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340 Part IV / Practical Issues and Future Applications
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Chapter 16 / Interaction of GPIIb/IIIa Antagonists with Thrombin Inhibitors 341
341
From: Contemporary Cardiology: Platelet Glycoprotein IIb/IIIa
Inhibitors in Cardiovascular Disease, 2nd Edition
Edited by: A. M. Lincoff © Humana Press Inc., Totowa, NJ
16 Platelet Glycoprotein IIb/IIIa
Antagonists
Their Interaction with Low-Molecular-Weight
Heparins and Direct Thrombin Inhibitors
Amol S. Bapat, MD, Naji Yazbek, MD,
and Neal S. Kleiman,
MD
CONTENTS
INTRODUCTION
PERTINENT BIOLOGY OF THROMBIN AND THROMBIN INHIBITORS
COMBINED GPIIb/IIIa ANTAGONISTS AND ANTITHROMBINS
LOW-MOLECULAR-WEIGHT HEPARIN IN ACUTE CORONARY
SYNDROMES
LOW-MOLECULAR-WEIGHT HEPARINS IN PERCUTANEOUS
CORONARY INTERVENTION
GPIIb/IIIa AND LOW-MOLECULAR-WEIGHT HEPARIN
IN
PERCUTANEOUS CORONARY INTERVENTION
GPIIb/IIIa ANTAGONISTS AND LOW-MOLECULAR-WEIGHT
HEPARIN IN ACUTE CORONARY SYNDROMES AND ACUTE
MYOCARDIAL INFARCTION
DIRECT THROMBIN INHIBITORS IN ACUTE CORONARY SYNDROMES AND
MYOCARDIAL INFARCTION
DIRECT THROMBIN INHIBITORS IN PERCUTANEOUS CORONARY
INTERVENTION
GPIIb/IIIa AND DIRECT THROMBIN INHIBITOR IN PERCUTANEOUS
CORONARY INTERVENTION
CONCLUSIONS
REFERENCES
INTRODUCTION
The availability of new drugs for the inhibition of platelets and thrombin may alter the
strategies used to manage patients with acute coronary syndromes and those undergoing
percutaneous coronary interventions. The critical role of the activated platelet in these
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342 Part IV / Practical Issues and Future Applications
settings has been demonstrated numerous times, and the inhibition of thrombin, one of
the most potent naturally occurring platelet agonists, also appears to be necessary to pre-
vent thrombus formation and propagation. Large clinical studies have investigated plate-
let glycoprotein (GP) IIb/IIIa antagonists in percutaneous coronary intervention, unstable
angina, and ST-elevation myocardial infarction. In most of these trials, unfractionated
heparin has been used as a concomitant thrombin antagonist, but recent experience now
includes low-molecular-weight heparins and direct thrombin antagonists in these settings.
It has been argued that event rates for acute coronary syndromes remain unacceptably
high, in spite of aggressive care (1).
A time-honored saw has been that as the efficacy of new antithrombotic treatments
increases, the risk of bleeding will increase. Although this finding has been true to a cer-
tain extent, more sophisticated approaches based on a more thorough understanding of
coagulation tend to belie this paradigm. The natural progression of clinical research has
led to exploration of the low-molecular-weight heparins and direct thrombin inhibitors
as “foundation” anticoagulants for use with GPIIb/IIIa antagonists. Their hypothetical
and often established advantages over unfractionated heparin may lead to the evolution
of safer and more effective therapies for unstable angina, ST-elevation myocardial infarc-
tion, and percutaneous coronary intervention and suggest that they may provide superior
platforms on which to use antiplatelet agents. This chapter reviews the extant data con-
cerning these new anticoagulants in combination with GPIIb/IIIa antagonists.
