe bleeding complications occurred in 4% of the high-dose eptifibatide
(one patient had intracranial hemorrhage) and 5% of t-PA control patients, whereas severe
thrombocytopenia was found in 4 and 6%, respectively.
Eptifibatide and Streptokinase in Acute Myocardial Infarction
Streptokinase and eptifibatide were combined in a similar study (16). One hundred eighty-
one patients with AMI received aspirin, heparin, and full-dose streptokinase (1.5 million
U) and were randomized to additional eptifibatide or placebo. The doses of eptifibatide
tested were 180 µg/kg bolus followed by an infusion of 0.75 (IMPACT-AMI dose), 1.33,
or 2.0 (PURSUIT dose) (17) µg/kg/min. The primary endpoint (TIMI grade 3 flow at 90
min) was achieved in 38% of the streptokinase alone group and 53, 44, and 52% of the
eptifibatide groups, respectively. The two higher doses of the platelet inhibitor were asso-
ciated with an incidence of moderate or severe bleeding of 40%, compared with 16% and
3% for the low-dose eptifibatide- and streptokinase-alone groups, respectively. The lack
of a significant dose-effect response in arterial patency and the high rate of bleeding led
to discontinuation of enrollment in the high-dose group.
The Platelet Aggregation Receptor Antagonist Dose Investigation
and Reperfusion Gain in Myocardial Infarction (PARADIGM) Trial
The PARADIGM investigators enrolled 353 patients with AMI of <12 h in three phases
of a dose-finding study (18). All patients received aspirin and heparin. t-PA (75% of patients)
or streptokinase (25%) were administered in the usual fashion. Placebo or lamifiban (a
highly selective nonpeptide inhibitor of the GPIIb/IIIa receptor) in escalating doses of
300–400 µg/kg bolus and infusions of 1.0, 1.5, or 2.0 µg/kg/min for 24 h were added. The
primary efficacy endpoint was achievement of >85% platelet inhibition in response to
ADP and thrombin receptor agonist peptide (TRAP). Lamifiban at the highest dose induced
marked platelet inhibition both after the bolus and at steady state. The effects of lamifiban
were more pronounced in the streptokinase-treated patients. As in IMPACT-AMI, time
to steady-state recovery of the ST-segment deviation was shortened by lamifiban from
122 to 88 min (p = 0.003). There was no systematic angiography in this trial. Adverse clin-
ical events occurred insignificantly less often in the patients treated with lamifiban than
with placebo, and major bleeding was noted in 3.0 and 1.7%, respectively.
REDUCED-DOSE FIBRINOLYIS WITH
GPIIb/IIIa ANTAGONISM: PHASE II ANGIOGRAPHIC STUDIES
Six phase two clinical trials have completed enrolling approx 3500 AMI patients in
angiographically controlled evaluations of the optimal combination of fibrinolytic agents
[tissue plasminogen activator (t-PA), streptokinase, reteplase (r-PA), and tenecteplase (TNK)-
t-PA] and a GPIIb/IIIa antagonist (abciximab, eptifibatide or tirofiban) (19–23). Earlier
studies consisted of dose-finding and dose-confirmation phases. All were similar with
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292 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
respect to inclusion (6–12 h from symptom onset, eligibility for fibrinolysis) and exclu-
sion criteria (cardiogenic shock) and angiographic endpoint, as shown in Table 1. One
study (23) also evaluated the contribution to reperfusion of low-molecular-weight hepa-
rin (enoxaparin) compared with unfractionated heparin. The principal assumptions tested
were that:
1. Reduced-dose fibrinolysis (50–75%) will not compromise efficacy and will enhance safety,
in particular reducing the incidence of ICH.
2. The addition of GPIIb/IIIa antagonism will enhance efficacy compared with full-dose fibrin-
olysis alone without a significant increase in major bleeding complications.
3. The combination of the two agents will improve, beyond epicardial flow restoration, other
parameters of reperfusion, such as resolution of ST-segment elevation and myocardial blush
score.
4. The combination regimen will facilitate percutaneous revascularization, usually performed
at the time of the protocol-mandated angiography.
None of the studies were powered to detect differences in 30-d ischemic endpoints and
thus served as hypothesis-generating efforts, rather than as a definitive shift in the paradigm
of reperfusion therapy.
The principal angiographic results of the six trials are shown in Figs. 1 and 2, including
only direct comparisons between a full-dose fibrinolytic agent and a combination regimen.
The brief attempt to administer streptokinase and abciximab resulted in a high incidence
of bleeding, similar to the combination with eptifibatide, and is not included in this com-
pilation (19). The impact on ST-segment elevation resolution is shown in Fig. 3 for trials
that reported this outcome. In small subsets of patients treated with combination therapy,
there was also improvement in the TIMI myocardial perfusion grade (blush score) (24).
