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Antithrombotic Therapy in Patients With Acute Coronary Syndromes
Glenn N. Levine, MD;
M. Nadir Ali, MD;
Andrew I. Schafer, MD
Arch Intern Med. 2001;161:937-948.
ABSTRACT
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The potential armamentarium of agents used in the treatment of acute
coronary syndromes continues to expand, including such well-tested agents
as aspirin, unfractionated heparin, and earlier-generation fibrinolytic agents,
and newer agents such as low-molecular-weight heparins, direct thrombin inhibitors,
thienopyridines, platelet glycoprotein IIb/IIIa receptor inhibitors, and bolus-administration
fibrinolytic agents. Older and newer antithrombotic agents have undergone
and continue to undergo intensive clinical investigation in patients with
the clinical spectrum of acute coronary syndromes, which includes unstable
angina, non–Q-wave (non–ST-segment elevation) myocardial infarction,
and ST-segment elevation myocardial infarction. These studies, often conducted
on an international scope and involving thousands of patients, provide data
allowing practitioners to optimize the care of patients with acute coronary
syndromes. In this article, studies of these established and newer agents
in the treatment of patients with acute coronary syndromes are reviewed critically
and summarized. Recommendations regarding use of antithrombotic agents in
patients with acute coronary syndromes are then given.
UNDERSTANDING THE NOMENCLATURE USED IN CLINICAL TRIALS
Although older studies of antithrombotic therapy have addressed unstable
angina as a distinct condition, more recent studies have recognized that unstable
angina and non–Q-wave myocardial infarction (MI) are part of a continuum
of coronary thrombotic disorders termed acute coronary syndromes and have assessed antithrombotic therapy in these patients as a group
(and used acute coronary syndrome to refer to this
group of patients). Acute coronary syndromes has
also been used variably in the literature to also include those patients who
present with ST-segment elevation MI. Further confusing the nomenclature is
the fact that Q waves may not develop in some patients who present with ST-segment
elevation (probably as a result of early spontaneous, pharmacological, or
mechanical reperfusion) and are later termed to have non–Q-wave
MI. Also, Q-wave MI may develop in a small proportion of patients who
present without ST-segment elevation.
For the purposes of clarity in this review, in studies in which patients
labeled as presenting with unstable angina or non–Q-wave MI were enrolled
and studied, the term non–ST-segment elevation acute
coronary syndromes will be used. The term acute coronary
syndrome will be reserved only for describing the broad spectrum of
patients that includes unstable angina, non–Q-wave MI, and ST-segment
elevation MI.
ANTIPLATELET AGENTS
Aspirin
Aspirin has been used medicinally since antiquity. Its antithrombotic
action is due to irreversible blockade of the formation of thromboxane A2, a potent mediator of platelet aggregation. The inhibitory effects
of aspirin on platelet aggregation are rapid, with maximal effects achieved
within 15 to 30 minutes of oral administration of a dose as low as 81 mg.1
The beneficial effects of aspirin in patients with unstable angina were
demonstrated in several studies conducted in the 1980s,2-5
including a study conducted at the Montreal Heart Institute.4
In that study, 479 patients with unstable angina were randomized to treatment
with aspirin (325 mg twice daily), intravenous heparin sodium, both, or neither
(Figure 1). Compared with patients
who received neither therapy, those who were treated with aspirin were 71%
less likely to suffer a nonfatal or fatal MI (absolute rates, approximately
12% vs 3%, respectively). In the larger Research Group on Instability in Coronary
Artery Disease (RISC) study of patients with unstable angina or non–Q-wave
MI, the risk for subsequent MI or death was reduced by aspirin therapy (75
mg/d) at 5-day follow-up by 57% (from 5.8% to 2.5%).5
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Figure 1. Results of the Montreal Heart
Institute study of patients with unstable angina, showing the reduction in
adverse events in patients treated with aspirin, heparin sodium, or both,
compared with those treated with neither agent. MI indicates myocardial infarction.
Adapted from data in Theroux et al.4
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In the ISIS-2 (Second International Study of Infarct Survival) trial,
more than 17 000 patients with suspected MI were randomized to aspirin
therapy (160 mg/d), streptokinase, both therapies, or neither.6
The study included patients with ST-segment elevation, ST-segment depression,
bundle-branch block, or other electrocardiographic (ECG) abnormalities. Treatment
with aspirin decreased vascular mortality by 23%, a reduction comparable to
the 25% reduction achieved with streptokinase therapy. Patients in the ISIS-2
trial treated with streptokinase derived additional benefit from concomitant
therapy with aspirin. In those treated with both agents, vascular mortality
was decreased by 42%. The additional beneficial effect of aspirin in those
receiving thrombolytic therapy is believed to be due at least in part to aspirin's
decreasing the rates of vessel reocclusion and thus of myocardial reinfarction.
The result of these treatment regimens on vascular mortality in the ISIS-2
trial are shown in Figure 2. These
trials thus firmly established the clinically relevant beneficial effect of
aspirin therapy for the broad range of patients with acute coronary syndromes.
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Figure 2. Results of the Second International
Study of Infarct Survival (ISIS-2) in which patients with suspected myocardial
infarction were treated with aspirin, streptokinase, both, or placebo. Aspirin
or streptokinase therapy alone reduced vascular mortality by 23% to 25% compared
with placebo therapy; treatment with both agents reduced vascular mortality
by 42%. Adapted with permission from the ISIS-2 Collaborative Group.6
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Ticlopidine and Clopidogrel
The thienopyridines ticlopidine hydrochloride and clopidogrel block
adenosine diphosphate (ADP)–mediated platelet activation and lead to
irreversible inhibition of platelet aggregation.7
The inhibitory effects of the thienopyridines on platelet aggregation may
be synergistic to those achieved with aspirin therapy.7
Like aspirin, the thienopyridines are relatively weak inhibitors of platelet
activation compared with the platelet glycoprotein IIb/IIIa (GpIIb-IIIa) inhibitors.
Although the thienopyridines have become an integral part of pharmacological
therapy in patients undergoing coronary stent implantation, there remain only
scant data on the role of these agents in patients with acute coronary syndromes.
In an Italian study, 652 patients with unstable angina were treated with ticlopidine
hydrochloride (Ticlid), 250 mg twice daily, plus conventional therapy or with
conventional therapy alone during hospitalization, with continued therapy
for approximately 6 months after discharge.8
Treatment with ticlopidine decreased the incidences of nonfatal MI and vascular
death by 46%. However, the conventional therapy arm did not include aspirin
or heparin, and most of the reduction in events with ticlopidine therapy occurred
not during the initial hospitalization but in the months after discharge.
The relatively short onset of action (in terms of platelet inhibition)
provided by a loading dose of clopidogrel (Plavix), the once-daily dosing
schedule, and the moderate degree of platelet inhibition achieved might make
this agent a possible alternate therapy in patients with acute coronary syndromes
who have true aspirin allergies. However, such a role has not been established
or, at least in terms of published studies, evaluated. Nevertheless, given
the recognized importance of antiplatelet therapy in acute MI in patients
with true aspirin allergies, it has been recommended that other antiplatelet
agents such as clopidogrel or ticlopidine be considered as alternate therapies.9
Platelet GpIIb-IIIa Inhibitors
Each platelet contains approximately 60 000 to 80 000 GpIIb-IIIa
receptors for fibrinogen on its membrane. When platelets are activated, these
GpIIb-IIIa complexes undergo a conformational change that enables them to
bind fibrinogen. As illustrated in Figure
3, the binding to GpIIb-IIIa receptors located on different platelets
by the same fibrinogen dimer leads to platelet aggregation. The GpIIb-IIIa
inhibitor molecules bind to the GpIIb-IIIa complex and thereby block the binding
of fibrinogen to its receptor, leading to complete inhibition of platelet
aggregation.
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Figure 3. When the inactivated platelet
becomes activated, there is a conformational change in the glycoprotein IIb/IIIa
(GpIIb-IIIa) receptors, which are located on the platelet membrane. These
activated GpIIb-IIIa receptors can then bind fibrinogen dimers, leading to
platelet aggregation. The GpIIb-IIIa receptor blockers can themselves bind
to the GpIIb-IIIa receptors, and by doing so prevent fibrinogen-mediated platelet
aggregation.