Evidence Favors the Use of GPIIb/IIIa Antagonists
Platelet inhibition in various settings has been exhaustively examined. Although bio-
logic compounds such as thrombin, adenosine diphosphate, thromboxane, collagen, nor-
epinephrine, and serotonin may cause platelet activation, ligation of platelet GPIIb/IIIa
by fibrinogen and von Willebrand factor is probably the “final common pathway” for
platelet aggregation. GPIIb/IIIa (α
IIb
β
3
) is a member of the integrin family unique to the
platelet (2) and is the most expressed receptor on the platelet surface (3). Approximately
80,000 copies of GPIIb/IIIa are expressed on the surface of a quiescent platelet (4), and
about 20,000–30,000 more receptors reside in the α-granules and remain in equilibrium
with the surface via the open cannicular system (5). Platelet activity plays an important
role in ischemic coronary syndromes. Acute coronary syndromes are initiated when the
unstable atherosclerotic plaque’s fibrous cap is disrupted (6–9). The highly reactive lipid
core then acts as a catalyst for platelet activation and thrombosis. Platelets initiate the for-
mation of thrombus at the plaque rupture site and further render the thrombus resistant
to clot lysis, delay perfusion, and promote cycles of patency and reocclusion (10). Upon
platelet activation, GPIIb/IIIa is expressed on the platelet surface. Findings from animal
models that examined the effect of monoclonal antibodies in the setting of thrombosis
and reperfusion indicate that approx 80% or more of surface GPIIb/IIIa receptors must
be functionally eliminated to achieve clinically significant inhibition of platelet aggre-
gation (11). GPIIb/IIIa antagonists prevent the binding of fibrinogen, which in turn pre-
vents platelets from crosslinking and thereby reduces platelet-induced thrombus formation.
Therefore, antagonism of the GPIIb/IIIa receptor is a very tempting target for a host of
coronary syndromes.
There are currently three approved GPIIb/IIIa antagonists in the United States: the Fab
fragment of chimeric human-murine monoclonal antibody 7E3, abciximab (ReoPro), the
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Chapter 16 / Interaction of GPIIb/IIIa Antagonists with Thrombin Inhibitors 343
nonpeptide tirofiban (Aggrastat), and the semisynthetic cyclic heptapeptide eptifibatide
(Integrilin). Abciximab has been approved for use in percutaneous coronary intervention
but has also been studied in the acute coronary syndrome and ST-elevation myocardial
infarction populations as well; it avidly and irreversibly binds the β-subunit of the GPIIb/
IIIa receptor. It has a short plasma half-life but in its bound form has a much longer bio-
logic half-life. After an intravenous bolus, the free drug is rapidly cleared, with an initial
half-life of 10 min and a second-phase half-life of 30 min (2): unbound abciximab is cleared
by protease degradation. Tirofiban has been approved for use in patients with unstable
angina and binds to the RGD motif of GPIIb/IIIa. Tirofiban, in contrast to abciximab, has
a less avid binding to its target site but a longer half-life in its unbound form and is renally
and hepatically excreted. Eptifibatide has been approved for use in both acute coronary syn-
dromes and percutaneous coronary intervention. It has a sequence specifically targeted
for the RGD recognition sequence of GPIIb/IIIa; like tirofiban, has competitive and rever-
sible binding and is also renally excreted. A large number of clinical trials have been per-
formed using these agents in the clinical settings of percutaneous coronary intervention,
acute coronary syndromes, and ST-elevation myocardial infarction; these are reviewed
extensively in other chapters.
PERTINENT BIOLOGY
OF THROMBIN AND THROMBIN INHIBITORS
Thrombin
Whereas antagonists of platelet GPIIb/IIIa inhibit the “final common pathway” of
platelet activation, activation of the soluble coagulation cascade is also important in arterial
thrombosis. Thrombin (coagulation factor IIa) acts as a central mediator of clot formation
through a variety of related actions. In addition to converting fibrinogen to fibrin, throm-
bin activates platelets largely through a recently discovered receptor known as protease-
activated receptor-1 (PAR-1) (12). The concentrations of thrombin required to activate
platelets are considerably lower than those required to convert fibrinogen to fibrin. Even
minute concentrations of thrombin are capable of initiating (or amplifying) coagulation
by activating platelets, thus permitting assembly of the tenase and prothrombinase com-
plexes that lead to a virtual explosion in the rate of thrombin formation (13). In addition
to amplification of its own generation in this fashion, thrombin activates factors VIII and
XIII (14–16). The former action is responsible for amplifying the coagulation cascade,
whereas the latter leads to crosslinking and clot stabilization.
Human thrombin exists in a “pleated sheet” configuration. Through X-ray crystallo-
graphic studies, the structure of this molecule has been elucidated (17). The active site
of thrombin is responsible for most of the molecule’s proteolytic activity. This site is situ-
ated within a cleft or “canyon” in the center of the molecule, and access is permitted only
to macromolecules with specific configurations. From a teleologic perspective, this struc-
ture would seem to confer specificity on thrombin’s activity, allowing the cleavage of only
a select subgroup of substrates. The exterior surface of thrombin contains several distinct
domains including at least two exosites. These exosites are of particular clinical importance
with regard to antithrombin therapy. The region known as exosite-1 (or the substrate-bind-
ing exosite) is responsible for tethering fibrinogen so that the appropriate region of this mole-
cule is exposed to thrombin’s active site. Exosite-1 also plays another critically important
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344 Part IV / Practical Issues and Future Applications
role, as it is the region of thrombin responsible for activating the platelet PAR-1 receptor
(18). Additionally, a heparin-binding exosite, exosite-2, has been identified that is respon-
sible for tethering the heparin-antithrombin complex onto the thrombin molecule (19,20).