There were no significant differences in the incidence of death or reinfarction at 30 d in
any of the trials between combination and monotherapy. Death occurred in approx 4%
of patients and reinfarction in approx 3%. Major bleeding, including ICH, was reported
using the TIMI definition (25) for all trials except SPEED, for which the GUSTO formula
was utilized (20). The incidence of important bleeding was in general higher in the com-
bination than the monotherapy regimen, although this difference did not reach statistical
significance. The incidence of ICH varied between 0 and 3%, representing very few patients
in many small groups allocated to various regimens.
Table 1
Trials of Reduced-Dose Fibrinolysis
and Platelet Glycoprotein (GP) Inhibition
1st angiogram
Acronym (ref.) No. Lytic GP inhibitor (min)
TIMI 14 (19) 888 t-PA Abciximab 90
SPEED (20) 528 r-PA Abciximab 60–90
INTRO-AMI (21) 649 t-PA Eptifibatide 60
INTEGRITI (22) 438 TNK Eptifibatide 60
ENTIRE (23) 483 TNK Abciximab 60
FASTER 408 TNK Tirofiban 60
Abbreviations: r-PA, reteplase; TNK, tenecteplase; t-PA, tissue plasminogen activator.
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Chapter 13 / Adjunctive Therapy to Fibrinolysis 293
The recommendations for immediate percutaneous revascularization following con-
trol angiography were not standardized in the various trials. In some, it was recommended
for less than optimal pharmacologic reperfusion (rescue angioplasty), whereas in others it
was encouraged (when feasible) even for patients with TIMI grade 3 flow (facilitated
angioplasty). The most comprehensive analysis on this subject was performed in SPEED
(26). Patients treated with immediate angioplasty (n = 322, 71% of enrolled patients) had
a significantly higher incidence of freedom from ischemic events at 30 d than those not
Fig. 1. Incidence of TIMI grade 3 flow at 60 min from drug administration (randomized comparison
of combination therapy vs monotherapy). *, p < 0.05.
Fig. 2. Corrected TIMI frame counts at 60 min from drug administration. *, p < 0.05. Data for ENTIRE
are not yet available.
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294 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
undergoing revascularization. (Fig. 4) Similar results were reported from a subgroup of
patients in TIMI 14 undergoing immediate angioplasty (27). Among 113 patients under-
going immediate PCI after reperfusion therapy in TIMI 14, mean ST-segment deviation
resolution was 8% in recipients of lytic monotherapy and 49% in those treated with com-
bination abciximab and t-PA (p = 0.002).
To interpret results properly across different therapeutic regimens, some methodologic
aspects of the trials merit attention. Early (60 min) angiographic evaluation, although
clinically important, penalizes lytic regimens based on t-PA, whose completion requires
the whole interval up to angiography. In contrast, single- (TNK) or double-bolus (r-PA)
regimens are completed well in advance of the angiographic evaluation. In some instances
(21), angioplasty following the 60-min evaluation, although not recommended, was per-
formed, complicating the assessment of TIMI grade 3 flow at 90 min and comparison with
other regimens. This is also relevant to ST-segment elevation resolution at 180 min, which,
in many cases, was measured after percutaneous revascularization. Finally, the concept of
facilitated angioplasty after pharmacologic reperfusion cannot be clearly assessed in these
trials, as the performance, timing, and indications for percutaneous revascularization were
not standardized and tended to reflect the investigators’ preference.
Despite these limitations, several broad conclusions can be drawn:
1. Combination fibrin and platelet-lysis tends to increase the incidence of TIMI grade 3 flow
at 60 and 90 min, compared with fibrinolytic monotherapy. The absolute difference varies
across regimens and studies between 10 and 20%. Based on the findings from the Global
Utilization of Strategies to Open Occluded Arteries (GUSTO) I trial (3), such an advantage
is unlikely to translate into a significant reduction in mortality in small trials, particularly
in a low-risk population with mortality rates of <5%.
2. The combination regimens tend to improve myocardial reperfusion, as measured by ST-
segment elevation resolution and myocardial blush score.
Fig. 3. Incidence of complete ST-segment elevation resolution at 180 min from drug administration.
*p < 0.05.
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Chapter 13 / Adjunctive Therapy to Fibrinolysis 295
3. Bleeding complications, including ICH, have not been reduced by combination therapy.
In fact, there were nominally more episodes of major bleeding in the combination regimens.