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There are currently 3 intravenously administered approved GpIIb-IIIa
inhibitors. Abciximab (ReoPro) is the Fab fragment of a monoclonal antibody
to GpIIb-IIIa that has been humanized to reduce immunogenicity.10
As the antibody fragment binds tightly to the GpIIb-IIIa receptor, the effective
physiological half-life of platelet inhibition is relatively long (approximately
12 hours). Eptifibatide (Integrilin) is a synthetic cyclic heptapeptide.11 Tirofiban hydrochloride (Aggrastat) is a nonpeptide
mimetic.12 Eptifibatide and tirofiban are competitive
inhibitors of the GpIIb-IIIa receptor. The half-lives of the smaller molecules
eptifibatide and tirofiban, which are predominantly renally cleared, are on
the order of 90 to 120 minutes. Because these smaller molecules are predominantly
renally cleared, the dose of these agents should be adjusted in patients with
renal insufficiency.
At currently used doses, the GpIIb-IIIa receptors are able to inhibit
platelet aggregation on the order of at least 80%.13
The contraindications to GpIIb-IIIa inhibitor use are primarily related to
bleeding risks, and are, in general terms, comparable to those of thrombolytic
therapy. Patients with platelet counts of less than 100x109/L
should not be treated with these agents.
Most trials of the GpIIb-IIIa inhibitors have been performed in the
setting of patients undergoing percutaneous revascularization. Several studies,
however, have focused on the use of GpIIb-IIIa inhibitors as the initial or
primary therapy in patients with non–ST-segment elevation acute coronary
syndromes. Inclusion criteria for these trials generally consisted of the
presence of (1) ischemic ST-segment depression, (2) transient and/or minor
(<1 mm) ST-segment elevation, (3) ischemic T-wave inversions, or (4) elevated
levels of creatine phosphokinase of muscle band (CPK-MB levels) on admission.
In the Platelet Receptor Inhibition in Ischemic Syndrome Management
in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) study,14 patients with non–ST-segment elevation acute
coronary syndromes were initially treated with heparin alone, tirofiban alone,
or tirofiban plus heparin for 48 hours before undergoing cardiac catheterization
and, when appropriate, revascularization. The tirofiban-alone arm was terminated
prematurely due to an excess of deaths compared with the heparin-alone arm.
The primary composite end point of death, MI, or refractory ischemia at 7
days was lower in those treated with tirofiban plus heparin compared with
those treated with heparin alone (12.9% vs 17.9%; P
= .004). Most of this benefit was maintained at the 30-day and 6-month follow-ups.14
In the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppresion
Using Integrilin Therapy (PURSUIT) study,15
almost 11 000 patients with non–ST-segment elevation acute coronary
syndromes were randomized to treatment with eptifibatide (Integrilin) or placebo;
heparin therapy was encouraged but not mandated. Patients could be treated
medically alone, or could undergo subsequent cardiac catheterization and revascularization
at the discretion of their physicians. Most patients in the study were treated
solely with medical therapy. Overall, the primary composite end point of death
or MI at 30 days occurred in fewer patients treated with eptifibatide than
in those who received placebo (14.2% vs 15.7%; P
= .04); in those patients in North America enrolled in PURSUIT, there was
an approximate 22% reduction in death and MI with eptifibatide therapy (11.7%
vs 15.0%). Those patients in PURSUIT who underwent percutaneous revascularization
had the greatest relative reduction in adverse outcome (11.6% vs 16.7%; P = .01).15
In the Chimeric 7E3 Antiplatelet Therapy in Unstable Refractory Angina
(CAPTURE) study of patients with refractory unstable angina who were found
during cardiac catheterization to have lesions amenable to percutaneous transluminal
coronary angioplasty (PTCA) and were then subsequently treated with abciximab
or placebo for 18 to 24 hours before undergoing PTCA, treatment with abciximab
was associated with a lower incidence of adverse outcomes.16
The more general role of abciximab in the treatment of patients with non–ST-segment
elevation acute coronary syndromes is being evaluated as part of the Global
Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IV study.
A fourth intravenously administered GpIIb-IIIa inhibitor, lamifiban,
which has been evaluated as therapy for non–ST-segment acute coronary
syndromes in the Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary
Syndrome Events in a Global Organization Network (PARAGON)–A17 and PARAGON-B18 trials,
has not been shown to be of significant benefit, and is not approved for clinical
use.
Boersma and colleagues19 analyzed the
combined data from the PURSUIT, PRISM-PLUS, and CAPTURE studies, examining
the benefits of GpIIb-IIIa therapy in patients with non–ST-segment elevation
acute coronary syndromes during pharmacological therapy alone and for the
first 48 hours after percutaneous coronary intervention in those patients
who subsequently underwent the procedure. During the period of pharmacological
therapy alone, those patients who received GpIIb-IIIa therapy had a 34% relative
reduction in the incidence of death or nonfatal MI compared with those who
received placebo therapy (absolute event rates, 2.5% and 3.8%, respectively; P<.001). The incidence of death or nonfatal MI during
the first 48 hours after percutaneous coronary intervention in those who subsequently
underwent the procedure was reduced by 41% with GpIIb-IIIa therapy (absolute
rates, 4.9% and 8.0%, respectively; P<.001).19 These findings are illustrated in Figure 4.
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Figure 4. Cumulative incidence of death
or nonfatal myocardial infarction (MI; reinfarction) in patients with non–ST-segment
elevation acute coronary syndromes randomized to treatment with a glycoprotein
IIb/IIIa (GpIIb-IIIa) inhibitor or placebo. From the Platelet Glycoprotein
IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy
(PURSUIT), Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression
Using Integrilin Therapy (PRISM-PLUS), and Chimeric 7E3 Antiplatelet Therapy
in Unstable Refractory Angina (CAPTURE) studies. Adapted with permission from
Boersma et al.19
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Given the overall positive results of trials of intravenous GpIIb-IIIa
inhibitors, and observations that a prothrombotic state may exist for weeks
or even several months after acute ischemic events, it was hypothesized that
postdischarge longer-term treatment with oral GpIIb-IIIa inhibitors would
decrease ischemic events in patients with acute coronary syndromes. Despite
initial encouraging results and high hopes for these trials, the results of
phase 3 studies thus far have been disappointing. Treatment with oral GpIIb-IIIa
inhibitors has been associated with increased rates of bleeding complications
and/or trends toward an increased incidence of adverse ischemic events.20-24
Although the explanation(s) for the disappointing results from these trials
of oral GpIIb-IIIa inhibitors remains speculative,23
a partial explanation may be provided from a substudy of the Oral GpIIb-IIIa
Inhibition With Orbofiban in Patients With Unstable Coronary Syndromes (OPUS)–Thrombin
Inhibition in Myocardial Ischemia (TIMI) 16 trial, in which it was found that
patients treated with the oral GpIIb-IIIa inhibitor orbofiban had a paradoxical
increase in platelet reactivity (perhaps due to ligand-induced receptor activation).25
ANTITHROMBIN AGENTS: UNFRACTIONATED HEPARIN, DIRECT THROMBIN
INHIBITORS, AND LOW-MOLECULAR-WEIGHT HEPARINS
Unfractionated Heparin
Commercial preparations of unfractionated heparin consist of a heterogeneous
mixture of glycosaminoglycans, with molecular weights ranging from approximately
3000 to 30 000. Only about one third of the molecules in these products
are anticoagulantly active. Heparin exerts its anticoagulant effect by interacting
with antithrombin III, dramatically increasing its ability to bind to and
neutralize thrombin and other activated clotting factors. Thrombin that is
already fibrin bound, however, is relatively protected from inactivation by
the heparin–antithrombin III complex.26
In 1981, Telford and Wilson27 demonstrated
that in patients with unstable angina, intravenous administration of unfractionated
heparin reduced the rate of progression to MI from 15% to 3%, a relative reduction
of 80%. In the Montreal Heart Institute trial, the incidence of nonfatal or
fatal MI was reduced by treatment with intravenous heparin therapy from a
rate of 12% in those treated with placebo alone to a rate of only 0.8% in
those treated with heparin alone.4
The role of unfractionated heparin in the treatment of MI in the modern
era is still not well resolved. Individual studies of heparin in the prethrombolytic
era produced inconsistent results.28 An overview
of these studies of heparin therapy for acute MI found that patients who were
not treated with aspirin had an 18% reduction in reinfarction and a 23% reduction
in death; however, in those patients who were also treated with aspirin, the
reductions were on the order of only 5% to 10%.29
The role of adjuvant heparin therapy in patients with acute MI who are
treated with thrombolytic therapy and aspirin is undergoing reevaluation.