Thrombin molecules are bound to fibrin within the evolving mural coronary thrombus
and become exposed during endogenous or exogenous thrombolysis. Thrombolytic agents
(and presumably mechanical disruption of a thrombus) can lead to enhanced thrombin
generation directly (21,22) or indirectly through the activation of plasmin (23,24) by pro-
thrombin and factors V and X (25). Enhanced thrombin activity at the site of plaque rup-
ture thus serves as a powerful stimulus for thrombosis and rethrombosis (19) (Fig. 1).
The Heparins
The heparins are indirect inhibitors of thrombin. Antithrombin therapy appears to be
a necessary adjunct in the therapy of acute coronary syndromes. In a meta-analysis of data
from six studies, Oler et al. (26) observed a 33% reduction in the rates of death and myo-
cardial infarction among patients with unstable angina when heparin and aspirin were com-
pared with aspirin alone. Studies in which GPIIb/IIIa antagonists have been used to treat
acute coronary syndromes without accompanying unfractionated heparin have also sug-
gested that at least some degree of thrombin antagonism may be justified (27,28). Further
anecdotal experience suggests that omission of a thrombin antagonist during percutaneous
coronary intervention is likely to lead to overt coronary thrombosis.
Unfractionated heparin consists of a mixture of polysaccharide chains of varying lengths,
about one-third of which have biologic activity. The heparins must complex with circulat-
ing antithrombin (formerly known as antithrombin III) in order to be active. The heparin-
antithrombin complex becomes a rapid inactivator of thrombin, factor Xa, and (to a lesser
extent) factors XIIa, XIa, and Ixa (29). This activity relies on the presence of a pentasac-
charide sequence known as the essential pentasaccharide (Fig. 2), which is present in about
one-third of the molecules present in pharmaceutical preparations of unfractionated hep-
arin, predominantly in the shorter polysaccharide chains. Anchoring to thrombin requires
the presence of an 18-saccharide sequence, found predominantly on higher molecular
weight chains within the mixture. Heparin also inhibits thrombin through a complex formed
with heparin cofactor-2, although the clinical significance of this interaction is not known
Fig. 1. The thrombin molecule. (From ref. 105.)
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Chapter 16 / Interaction of GPIIb/IIIa Antagonists with Thrombin Inhibitors 345
(19,30). The requirement of cofactors for heparin’s activity presents a significant limita-
tion to its use. Varying levels of cofactors between patients as well as temporal variations
in cofactor concentrations within a patient (particularly in acute coronary syndromes and
after recent heparin therapy) render the biologic response to heparin variable (31).
In addition, steric considerations may limit the ability of the heparin-cofactor complexes
to inhibit clot-bound thrombin (31). Thrombin binds to fibrin via exosite-1 (19,20), and
heparin simultaneously binds to exosite-2 of thrombin and to fibrin. Formation of this ter-
nary heparin/thrombin/fibrin complex actually increases the affinity of the thrombin-
fibrin interaction. (Fig. 3) When both thrombin exosites are occupied within this ternary
Fig. 2. The structure of the essential heparin pentasaccharide. (Courtesy of Neal Kleiman, MD.)
Fig. 3. Thrombin (IIa) interactions with fibrin. (A) Thrombin possesses two positively charged exo-
sites; exosite 1 serves as the substrate-binding domain, whereas exosite 2 binds heparin. (B) Thrombin
binds to fibrin via exosite 1. Heparin bridges thrombin to fibrin, thereby heightening the apparent affin-
ity of thrombin for fibrin and including conformational changes at the active site of the enzyme.
Because exosite 2 is occupied by the heparin molecule bridging thrombin to fibrin, antithrombin (AT)-
bound heparin cannot bind to thrombin to form a ternary heparin/thrombin/antiithrombin complex.
(C) Active site-directed inhibitors (such as argatroban) inhibit fibrin-bound thrombin without displac-
ing of the enzyme from fibrin. Bivalent inhibitors (hirudin or bivalirudin) displace thrombin from
fibrin during the inactivation process. (From ref. 32.)