4. Rescue (for failed reperfusion) or facilitated (for residual stenosis with TIMI grade 3 flow)
angioplasty was in general associated with acceptable results, particularly when compared
with historical controls (28–30). The excess ischemic complications observed earlier, par-
ticularly the high incidence of death in patients with failed PCI, did not occur in the context
of frequent stenting and use of potent platelet antagonists.
REDUCED-DOSE FIBRINOLYIS
WITH GPIIb/IIIa ANTAGONISM: PHASE III STUDIES
Two large clinical trials, powered to detect differences in mortality and other impor-
tant ischemic and bleeding complications at 30 d between regimens, have examined the
role of combination anti-fibrin and platelet therapy in AMI.
Global Utilization of Strategies
to Open Occluded Coronary Arteries (GUSTO) V
Eight-hundred twenty hospitals randomized in an open-label design 16,588 patients
with AMI within 6 h of symptom onset to full-dose r-PA or half-dose r-PA (5 MU twice,
30 min apart) and full-dose abciximab (0.25 µg/kg bolus and 0.125 µg/kg/minute infusion
for 12 h) (31). Patients selected for primary angioplasty were excluded. The important
baseline characteristics are shown in Table 2. The primary endpoint was all-cause mortal-
ity at 30 d. Data were collected by investigators with respect to reinfarction and 15 other
complications of AMI up to 7 d or hospital discharge. Bleeding and neurologic complica-
tions were assessed independently.
At 30 d (Fig. 5), the incidence of death in the mono- and dual-therapy groups was 5.9
and 5.6%, respectively (p = 0.43 for superiority and p = 0.95 for noninferiority), relative
risk 0.95 (0.84–1.08). Mortality rates in prespecified subgroups are shown in Fig. 6. With
Fig. 4. Facilitated or rescue angioplasty in SPEED. PCI, percutaneous coronary intervention. (From
ref. 26.)
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296 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
the exception of pulmonary embolism and pericardial effusion, all other 14 prespecified
post-MI complications were less common in the combination therapy arm. Reinfarction
by d 7, manifested by enzyme reelevation and new electrocardiographic changes, was sig-
nificantly less common in the combination arm than in the monotherapy group (2.3% vs
3.5%, p < 0.0001. Urgent (<6 h) percutaneous revascularization was significantly less often
needed in the combination arm than in the monotherapy group (5.6% vs 8.6%, p = 0.001).
In contrast, bleeding complications were more common in the dual-therapy group;
severe bleeding (1.1% vs 0.5%), any bleeding (24.6% vs 13.7%), and requirement for trans-
fusion (5.7% vs 4.0%) were significantly increased in the combination arm (p < 0.0001
for all). This excess was related to spontaneous bleeding and not to surgical or percutane-
ous revascularization procedures.
The overall rate of any stroke (0.9% vs 1.0%) and ICH (0.6% vs 0.6%) was similar between
the two groups. Nevertheless, there was a statistically significant interaction between treat-
Table 2
Baseline Characteristics (%) of Patients in GUSTO V
r-PA r-PA+ abciximab
(n = 8260) (n = 8328)
Age (yr) 61 ± 12 62 ± 12
Women 24 25
Diabetes 16 16
Previous MI 15 16
Hypertension 33 35
Prior PCI/CABG 10 10
Anterior MI 37 38
Time to therapy (h) 2.9 ± 1.6 3.1 ± 2.2
Abbreviations: CABG, coronary artery bypass graft; MI,
myocardial infarction; PCI, percutaneous coronary intervention;
r-PA, reteplase.
Fig. 5. Thirty-day mortality in GUSTO V.
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Chapter 13 / Adjunctive Therapy to Fibrinolysis 297
ment assignment and age with respect to ICH. Patients older than 75 yr had a significantly
higher incidence of ICH with combination therapy than with monotherapy (2.1% vs 1.1%),
compared with 0.4% vs 0.5%, respectively, for younger patients ( p = 0.033 for interaction).
This excess in ICH is probably responsible for the lack of any benefit of the combination
regimen in elderly patients.
Although this trial did not show improved survival at 30 d for patients treated with com-
bination fibrin and platelet antagonists, it is noteworthy that the overall mortality was much
lower than expected (5.9% vs 7.5% for the r-PA groups in GUSTO V and GUSTO III,
respectively). This may represent a secular trend of improvement in AMI outcome or
selection of patients at lower risk than in previous fibrinolytic trials. The latter appears
plausible, as the incidence of ICH in the r-PA monotherapy arms in GUSTO V was 0.6%,
compared with 0.9% in GUSTO III. Within this context, the power of the study to detect
noninferiority is <80%, and it is possible that the combination regimen could be associ-
ated with a 7% increase or a 15% decrease in mortality, compared with r-PA monotherapy.