The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico
(ISIS-2)6 and ISIS-330
studies included arms in which patients treated with thrombolytic therapy,
most of whom presented with ST-segment elevation, were randomized to adjunctive
subcutaneous heparin sodium therapy (12 500 U twice daily) or no heparin
therapy. When the results of both studies are combined, it appears that subcutaneous
heparin therapy modestly reduces the incidence of in-hospital mortality, although
this benefit is no longer apparent at 5 weeks and is associated with a small
increased risk for bleeding complications.30
In the GUSTO-1 trial, in patients treated with streptokinase, there were no
significant differences in 90-minute coronary artery patency or mortality
between those treated with subcutaneous heparin and those treated with intravenous
heparin.31-32
Although in patients treated with tissue plasminogen-activator (tPA),
intravenous heparin does not appear to improve early vessel patency when assessed
angiographically 90 minutes after administration of the thrombolytic agent,
it may have a role in maintaining vessel patency in the 1 to 4 days after
tPA administration.28 An overview of randomized
trials involving intravenous heparin therapy, however, did not detect any
significant effects of heparin therapy on rates or recurrent ischemia, reinfarction,
or mortality.33
The dosing recommendations for intravenous heparin administration in
patients treated with tPA has recently been revised by the American College
of Cardiology–American Heart Association (ACC/AHA) Committee on Management
of Acute Myocardial Infarction. These recommendations now call for even less
aggressive heparin administration, with a bolus dose of 60 U/kg (maximum,
4000 U) at the initiation of tPA infusion and an initial maintenance infusion
of approximately 12 U/kg per hour (maximum, 1000 U/h), subsequently adjusted
as needed to a target activated partial thromboplastin time (aPTT) of 1.5
to 2.0 times control (50-70 seconds).9 Although
not specifically addressed in the Committee recommendations, it may be reasonable
to extrapolate this heparin dosing regimen to patients treated with reteplase
(r-PA) (and possibly tenecteplase [TNK-tPA]).
Direct Thrombin Inhibitors
As their name implies, the direct thrombin inhibitors can inactivate
thrombin directly, without the need for antithrombin III. The prototype of
the direct thrombin inhibitors is hirudin, a 65-amino acid polypeptitde originally
isolated from the saliva of the medicinal leech (but now produced by recombinant
DNA technology). Bivalirudin (Hirulog) is a synthetic 20–amino acid
polypeptide.
The introduction of direct thrombin inhibitors was accompanied by high
hopes that these agents would prove superior to unfractionated heparin in
the treatment of acute ischemic heart disease. Unlike unfractionated heparin,
direct thrombin inhibitors do not require any cofactors, can neutralize clot-bound
thrombin, and are not inactivated by plasma proteins or platelet factor 4.34-35 They also may provide a more reliable
degree of anticoagulation and enhance the rate of thrombolysis with thrombolytic
therapy better than unfractionated heparin.34-35
Early, generally modest-sized studies of these agents in patients who were
and were not treated with thrombolytic therapy suggested that the direct thrombin
inhibitors were safe, led to dose-dependent and therapeutic degrees of anticoagulation,
improved angiographic findings and TIMI grade coronary arterial flow, and
were associated with low rates of adverse outcomes.36-44
Several larger trials subsequently compared hirudin with unfractionated
heparin in patients with non–ST-segment elevation acute coronary syndromes.
As part of the GUSTO IIb Study, more than 8000 patients were randomized to
treatment with hirudin or unfractionated heparin. The primary end point of
death or MI at 30 days was not notably different between treatment groups
(8.3% vs 9.1%; P = .22).45
In the Organization to Assess Strategies for Ischemic Syndromes (OASIS)–1
pilot study, the combined end point of death, MI, or refractory angina occurred
in 4.4% of patients treated with low-dose hirudin (0.2-mg/kg bolus, then 0.1-mg/kg
per hour infusion), 3.0% of patients treated with moderate-dose hirudin (0.4-mg/kg
bolus, then 0.15-mg/kg per hour infusion) and 6.5% of patients treated with
unfractionated heparin.46 Based on these findings,
in OASIS-2, more than 10 000 patients were randomized to treatment with
this moderate dose regimen of hirudin or unfractionated heparin. The primary
end point of death or new MI at 7 days occurred in 3.6% of those treated with
hirudin and 4.2% of those treated with heparin (P
= .08). The composite end point of death, myocardial infraction, or refractory
angina occurred in 5.6% of those treated with hirudin and 6.7% of those treated
with heparin (P = .01). These results are shown in Figure 5. Major bleeding was more common
with hirudin, although the number of life-threatening episodes and hemorrhagic
strokes were similar.47 Pooled analysis of
GUSTO IIb, OASIS-1, and OASIS-2, shown in Figure 6, demonstrates that at 72 hours the risk for death due to
MI in patients with non–ST-segment acute coronary syndromes is reduced
by 28% with hirudin therapy, although some of this early benefit is no longer
present by day 35.47
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Figure 5. Results of the Organisation to
Assess Strategies for Ischemic Syndromes (OASIS)–2 study comparing hirudin
with unfractionated heparin sodium therapy in patients with acute coronary
syndromes. MI indicates myocardial infarction. Adapted with permission from
OASIS Investigators.47
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Figure 6. Combined results from the Global
Use of Strategies to Open Occluded Coronary Arteries IIb, Organisation to
Assess Strategies for Ischemic Syndromes (OASIS)–1, and OASIS-2 studies
comparing hirudin therapy with unfractionated heparin sodium therapy in patients
with acute coronary syndromes. RR indicates relative risk. Adapted with permission
from OASIS-2 Investigators.47
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Several recent, generally larger, trials have also evaluated the utility
of direct thrombin inhibitors as adjunctive therapy in patients with ST-segment
elevation treated with thrombolytic therapy. In the TIMI 9A,48
GUSTO IIA,49 and Hirudin for Improvement of
Thrombolysis–III50 trials, the use of
relatively high doses of hirudin was associated with unacceptably high rates
of intracranial bleeding. The TIMI and GUSTO trials were reconfigured (and
were designated TIMI 9B and GUSTO IIb), and compared lower doses of hirudin
and unfractionated heparin. In the TIMI 9B trial, the composite primary end
point occurred in 12.9% of hirudin-treated patients and 11.9% of heparin-treated
patients (P = NS).51
In the GUSTO IIb trial, death or MI at 30 days occurred in 9.9% of those treated
with hirudin and 11.3% of those treated with heparin (P = .06). Taken together, the TIMI 9B and GUSTO IIb findings suggest
little if any benefit of routinely using hirudin over unfractionated heparin
as an adjunctive therapy in patients treated with thrombolytic therapy and
aspirin.
Preliminary studies of other direct thrombin inhibitors as adjunctive
therapy in patients treated with thrombolytic agents have so far produced
mixed results.52-55
The Hirulog and Early Reperfusion/Occlusion (HERO)–2 trial is currently
assessing clinical end points in 17 000 patients treated with streptokinase
randomized to adjunctive bivalirudin or heparin therapy.56
Low-Molecular-Weight Heparin
Low-molecular-weight heparins are derived from enzymatic or chemical
cleavage of unfractionated heparin (Figure
7). The potential advantages of low-molecular-weight heparins (LMWHs)
have made them attractive subjects for study in acute coronary syndromes.
Compared with unfractionated heparin, the LMWHs have less nonspecific binding,
greater resistance to inactivation by platelet factor 4, greater anti–factor
Xa activity (leading to greater "upstream" inhibition of the coagulation cascade),
greater inhibition of thrombin generation, longer half-lives, and a more reliable
anticoagulation effect (Figure 8).58-59 In addition, the LMWHs can be administered
subcutaneously and require no monitoring of the aPTT.
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Figure 7. The low-molecular-weight heparins
(LMWH) are produced from chemical or enzymatic degradation and cleavage of
unfractionated heparin. Methods of cleavage and isolation vary for different
commercially produced LMWHs. Adapted with permission from Fareed et al.57
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Figure 8. Percentage of composition of unfractionated
and low-molecular-weight heparin (LMWH) in terms of molecular weight. The
3 LMWHs that have been evaluated in clinical trials of acute coronary syndromes
are shown, along with their respective anti–factor Xa/anti–factor
IIa activity. The LMWHs have relatively greater anti–factor Xa activity,
resistance to inactivation from platelet factor 4 (PF4), less nonspecific
binding, and greater inhibition of thrombin generation. Based on data from
Weitz,59 Zed et al,60
and Antman and Handin.58
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The incidence of heparin-induced thrombocytopenia is much lower with
LMWH than with unfractionated heparin.61-62
However, it should be noted that LMWH should not be administered to patients
with established heparin-induced thrombocytopenia because of a high degree
of cross-reactivity with the antibody associated with unfractionated heparin–induced
thrombocytopenia (a direct thrombin inhibitor or danaparoid sodium should
be used instead in such patients).59
Clinical studies of these agents have produced agent-dependent results
(Table 1). Two studies of enoxaparin
sodium (Lovenox) have determined that treatment with this LMWH may be superior
to treatment with unfractionated heparin in patients with non–ST-segment
elevation acute coronary syndromes. In the Efficacy and Safety of Subcutaneous
Enoxaparin in Non–Q-Wave Coronary Events (ESSENCE) study, the 14-day
incidence of the combined end point of death, MI, or recurrent angina was
lower in patients treated with subcutaneous enoxaparin sodium (1 mg/kg every
12 hours) than with intravenous unfractionated heparin sodium (16.6% vs 19.8%).62 The TIMI 11B study also found that treatment with
enoxaparin sodium (30-mg intravenous bolus then 1 mg/kg subcutaneously every
12 hours) was superior to treatment with intravenous heparin in reducing the
14-day composite end point of death, MI, or need for urgent revascularization
(14.2% vs 16.7%).63 Meta-analysis of these
2 trials showed an approximate 20% reduction in death and cardiac ischemic
events with enoxaparin therapy (Figure 9).67 An economic analysis of the ESSENCE data, shown in Figure 10, found treatment with enoxaparin
to be cost-effective.