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346 Part IV / Practical Issues and Future Applications
complex, thrombin is relatively protected from inactivation by the heparin-antithrombin
complex, and therefore the ternary thrombin/heparin/antithrombin is unable to be formed
(32). Other shortcomings of heparin include binding to a variety of circulating “heparin-
binding proteins” [many of which are acute-phase reactants (33)], which leads to inhibition
by plasma proteins and platelet factors (such as platelet factor 4 and thrombospondin)
that compete with antithrombin for heparin. Concentrations of these factors vary among
patients, resulting in unreliable and unpredictable anticoagulation responses to a given dose
of heparin (31). Heparin has also been shown to enhance platelet aggregation (34), pos-
sibly through platelet activation (35), or alternatively by promoting agglutination through
the platelet surface glycoprotein GPIb/IX/V-von Willebrand factor pathway (36).
Heparin also has several clinically confirmed limitations. The pharmacodynamic response
to heparin is nonlinear, and a large proportion of heparin-treated patients have activated
partial thromboplastin time (aPTT) values outside the “therapeutic range” despite vigorous
attention to dosing considerations. In some studies, this proportion has approached one-half
of treated patients (37–39). In addition, a well-demonstrated “rebound” effect of increased
thrombotic events has also been described after discontinuing unfractionated heparin ther-
apy (40,41). Finally, heparin-induced thrombocytopenia and thrombosis (HITT) is a well-
recognized autoimmune prothrombotic state that is associated with considerable morbidity
and precludes the continued use of heparin (42).
Low-Molecular-Weight Heparins
Low-molecular-weight heparins are produced by depolymerization of unfractionated
heparin. This process allows elimination of many of the higher weight molecular chains.
Although the mixture still contains some of the larger polysaccharide chains, the proportion
of lower weight chains is increased, resulting in a mean molecular weight of approx 4000–
6000 Daltons (43). Low-molecular-weight heparins retain the critical “essential penta-
saccharide” sequence required for the formation of heparin-antithrombin complex. Since
most low-molecular-weight heparins consist of <18 saccharide units, fewer chains in the
mixture support binding to thrombin. The greater proportion of shortened chain lengths
leads to preferential inhibition of factor Xa. An important pharmacologic difference among
the low-molecular-weight heparins revolves around the fragment sizes after depolymeri-
zation and the resulting Xa/IIa activity ratio (44).
The theoretical advantages of the low-molecular-weight heparins over unfractionated
heparin have been described elsewhere and include ease of administration, high biologic
availability after subcutaneous injection, less binding to plasma proteins, greater Xa/IIa
inhibition ratio (i.e., greater inhibition of thrombin generation), more predictable dose
response, and reduced inactivation by platelet factor 4 (45). Clinically reported advantages
include a lower incidence of heparin-induced thrombocytopenia (46) and the ability to
avoid routine monitoring of anti-Xa/IIa activity. However, the superiority of each low-
molecular-weight heparin to unfractionated heparin has not been proved in all settings.
Potentially, the primary disadvantage of the low-molecular-weight heparins consists of
the lack of an easily available, rapid, and reliable measure of antithrombotic activity. Some
clinical trials of low-molecular-weight heparins in patients with coronary artery disease
have also shown trends toward increased rather than decreased rates of hemorrhage, although
most of these bleeding episodes have been classified as “minor” (47,48).
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Chapter 16 / Interaction of GPIIb/IIIa Antagonists with Thrombin Inhibitors 347
Direct Thrombin Inhibitors
Direct thrombin inhibitors such as hirudin, bivalirudin, and argatroban were initially
used as anticoagulants in patients with heparin-induced thrombocytopenia (49,50). The
greater predictability of clinical response to these agents has suggested that they may be
more useful than unfractionated heparins for routine antithrombotic treatment in patients
with acute coronary syndromes and ST-segment elevation myocardial infarction and in
those undergoing percutaneous coronary interventions. Direct thrombin inhibitors have
several potential advantages. These drugs inhibit protein access to the active site of throm-
bin without requiring the intermediary molecule antithrombin. They are also able to antag-
onize clot-bound thrombin more efficiently than can the heparin-antithrombin complex.
Finally, they are not affected by plasma proteins or platelet factor 4 (51). Thus, they have
a more predictable anticoagulant response than unfractionated heparin on measures of
coagulation (39).