It is also important to note that many other complications of AMI, particularly reinfarc-
tion, were reduced by the dual-therapy regimen, an advantage that may translate into sur-
vival advantage at 1 yr. In previous fibrinolytic trials, reinfarction was associated with
at least doubling of mortality, compared with patients without reinfarction (32). Never-
theless, 1-yr mortality was identical (8.38%) in both groups (32a). Preliminary analyses did
not suggest that rescue PCI was favorably impacted by combination therapy, although
it is difficult to eliminate the selection bias and the knowledge of the treatment assigned
(A. M. Lincoff, personal communication).
Fig. 6. Thirty-day mortality in GUSTO V in prespecified subgroups. MI, myocardial infarction.
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298 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
The Assessment of Safety and Efficacy
of a New Thrombolytic Regimen (ASSENT)-3 Trial
Following the demonstration that TNK-t-PA and t-PA are equivalent as monotherapy
for AMI, this trial tested in an open-label design two new combination regimens against
TNK monotherapy (33). At 575 hospitals, 6095 patients within 6 h of onset of AMI were
randomized to full-dose TNK with enoxaparin (continued for up to 7 d), half-dose TNK
with abciximab and low-dose unfractionated heparin (UFH; for 48 h), or full-dose TNK
with weight-adjusted UFH (for 48 h). The activated partial thromboplastin time (aPTT) for
patients receiving UFH was maintained at 50–70 s and was first adjusted 3 h after TNK
administration. The primary efficacy endpoint was the 30-d composite of death, in-hos-
pital reinfarction, or in-hospital refractory ischemia. The same endpoints plus in-hospital
major bleeding or ICH constituted the primary efficacy and safety endpoint.
The baseline characteristics of the patients enrolled in ASSENT-3 are shown in Table
3. At 30 d, the incidence of the primary efficacy (Fig. 7) and efficacy and safety endpoints
(Fig. 8) were significantly reduced in comparison with the standard TNK therapy in both
experimental arms. This difference in efficacy was already evident by 48 h, the time of
discontinuation of UFH (6.1, 5.2, and 8.8%, respectively, p < 0.0001). Death (5.4, 6.6, and
6.0%, respectively, p = 0.25) and ICH (0.88, 0.94, and 0.93%, p = 0.98) were similar among
the three groups. In contrast, in-hospital reinfarction (2.7, 2.2, and 4.2%, p = 0.0009) and
refractory ischemia (4.7, 3.2, and 6.5%, respectively, p < 0.0001) occurred significantly
less frequently in the experimental arms, particularly in the abciximab-treated cohort.
Non-ICH major bleeding was more common in the abciximab group (3.0, 4.3, and 2.2%,
respectively, p = 0.0005).
Prespecified subgroup analysis based on gender, age, diabetes, infarct location, and
time-to-treatment identified two interesting findings: there was a significant interaction
(p = 0.0004) between diabetes and treatment allocation for efficacy (Fig. 9) and between
diabetes (p = 0.0007) and age (p = 0.001) and treatment allocation for efficacy and safety
(Fig. 10). Whereas the age-treatment interaction was similar to that observed in GUSTO
V, the findings in the diabetic patients are puzzling and unexpected. The need for urgent
PCI was reduced in the experimental arms, particularly in the abciximab group (11.9, 9.1,
and 14.4%, respectively, p < 0.001).
Table 3
Baseline Characteristics (%) of Patients in ASSENT-3
TNK+Enox TNK+Abcix TNK+UFH
(n = 2040) (n = 2017) (n = 2038)
Age (yr) 61 ± 12 61 ± 12 61 ± 13
Women 23 24 23
Diabetes 19 18 18
Previous MI 14 13 14
Hypertension 41 41 41
Prior PCI/CABG 10 9 9
Anterior MI 39 39 38
Time to therapy (h) 3.0 ± 1.7 3.1 ± 1.4 3.1 ± 1.6
Abbreviations: Enox, enoxaparin; Abcix, abciximab; TNK, tenecteplase; UFH,
unfractionated heparin. For other abbreviations, see Table 2 footnote.
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Chapter 13 / Adjunctive Therapy to Fibrinolysis 299
Fig. 7. Thirty-day mortality or in-hospital reinfarction or refractory angina in ASSENT-3. (From
ref. 33, with permission.)
Fig. 8. Thirty-day primary efficacy and safety endpoint in ASSENT-3. ICH, intracranial hemorrhage.
(From ref. 33, with permission.)
Fig. 9. Primary efficacy endpoint by diabetes mellitus (DM) status in ASSENT-3.
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