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Results of Studies Comparing LMWHs With Unfractionated Heparin in Patients
With Non-ST-Segment Elevation Acute Coronary Syndromes*
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Figure 9. Individual and combined results
from the Thrombin Inhibition in Myocardial Infarction (TIMI) 11B and Efficacy
and Safety of Subcutaneous Enoxaparin in Non–Q-Wave Coronary Events
(ESSENCE) studies comparing enoxaparin sodium (Lovenox) and unfractionated
heparin in the treatment of patients with acute coronary syndromes. Results
are shown for follow-up days 8, 14, and 43. Based on data from Antman et al.67 Figure provided courtesy of Elliott M. Antman, MD.
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Figure 10. Economic analyses from the Efficacy
and Safety of Subcutaneous Enoxaparin in Non–Q-Wave Coronary Events
study comparing resource use and costs in patients with acute coronary syndromes
treated with enoxaparin sodium (Lovenox) or unfractionated heparin. Cath indicates
coronary catheterization; PTCA, percutaneous transluminal coronary angioplasty;
CABG, coronary artery bypass graft; ICU, intensive care unit; and MD, physician.
Data from Mark et al.68
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Although an earlier small study by Gurfinkel and colleagues64 found that treatment with nadroparin calcium (Fraxiparine)
resulted in lower incidences of adverse events than treatment with placebo
or intravenous unfractionated heparin, results from the larger Fraxiparine
in Ischaemic Syndrome (FRAXIS) study demonstrate that outcome may be worse
with nadroparin therapy when compared with intravenous unfractionated heparin
therapy.65 In the Fragmin During Instability
in Coronary Artery Disease (FRIC) study, treatment with dalteparin sodium
(Fragmin) proved no better than that with unfractionated heparin, and in fact
there were more deaths in those treated with dalteparin.66
Studies of postdischarge, longer-duration LMWH therapy in patients with
acute coronary syndromes have been generally discouraging.63, 66, 69
Despite the theoretical benefits of continuing antithrombin therapy for 1
to several months after discharge, no clinical trial has demonstrated a statistically
significant benefit for such routine outpatient therapy in patients with non–ST-segment
elevation acute coronary syndromes.
THROMBOLYTIC (FIBRINOLYTIC) THERAPY
The thrombolytic (fibrinolytic) agents convert inactive plasminogen
to active plasmin. Plasmin in turn acts to degrade fibrin, although plasmin
is relatively substrate nonspecific and can degrade other proteins, including
fibrinogen. The earliest thrombolytic agent tested in clinical trials, streptokinase,
was not fibrin specific or clot specific, meaning that it would lead to indiscriminate
systemic plasmin production, a situation that could lead to a systemic lytic
state. The newer thrombolytic agents, beginning with the tPA alteplase and
now including reteplase (r-PA) and tenecteplase (TNK-tPA), were designed to
be more fibrin specific or clot specific, meaning that they would generate
plasmin preferentially at the fibrin surface in a preformed thrombus, in the
hopes that this would decrease bleeding complications (a hope that was not
found to be the case). The longer half-lives of the next-generation thrombolytic
agents, reteplase (r-PA) and tenecteplase (TNK-tPA), allow them to be administered
as bolus therapy.
Thrombolytic Therapy in Non–ST-Segment Elevation Acute Coronary
Syndromes
Pathological, angiographic, and angioscopic studies performed during
the 1980s demonstrated that intracoronary thrombus was a common finding in
patients with unstable angina.70-74
This finding led to the hypothesis that thrombolytic therapy would be of benefit
in reducing adverse outcomes in patients with unstable angina. Early angiographic
and clinical studies produced conflicting results.73, 75-83
These trials found that MI developed in a greater percentage of patients treated
with thrombolytic therapy than in those who were treated with heparin alone.84
As part of the TIMI 3B trial, 1473 patients with unstable angina or
non–Q-wave MI were randomized to treatment with tPA or placebo. All
patients were treated with aspirin and intravenous heparin. The composite
primary end point of death, MI, or spontaneous recurrent or inducible ischemia
occurred in a similar percentage of the tPA- and placebo-treated patients
(54.2% and 55.5%, respectively).
The Fibrinolytics Therapy Trialists' Collaborative Group reviewed the
data from all large trials of thrombolytic therapy in suspected acute MI.
In patients who presented with ST-segment depression or with nonspecific ECG
abnormalities, there was no benefit with thrombolytic therapy (Figure 11). If fact, those who presented with ST-segment depression
actually tended to worsen if treated with thrombolytic therapy.85
Taken as a whole, analyses of studies in which thrombolytic therapy was administered
to patients with non–ST-segment elevation acute coronary syndromes (unstable
angina or non–ST-segment elevation MI) demonstrate that thrombolytic
therapy leads to no net benefit and may actually increase the incidence of
subsequent MI and death in such patients.
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Figure 11. Benefits in terms of lives saved
per thousand patients with acute myocardial infarction treated with thrombolytic
therapy in terms of time from chest pain onset to treatment (A) and electrocardiographic
abnormality (B). BBB indicates bundle-branch block. Data from Fibrinolytic
Therapy Trialists' Collaborative Group.85
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Thrombolytic Therapy in ST-Segment Elevation MI
The role of thrombolytic therapy in patients who present with ST-segment
elevation MI has been demonstrated repeatedly and definitively. Studies comparing
thrombolytic therapy with placebo have consistently shown a statistically
and clinically significant reduction (usually on the order of 25%-33%) in
mortality with thrombolytic therapy. Although initial studies relied on intracoronary
administration of the thrombolytic agent, later studies demonstrated that
the more practical intravenous administration of these agents was also efficacious.
Thrombolytic agents that have been shown in placebo-controlled landmark studies
to be efficacious include streptokinase (GISSI-1, Intravenous Streptokinase
in Acute Myocardial Infarction [ISAM], and ISIS-2), anistreplase (APSAC [anisoylated
plasminogen streptokinase activator complex] Intervention Mortality Study
[AIMS]), and tPA (Anglo-Scandinavian Study of Early Thrombolysis [ASSET],
Estudio Multicentrico Estreptoquinasa Republicas de America del Sur [EMERAS],86 and Late Assessment of Thrombolytic Efficacy [LATE]87).85
The relative benefit of thrombolytic treatment in terms of lives saved
per 1000 patients treated based on time to treatment from chest pain onset
and initial ECG findings are shown in Figure
11. Patients who are treated within several hours of chest pain
onset derive the greatest benefit.85
As most earlier trials of thrombolytic therapy had enrolled patients
who could be treated within 6 hours of chest pain onset, 2 trials addressed
whether treatment of patients who presented later than 6 hours after chest
pain onset could also derive benefit. In the EMERAS trial, which compared
streptokinase with placebo, there was a trend toward decreased mortality in
those treated 7 to 12 hours after symptom onset (11.7% vs 13.2%).86 In the LATE study, which compared tPA with placebo,
there was a statistically significant 25.6% reduction in mortality in those
who were treated 6 to 12 hours after chest pain onset.87
These 2 trials,86-87 as well as
another analysis,85 provided data that extended
the therapeutic window for thrombolytic therapy to 12 hours.
Among patients with ECG findings of ST-segment elevation, those with
ST-segment elevation in the anterior leads derive the greatest benefit. Those
with inferior ST-segment elevation derive a more modest but still clinically
important reduction in mortality.85 Selected
patients who present with symptoms highly suggestive of acute MI and ECG findings
demonstrating bundle-branch block obscuring ST-segment analysis also derive
significant benefit from thrombolytic therapy.85, 88
In particular, those found to have a left bundle-branch block that is known
or presumed to be new derive great benefit from thrombolytic therapy. The
benefits of thrombolytic therapy based on time to treatment and on ECG findings
are shown in Figure 11.
Several large trials have been performed comparing the relative efficacy
of different thrombolytic agents. In the GISSI-289
and ISIS-330 trials, no significant differences
in efficacy were found between streptokinase and tPA. However, proponents
of tPA have noted that in these trials, heparin was administered subcutaneously
(not intravenously) and was only started 4 to 12 hours after thrombolytic
administration. In the first GUSTO trial, there was a statistically significant
lower mortality rate in those treated with tPA and intravenous heparin therapy
(started at the time of thrombolytic therapy) compared with those treated
with streptokinase and intravenous or subcutaneous heparin (6.3% with tPA
vs 7.3% with streptokinase; P = .001).32
In these trials, tPA was associated with a small increased risk for intracranial
hemorrhage compared with treatment with streptokinase.
The GUSTO-III trial compared tPA with the newer recombinant plasminogen
activator (reteplase [r-PA]), which is administered in two 10-mg boluses given
30 minutes apart. There were no statistically significant differences in 30-day
mortality, overall stroke rates, or combined end points between agents.90 In the Assessment of the Safety and Efficacy of a
New Thrombolytic (ASSENT)–2 trial including almost 17 000 patients
with acute MI, tPA therapy was compared with another newer plasminogen activator,
tenecteplase (TNK-tPA), a modified form of tPA that can be administered as
a single bolus (30-50 mg, based on weight). Compared with tPA, tenecteplase
(TNK-tPA) has slower plasma clearance, better fibrin specificity, and higher
resistance to plasminogen-activator inhibitor-1. The 30-day mortality rate
and the rate of intracranial hemorrhage, however, were similar with tPA and
tenecteplase (TNK-tPA).91
Decisions about whether to use tPA or streptokinase can be based to
some extent on such factors as relative mortality reductions, intracranial
hemorrhage risk, and cost (tPA is approximately 10 times more expensive than
streptokinase). It has been proposed that tPA be preferentially considered
in patients who present early after symptom onset with a large area of myocardium
in jeopardy (eg, large anterior MI) and low risk for intracranial hemorrhage,
whereas streptokinase be considered in those with less potential for mortality
benefit and greater risk for intracranial hemorrhage.88
The newer thrombolytic agents reteplase (r-PA) and tenecteplase (TNK-tPA)
appear to have similar overall efficacy compared with tPA; however, these
newer agents are more easily administered and present the potential to treat
selected patients with ST-segment elevation myocardial infraction before arrival
in the emergency department.
COMBINATION ANTITHROMBOTIC THERAPY
The demonstrated efficacy of newer antithrombotic agents has led investigators
to begin exploring the use of these newer agents in combination with thrombolytic
therapy.
As LMWHs and platelet GpIIb-IIIa inhibitors have been shown to be of
benefit in patients with non–ST-segment elevation MI, investigators
have begun to explore using these medications in combination. Recent preliminary
observational data, presented by James J. Ferguson III, MD, at the European
Society of Cardiology,92 suggested that the
combination of the LMWH enoxaparin and a platelet GpIIb-IIIa inhibitor was
safe and associated with a very low incidence of major adverse cardiac events
(James J. Ferguson III, MD, written communication, November 1, 2000).
Preliminary studies in patients with ST-segment elevation MI suggest
that the combination of GpIIb-IIIa receptor inhibition with modified doses
of thrombolytic agents can lead to a greater incidence of normal coronary
blood flow (TIMI 3 flow) as assessed using 60- to 90-minute angiograms than
with that achieved with thrombolytic therapy alone.93-95
Normal coronary blood flow in the culprit coronary artery, as assessed using
90-minute angiography, is restored with thrombolytic therapy alone in approximately
50% to 55% of treated patients, whereas these preliminary results have found
that combining GpIIb-IIIa therapy with half-dose thrombolytic therapy can
result in restoration of normal blood flow in approximately 70% to 75% of
treated patients.93, 96-97
In general, results of combination therapy have been better with tPA or reteplase
(r-PA) than with streptokinase, as therapy with streptokinase has resulted
in lower rates of normal coronary blood flow and a greater incidence of bleeding
complications.93-95,98
The results of larger trials of combination GpIIb-IIIa and thrombolytic therapy,
including GUSTO IV–Acute Myocardial Infarction (AMI) (abciximab + half-dose
reteplase [r-PA]), Integrilin and Tenecteplase in Acute Myocardial Infartion
(INTEGRITI)–TIMI 20 (eptifibatide + half-dose tenecteplase [TNK-tPA]),
and Fibrinolytic and Aggrastat ST Elevation Resolution (FASTER)–TIMI
24 (tirofiban + half-dose tenecteplase [TNK-tPA]), should become available
shortly, and could have a significant impact on our understanding of optimal
treatment of patients with acute MI (Herbert B. Lee, PhD, written communication,
March 3, 2000).
Preliminary data presented at the 2000 Meeting of the American College
of Cardiology from theHeparin Aspirin Reperfusion Trial (HART)–II study
assessing the utility of enoxaparin as antithrombin therapy in patients with
ST-segment elevation MI treated with accelerated tPA demonstrated trends toward
greater 90-minute normal coronary blood flow in the infarct-related artery
and lower reocclusion rates in patients who received enoxaparin compared with
those who were treated with standard unfractionated heparin.
The Enoxaparin and TNK-tPA With or Without GP-IIb/IIIa Inhibitor as
Reperfusion Strategy in ST Elevation MI (ENTIRE)–TIMI 23 trial will
help tie together advances in antiplatelet, antithrombin, and thrombolytic
therapy, and will compare treatment with tenecteplase (TNK-tPA) and unfractionated
heparin or enoxaparin with therapy with tenecteplase (TNK-tPA) plus abciximab
and unfractionated heparin or enoxaparin.
RECOMMENDATIONS
Clinical studies now provide a wealth of information to guide treatment
in patients with acute coronary syndromes. Planned and ongoing studies should
help serve to further refine and define these recommendations.
Non–ST-Segment Acute Coronary Syndromes
All patients who present with unstable angina or non–ST-segment
MI (non–Q-wave MI) should be treated with aspirin. Although there is
scant clinical data, it seems reasonable to treat those with true aspirin
allergies with clopidogrel or ticlopidine. Patients who present with ST-segment
depression, transient ST-segment elevation, ischemic T-wave inversion, and/or
positive cardiac enzymes and without contraindications should be strongly
considered for additional antiplatelet therapy with a GpIIb-IIIa inhibitor.
All patients without bleeding contraindications should be treated with
antithrombin therapy. In those patients treated with unfractionated heparin,
a weight-adjusted dosing regimen should be used, with an initial 80-U/kg bolus
followed by an initial maintenance infusion dose of 18 U/kg, subsequently
adjusted to maintain the aPTT at 1.5 to 2.5 times control. The direct thrombin
inhibitor hirudin (possibly at a dose of a 0.4-mg/kg bolus then an initial
infusion dose of 0.15 mg/kg per hour, subsequently adjusted to an aPTT level
at 1.5-2.5 times control) can be considered instead of intravenous unfractionated
heparin. Higher-risk patients (those with ischemic ECG abnormalities or positive
CPK-MB or troponin levels) should be treated preferentially with enoxaparin
(Lovenox). It may be reasonable to treat all patients with non–ST-elevation
acute coronary syndrome preferentially with such an LMWH, given other advantages
including patient comfort, ease of administration, and the fact that aPTT
levels do not need to be monitored.
Thrombolytic therapy in patients with non–ST-segment elevation
acute coronary syndromes is of no benefit (and indeed may be harmful) and
should not be used.
ST-Segment Elevation MI
All patients with ST-segment elevation MI (as well as those with bundle-branch
block obscuring ST-segment evaluation) should be treated with aspirin. No
clinical data exist as to whether thienopyridines should be administered to
those with true aspirin allergies, although this seems to be a reasonable
approach.
In current practice, patients with ST-segment elevation and treated
with tPA as well as reteplase (r-PA) (and tenecteplase [TNK-tPA] when approved)
are treated with unfractionated heparin also; studies of tenecteplase (TNK-tPA)
have also used intravenous heparin therapy. The recommended dose of heparin
sodium in patients treated with tPA has recently revised to a gentler dosing
regimen of an initial bolus dose of 60 U/kg (up to a maximum dose of 4000
U) at the initiation of tPA infusion and an initial maintenance infusion of
approximately 12 U/kg per hour (maximum, 1000 U/h), subsequently adjusted
to a target aPTT of 1.5 to 2.0 times control (50-70 seconds). It seems reasonable
to extrapolate this recommendation to patients treated with reteplase (r-PA)
or tenecteplase (TNK-tPA). The routine use of heparin in patients treated
with streptokinase is not recommended (although the use of heparin may be
appropriate in such patients for other indications). No data recommend the
direct thrombin inhibitor hirudin compared with unfractionated heparin in
patients treated with thrombolytic therapy; results of the HERO-2 study may
help to determine whether there is an adjunctive role for bivalirudin (Hirulog)
in patients treated with streptokinase. Low-molecular-weight heparin therapy
in patients treated with thrombolytic agents appears promising, but further
study is necessary before its use in this setting can be recommended.
Although preliminary studies combining GpIIb-IIIa inhibitors with half-dose
thrombolytic therapy are encouraging, such therapy cannot at present be recommended
outside the setting of clinical trials, pending the results of planned and
ongoing studies evaluating this combination therapy.
AUTHOR INFORMATION
Accepted for publication November 21, 2000.
We thank Elliott M. Antman, MD, for creating and providing Figure 9.
Corresponding author and reprints: Glenn N. Levine, MD, Section of
Cardiology 3C-330, Houston VA Medical Center (111b), 2002 Holcombe Blvd, Houston,
TX 77030 (e-mail: glevine{at}bcm.tmc.edu).
From the Department of Medicine, Baylor College of Medicine (Drs Levine,
Ali, and Schafer), the Section of Cardiology, Houston Veterans Administration
Medical Center (Drs Levine and Ali), and Methodist Hospital (Dr Schafer),
Houston, Tex. Dr Levine has received monetary compensation for speaking engagements
on behalf of several pharmaceutical companies, including Cor/Key, which markets
eptifibatide (Integrilin), and Aventis, which markets enoxaparin sodium (Lovenox).
Dr Ali has received monetary compensation for speaking engagements on behalf
of several pharmaceutical companies, including Merck & Co, Inc, which
markets tirofiban hydrochloride (Aggrastat), and Aventis.
REFERENCES
| |
1. Dabaghi SF, Kamat SG, Payne J, et al. Effects of low-dose aspirin on in vitro platelet aggregation in the
early minutes after ingestion in normal subjects. Am J Cardiol. 1994;74:720-723.
FULL TEXT
|
ISI
| PUBMED
2. Lewis HD, Davis JW, Archibald DG, et al. Protective effects of aspirin against acute myocardial infarction and
death in men with unstable angina: results of a Veterans Administration Cooperative
Study. N Engl J Med. 1983;309:396-403.
ABSTRACT
3. Cairns JA, Gent M, Singer J, et al. Aspirin, sulfinpyrazone, or both in unstable angina. N Engl J Med. 1985;313:1369-1375.
ABSTRACT
4. Theroux P, Ouimet H, McCans J, et al. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med. 1988;319:1105-1111.
ABSTRACT
5. The RISC Group. Risk of myocardial infarction and death during treatment with low dose
aspirin and intravenous heparin in men with unstable coronary artery disease. Lancet. 1990;336:827-830.
FULL TEXT
|
ISI
| PUBMED
6. ISIS-2 (Second International Study of Infarct Survival) Collaborative
Group. Randomized trial of intravenous streptokinase, oral aspirin, both,
or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet. 1988;2:349-360.
PUBMED
7. Sharis PJ, Cannon CP, Loscalzo J. The antiplatelet effects of ticlopidine and clopidogrel. Ann Intern Med. 1998;129:394-405.
FREE FULL TEXT
8. Balsano F, Paolo P, Violi F, et al. Antiplatelet treatment with ticlopidine in unstable angina. Circulation. 1990;82:17-26.
FREE FULL TEXT
9. Ryan TJ, Antman EM, Brooks NH, et al. 1999 update: ACC/AHA guidelines for the management of patients with
acute myocardial infarction: a report of the American College of Cardiology/American
Heart Association Task Force on Practice Guidelines (Committee on Management
of Acute Myocardial Infarction). J Am Coll Cardiol. 1999;34:890-911.
FREE FULL TEXT
10. Jordon RE, Mascelli MA, Nakada MT, et al. Pharmacology and clinical development of abciximab (c7E3 Fab, ReoPro). In: Sasahara AA, Loscalzo J, eds. Near Therapeutic
Agents in Thrombosis and Thrombolysis. New York, NY: Marcel Dekker
Inc; 1977:291-313.
11. Goa KL, Noble S. Eptifibatide: a review of its use in patients with acute coronary syndromes
and/or undergoing percutaneous coronary intervention. Drugs. 1999;57:439-462.
FULL TEXT
|
ISI
| PUBMED
12. Schafer AI. Antiplatelet therapy with glycoprotein IIb/IIIa receptor inhibitors
and other novel agents. Tex Heart Inst J. 1997;24:90-96.
ISI
| PUBMED
13. Keriakes DJ, Broderick TM, Roth EM. Time course, magnitude, and consistency of platelet inhibition by abciximab,
tirofiban, or eptifibatide in patients with unstable angina pectoris undergoing
percutaneous coronary intervention. Am J Cardiol. 1999;84:391-395.
FULL TEXT
|
ISI
| PUBMED
14. PRISM-PLUS Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban
in unstable angina and non–Q-wave myocardial infarction: platelet receptor
inhibition in ischemic syndrome management in patients limited by unstable
signs and symptoms. N Engl J Med. 1998;338:1488-1497.
FREE FULL TEXT
15. PURSUIT Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients
with acute coronary syndromes: Platelet Glycoprotein IIb/IIIa in Unstable
Angina: Receptor Suppression Using Integrilin Therapy. N Engl J Med. 1998;339:436-443.
FREE FULL TEXT
16. CAPTURE Investigators. Randomised placebo-controlled trial of abciximab before and during
coronary intervention in refractory unstable angina: the CAPTURE Study. Lancet. 1997;349:1429-1435.
FULL TEXT
|
ISI
| PUBMED
17. PARAGON Investigators. International, randomized, controlled trial of lamifiban (a platelet
glycoprotein IIb/IIIa inhibitor), heparin, or both in unstable angina. Circulation. 1998;97:2386-2395.
FREE FULL TEXT
18. Harrington RA. PARAGON-B Results. Paper presented at: 49th Annual Scientific Session of the American
College of Cardiology; March 10, 2000; Anaheim, Calif.
19. Boersma E, Akkerhuis M, Theroux P, et al. Platelet glycoprotein IIb/IIIa receptor inhibition in non–ST-elevation
acute coronary syndromes: early benefit during medical treatment only, with
additional protection during percutaneous coronary intervention. Circulation. 1999;100:2045-2048.
FREE FULL TEXT
20. The SYMPHONY Investigators. Comparison of sibrafiban with aspirin for prevention of cardiovascular
events after acute coronary syndromes: a randomised trial. Lancet. 2000;355:337-345.
FULL TEXT
|
ISI
| PUBMED
21. O'Neill WW for the EXCITE Investigators. Efficacy and safety of xemilofiban, an oral IIb/IIIa platelet inhibitor,
in patients undergoing PTCA or stent placement. Paper presented at: 48th Annual Scientific Session of the American
College of Cardiology; March 8, 1999; New Orleans, La.
22. Cannon CP. Orbofiban in patients with unstable coronary syndromes. Paper presented at: 48th Annual Scientific Session of the American
College of Cardiology; March 10, 1999; New Orleans, La.
23. Heeschen C, Hamm CW. Difficulties with oral platelet glycoprotein IIb/IIIa receptor antagonists. Lancet. 2000;355:330-331.
FULL TEXT
|
ISI
| PUBMED
24. Newby LK. SYMPHONY-2 Results. Paper presented at: 49th Annual Scientific Session of the American
College of Cardiology; March 10, 2000; Anaheim, Calif.
25. Holmes MB, Sobel BE, Cannon CP, Schneider DJ. Increased platelet reactivity in patients given orbofiban after an
acute coronary syndrome: an OPUS-TIMI 16 substudy. Am J Cardiol. 2000;85:491-493.
FULL TEXT
|
ISI
| PUBMED
26. Hirsh J, Warkentin TE, Raschke R, et al. Heparin and low-molecular-weight heparin. Chest. 1998;114(suppl):489S-510S.
27. Telford AM, Wilson C. Trial of heparin versus atenolol in prevention of myocardial infarction
in intermediate coronary syndrome. Lancet. 1981;1:1225-1228.
ISI
| PUBMED
28. Levine GN, Stein B, Ali MN. Antithrombotic therapy in cardiovascular disease. In: Loscalzo J, Schafer AI, eds. Thrombosis and
Hemorrhage. Baltimore, Md: Williams & Wilkins; 1998:1309-1336.
29. Collins R, Peto R, Baigent C, Sleight P. Aspirin, heparin, and fibrinolytic therapy in suspected acute myocardial
infarction. N Engl J Med. 1997;336:847-860.
FREE FULL TEXT
30. ISIS-3 (Third International Study of Infarct Survival) Collaborative
Group. ISIS-3: a randomised comparison of streptokinase vs tissue plasminogen
activator vs anistreplase and of aspirin plus heparin vs aspirin alone among
41,299 cases of suspected acute myocardial infarction. Lancet. 1992;339:753-770.
ISI
| PUBMED
31. The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both
on coronary artery patency, ventricular function, and survival after acute
myocardial infarction. N Engl J Med. 1993;329:1615-1622.
FREE FULL TEXT
32. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies
for acute myocardial infarction. N Engl J Med. 1993;329:673-682.
FREE FULL TEXT
33. Mahaffey KW, Granger CB, Collins R, et al. Overview of randomized trials of intravenous heparin in patients with
acute myocardial infarction treated with thrombolytic therapy. Am J Cardiol. 1996;77:551-556.
FULL TEXT
|
ISI
| PUBMED
34. Cannon CP, Braunwald E. Hirudin: initial results in acute myocardial infarction, unstable angina
and angioplasty. J Am Coll Cardiol. 1995;25(suppl 7):30S-37S.
35. Loscalzo J. Thrombin inhibitors in fibrinolysis: a Hobson's choice of alternatives. Circulation. 1996;94:863-865.
FREE FULL TEXT
36. Lidon RM, Theroux P, Juneau M, Adelman B, Maraganore J. Initial experience with a direct antithrombin, Hirulog, in unstable
angina: anticoagulant, antithrombotic, and clinical effects. Circulation. 1993;88:1495-1501.
FREE FULL TEXT
37. Fox KA. r-Hirudin in unstable angina pectoris: rationale and preliminary data
from the APT pilot study. Eur Heart J. 1995;16(suppl D):28-32.
38. Sharma GV, Lapsley D, Vita JA, et al. Usefulness and tolerability of Hirulog, a direct thrombin-inhibitor,
in unstable angina pectoris. Am J Cardiol. 1993;72:1357-1360.
FULL TEXT
|
ISI
| PUBMED
39. Fuchs J, Cannon CP and the TIMI 7 Investigators. Hirulog in the treatment of unstable angina: results of the Thrombin
Inhibition in Myocardial Ischemia (TIMI) 7 Trial. Circulation. 1995;92:727-733.
FREE FULL TEXT
40. Topol EJ, Fuster V, Harrington RA, et al. Recombinant hirudin for unstable angina pectoris: a multicenter, randomized
angiographic trial. Circulation. 1994;89:1557-1566.
FREE FULL TEXT
41. Lidon RM, Theroux P, Lesperance J, et al. A pilot, early angiographic patency study using a direct thrombin inhibitor
as adjunctive therapy to streptokinase in acute myocardial infarction. Circulation. 1994;89:1567-1572.
FREE FULL TEXT
42. Theroux P, Perez-Villa F, Waters D, Lesperance J, Shabani F, Bonan R. Randomized double-blind comparison of two doses of Hirulog with heparin
as adjunctive therapy to streptokinase to promote early patency of the infarct-related
artery in acute myocardial infarction. Circulation. 1995;91:2132-2139.
FREE FULL TEXT
43. Cannon CP, McCabe CH, Henry TD, et al. A pilot trial of recombinant desulfatohirudin compared with heparin
in conjunction with tissue-type plasminogen activator and aspirin for acute
myocardial infarction: results of the Thrombolysis in Myocardial Infarction
(TIMI) 5 trial. J Am Coll Cardiol. 1994;23:993-1003.
ABSTRACT
44. Lee LV. Initial experience with hirudin and streptokinase in acute myocardial
infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) 6
trial. Am J Cardiol. 1995;75:7-13.
FULL TEXT
|
ISI
| PUBMED
45. Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)
IIb Investigators. A comparison of recombinant hirudin with heparin for the treatment
of acute coronary syndromes. N Engl J Med. 1996;335:775-782.
FREE FULL TEXT
46. Organization to Assess Strategies for Ischemic Syndromes (OASIS) Investigators. Comparison of the effects of two doses of recombinant hirudin compared
with heparin in patients with acute myocardial ischemia without ST elevation:
a randomized trial. Circulation. 1997;96:769-777.
FREE FULL TEXT
47. Organisation to Assess Strategies for Ischemic Syndromes (OASIS-2)
Investigators. Effects of recombinant hirudin (lepirudin) compared with heparin of
death, myocardial infarction, refractory angina, and revascularisation procedures
in patients with acute myocardial ischaemia without ST elevation: a randomised
trial. Lancet. 1999;353:429-438.
FULL TEXT
|
ISI
| PUBMED
48. Antman EM for the TIMI 9A investigators. Hirudin in acute myocardial infarction: safety report from the thrombolysis
and thrombin inhibition in myocardial infarction (TIMI) 9A trial. Circulation. 1994;90:1624-1630.
FREE FULL TEXT
49. Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)
IIa Investigators. Randomized trial of intravenous heparin versus recombinant hirudin
for acute coronary syndromes. Circulation. 1994;90:1631-1637.
FREE FULL TEXT
50. Neuhaus KL, von Essen R, Tebbe U, et al. Safety observations from the pilot phase of the randomized r-Hirudin
for Improvement of Thrombolysis (HIT-III) study: a study of the Arbeitsgemeinschaft
Leitender Kardiologischer Krankenhausarzte. Circulation. 1994;90:1638-1642.
FREE FULL TEXT
51. Antman EM for the TIMI 9B Investigators. Hirudin in acute myocardial infarction: Thrombolysis and Thrombin Inhibition
in Myocardial Infarction (TIMI) 9B Trial. Circulation. 1996;94:911-921.
FREE FULL TEXT
52. Ferguson JJ. Meeting highlights: XIX Congress of the European Society of Cardiology. Circulation. 1997;96:3818-3821.
53. Alderman EL. Results from late-breaking clinical trials sessions at ACC '98. J Am Coll Cardiol. 1998;32:1-7.
FREE FULL TEXT
54. Cody RJ. Results from late breaking clinical trials session at ACC '97. J Am Coll Cardiol. 1997;30:1-7.
55. White HD, Aylward PE, Collins R, et al. Randomized, double-blind comparison of Hirulog versus heparin in patients
receiving streptokinase and aspirin for acute myocardial infarction (HERO). Circulation. 1997;96:2155-2161.
FREE FULL TEXT
56. White HD. Direct thrombin inhibition and thrombolytic therapy: rationale for
the Hirulog and Early Reperfusion/Occlusion (HERO-2) trial. Am J Cardiol. 1998;82:57P-62P.
57. Fareed J, Jeske W, Hoppensteadt D, Clarizio R, Walenga JM. Are the available low-molecular-weight heparin preparations the same? Semin Thromb Hemost. 1996;22(suppl 1):77-91.
58. Antman EM, Handin R. Low-molecular-weight heparins: an intriguing new twist with profound
implications. Circulation. 1998;98:287-289.
FREE FULL TEXT
59. Weitz JI. Low-molecular-weight heparins. N Engl J Med. 1997;337:688-698.
FREE FULL TEXT
60. Zed PJ, Tisdate JE, Borzak S. Low-molecular-weight heparins in the management of acute coronary syndromes. Arch Intern Med. 1999;159:1849-1857.
FREE FULL TEXT
61. Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight
heparin or unfractionated heparin. N Engl J Med. 1995;332:1330-1335.
FREE FULL TEXT
62. Cohen M, Demers C, Gurfinkel EP, et al for the Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-Wave
Coronary Events Study Group. A comparison of low-molecular-weight heparin with unfractionated heparin
for unstable coronary artery disease. N Engl J Med. 1997;337:447-452.
FREE FULL TEXT
63. Antman EM, McCabe CH, Gurfinkel EP, et al. 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. Circulation. 1999;100:1593-1601.
FREE FULL TEXT
64. Gurfinkel EP, Eustaquio EJ, Mejail RI, et al. Low molecular weight heparin vs regular heparin or aspirin in the treatment
of unstable angina and silent ischemia. J Am Coll Cardiol. 1995;26:313-318.
ABSTRACT
65. The FRAXIS Study Group. Comparison of two treatment durations (6 days and 14 days) of a low
molecular weight heparin in the initial management of unstable angina or non–Q
wave myocardial infarction: FRAXIX (FRAxiparine in Ischaemic Syndrome). Eur Heart J. 1999;20:1553-1562.
FREE FULL TEXT
66. Klein W, Buchwald A, Hillis SE, et al. Comparison of low-molecular-weight heparin with unfractionated heparin
acutely and with placebo for 6 weeks in the management of unstable coronary
artery disease. Circulation. 1997;96:61-68.
FREE FULL TEXT
67. Antman EM, Cohen M, Radley D, et al. Assessment of the treatment effect of enoxaparin for unstable angina/non–Q-wave
myocardial infarction: TIMI 11B-ESSENCE meta-analysis. Circulation. 1999;100:1602-1608.
FREE FULL TEXT
68. Mark DB, Cowper PA, Berkowitz SD, et al. Economic assessment of low-molecular-weight heparin (enoxaparin) versus
unfractionated heparin in acute coronary syndrome patients: results from the
ESSENCE randomized trial. Circulation. 1998;97:1702-1707.
FREE FULL TEXT
69. FRagmin and Fast Revascularisation during InStability in Coronary artery
disease (FRISC II) Investigators. Long-term low-molecular-mass heparin in unstable coronary-artery disease:
FRISC II prospective randomised multicentre study [published correction appears
in Lancet. 1999;354:1478]. Lancet. 1999;354:701-707.
FULL TEXT
|
ISI
| PUBMED
70. Bresnahan DS, David JL, Holmes DR. Angiographic occurrence of and clinical correlates of intraluminal
coronary artery thrombus: role of unstable angina. J Am Coll Cardiol. 1985;6:285-289.
ABSTRACT
71. Sherman CT, Litvack F, Grundfest W, et al. Coronary angioscopy in patients with unstable angina pectoris. N Engl J Med. 1986;315:913-919.
ABSTRACT
72. Vetrovec GW, Cowley MJ, Overton H. Intracoronary thrombus in syndromes of unstable myocardial ischemia. Am Heart J. 1981;102:1202-1208.
FULL TEXT
|
ISI
| PUBMED
73. de Zwaan C, Bar FW, Janssen JHA, et al. Effects of thrombolytic therapy in unstable angina: clinical and angiographic
results. J Am Coll Cardiol. 1988;12:301-309.
ABSTRACT
74. Falk E. Unstable angina with fatal outcome: dynamic coronary thrombosis leading
to infarction or sudden death. Circulation. 1985;71:699-708.
FREE FULL TEXT
75. Bar FW, Verheugt FW, Col J, et al. Thrombolysis in patients with unstable angina improves the angiographic
but not the clinical outcome: results of UNASEM, a multicenter, randomized,
placebo-controlled, clinical trial with anistreplase. Circulation. 1992;86:131-137.
FREE FULL TEXT
76. Freeman MR, Langer A, Wilson RF, et al. Thrombolysis in unstable angina: randomized double-blind trial of t-PA
and placebo. Circulation. 1992;85:150-157.
FREE FULL TEXT
77. Gold HK, Johns JA, Leinbach RC, et al. A randomized, blinded, placebo-controlled trial of recombinant human
tissue-type plasminogen activator in patients with unstable angina pectoris. Circulation. 1987;75:1192-1197.
FREE FULL TEXT
78. Ardissino D, Barberis P, de Servi S, et al. Recombinant tissue-type plasminogen activator followed by heparin compared
with heparin alone for refractory unstable angina pectoris. Am J Cardiol. 1990;66:910-914.
FULL TEXT
|
ISI
| PUBMED
79. Williams DO, Topol EJ, Califf RM, et al. Intravenous recombinant tissue-type plasminogen activator in patients
with unstable angina pectoris: results of a placebo-controlled, randomized
trial. Circulation. 1990;82:376-383.
FREE FULL TEXT
80. Ambrose JAHC, Hjemdahl-Monsen CE, Borrico S, Gorlin R, Fuster V. Quantitative and qualitative effects of intracoronary streptokinase
in unstable angina and non–Q wave infarction. J Am Coll Cardiol. 1987;9:1156-1165.
ABSTRACT
81. The TIMI-IIIA Investigators. Early effects of tissue-type plasminogen activator added to conventional
therapy on the culprit coronary lesion in patients presenting with ischemic
cardiac pain at rest: results of the Thrombolysis in Myocardial Ischemia (TIMI-IIIA)
trial. Circulation. 1993;87:38-52.
FREE FULL TEXT
82. Nicklas JM, Topol EJ, Kander N, et al. Randomized, double-blind, placebo-controlled trial of tissue plasminogen
activator in unstable angina. J Am Coll Cardiol. 1989;13:434-441.
ABSTRACT
83. Schreiber TL, Rizik D, White C, et al. Randomized trial of thrombolysis versus heparin in unstable angina. Circulation. 1992;86:1407-1414.
FREE FULL TEXT
84. Waters D, Lam JYT. Is thrombolytic therapy striking out in unstable angina? Circulation. 1992;86:1642-1644.
FREE FULL TEXT
85. Fibrinolytic Therapy Trialists' Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial
infarction: collaborative overview of early mortality and major morbidity
results from all randomized trials of more than 1000 patients. Lancet. 1994;343:311-322.
FULL TEXT
|
ISI
| PUBMED
86. EMERAS (Estudio Multicentrico Estreptoquinasa Republicas de America
del Sur) Collaborative Group. Randomised trial of late thrombolysis in patients with suspected acute
myocardial infarction. Lancet. 1993;342:767-772.
FULL TEXT
|
ISI
| PUBMED
87. LATE Study Group: Late Assessment of Thrombolytic Efficacy (LATE) study
with alteplase 6-24 hours after onset of acute myocardial infarction. Lancet. 1993;342:759-766.
FULL TEXT
|
ISI
| PUBMED
88. Ryan TJ, Anderson JL, Antman EM, et al. ACC/AHA guidelines for the management of patients with acute myocardial
infarction: a report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines (Committee on Management of
Acute Myocardial Infarction). J Am Coll Cardiol. 1996;28:1328-1428.
FULL TEXT
|
ISI
| PUBMED
89. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico. GISSI-2: a factorial randomized trial or alteplase vs streptokinase
and heparin vs no heparin among 12,490 patients with acute myocardial infarction. Lancet. 1990;336:65-71.
ISI
| PUBMED
90. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO
III) Investigators. A comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Med. 1997;337:1118-1123.
FREE FULL TEXT
91. Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2)
Investigators. Single-bolus tenecteplase compared with front-loaded alteplase in acute
myocardial infarction: the ASSENT-2 double-blind randomised trial. Lancet. 1999;354:716-722.
FULL TEXT
|
ISI
| PUBMED
92. Ferguson JJ. NICE-3: National Investigators Collaborating on Enoxaparin 3: prospective,
open-label non-randomized observational safety study on the combination of
LMWH and the clinically available IIb/IIIa inhibitors in 600 patients with
acute coronary syndromes. Paper presented at: 22nd Congress of the European Society of Cardiology;
August 30, 2000; Amsterdam, the Netherlands.
93. Ohman EM, Kleiman NS, Gacioch G, et al. Combination accelerated tissue-plasminogen activator and platelet glycoprotein
IIb/IIIa Integrin receptor blockade with Integrilin in acute myocardial infarction:
results of a randomized, placebo-controlled, dose-ranging trial. Circulation. 1997;95:846-854.
FREE FULL TEXT
94. Giugliano RP, Antman EM, McCabe CH, et al. Abciximab + tPA improves coronary flow in a wide range of subgroups:
results from TIMI 14 [abstract]. Circulation. 1998;98:I-560.
95. Ohman EM, Lincoff AM, Bode C, et al. Enhanced early reperfusion at 60 minutes with low-dose reteplase combined
with full-dose abciximab in acute myocardial infarction: preliminary results
from the GUSTO-4 pilot (SPEED) dose-ranging trail [abstract]. Circulation. 1998;98:I-504.
96. Antman EM, Giugliano RP, Gibson M, et al. Abciximab facilitates the rate and extent of thrombolysis: results
of the Thrombolysis in Myocardial Infarction (TIMI) 14 trial. Circulation. 1999;99:2720-2732.
FREE FULL TEXT
97. Califf RM. Combination therapy for acute myocardial infarction: fibrinolytic therapy
and glycoprotein IIb/IIIa inhibition. Am Heart J. 2000;139(pt 2):S33-S37.
98. Ronner E, van Kesteren HAM, Zijnen P, et al. Combined therapy with streptokinase and Integrilin [abstract]. J Am Coll Cardiol. 1998;31:191A.
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