Hirudin is the most potent and specific thrombin inhibitor currently known (52). It is
a 65-amino acid polypeptide originally isolated from the salivary glands of the medicinal
leach Hirudo medicinalis (53). Recombinant hirudin binds tightly to thrombin to form
a slowly reversible (essentially irreversible) 1:1 stoichiometric complex (32,54). It inhibits
clot-bound thrombin more effectively than heparin (55) but is still most active against
fluid phase thrombin (56). In individuals with normal renal function, hirudin has a half-
life of 40 min after intravenous administration, which increases to 120 min after subcu-
taneous injection (57). Hirudin binds both the first exosite (N-terminus) and active site
(C-terminus) of thrombin and is able to inhibit all proteolytic activity of the molecule.
Recombinant hirudin lacks a sulfated tyrosine residue at position 63 and has a 10-fold lower
affinity for thrombin than does native hirudin; however, it still remains a potent inhibitor
of thrombin (32).
Bivalirudin (originally termed hirulog) is a synthetic 20-amino acid peptide that was
designed based on the structure of hirudin. It consists of the amino and carboxy termini
of hirudin separated by a “spacer” consisting of four glycine residues (54,58). Like hiru-
din, bivalirudin attaches to the first exosite of thrombin and blocks access to the molecule’s
active site. Bivalirudin differs from hirudin in that, once complexed with thrombin, the
Arg-Pro bond on the amino-terminal extension is cleaved, converting bivalirudin into a
low-affinity (weakly bound) inhibitor of thrombin. Bivalirudin has a plasma half-life of
24 min after intravenous infusion (59), and upon intravenous administration has a linear
dose response. Although it is renally excreted, it is also probably degraded by endogenous
peptidases to constituent amino acids (60). Robson et al. (60) described bivalirudin phar-
macokinetics in subjects with normal renal function and in those with varying degrees of
renal insufficiency. Patients with normal and mildly impaired renal function had no reduc-
tion in bivalirudin clearance rate. Patients with moderate and severe renal insufficiency
had bivalirudin clearance rates that were reduced by 45 and 68%, respectively. However,
activated clotting time (ACT) values were elevated only in the severely impaired group (60).
Argatroban is a potent inhibitor of thrombin that has been approved in the United States
for use in patients with heparin-induced thrombocytopenia (50,61). In Japan it has been
approved for treatment of acute ischemic stroke and chronic peripheral arterial obstruc-
tive disease (62). Argatroban is a synthetically manufactured derivative of arginine and
is a small molecule that reversibly binds soluble and clot-bound thrombin. Unlike hirudin
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348 Part IV / Practical Issues and Future Applications
and bivalirudin, argatroban does not bind the first exosite of thrombin but inhibits only
the active site. Argatroban also differs from the latter two thrombin antagonists in that
it is primarily metabolized in the liver via the CYP3A4/5 microsomal system (63); it has
a half-life of 45 min, which is prolonged in patients with hepatic dysfunction (64).
COMBINED GPIIb/IIIa ANTAGONISTS AND ANTITHROMBINS
At a molecular and clinical level, there may be synergistic interactions between inhibi-
tors of thrombin and GPIIb/IIIa antagonists beyond inhibiting thrombosis at different
points. Mousa et al. (65) used computerized thromboelastography (TEG) to determine the
ability of platelets and fibrin to augment human blood clot formation and strength under
conditions of maximal platelet activation accelerated by tissue factor in human and dog
blood. Platelets were found to enhance clot strength significantly; the GPIIb/IIIa antago-
nists abciximab and roxifiban effectively inhibited the enhancement of clot strength. The
combination of subthreshold doses of tinzaparin (a low-molecular-weight heparin) and
roxifiban or abciximab (both GPIIb/IIIa antagonists) resulted in distinct synergy in improv-
ing the antiplatelet and anticoagulant efficacy mediated by tissue factor. Pratico et al. (66)
examined the effect of a direct thrombin inhibitor (napsagatran) alone and in combination
with a GPIIb/IIIa antagonist (lamifiban) prior to administration of tissue plasminogen acti-
vator in a canine coronary thrombosis model. The direct thrombin inhibitor dramatically
reduced time to reperfusion, prevented reocclusion, and demonstrated reduced platelet
activity. When subthreshold doses of both drugs were combined, the time to reperfusion
was shortened and the time duration of reperfusion was extended.
This potential additive benefit was not observed in a study by Ahmed et al. (67). These
investigators exposed blood from normal, healthy volunteers to tissue factor. The blood
was incubated with different low-molecular-weight heparins (with adjusted, equivalent
anti-Xa inhibition) in combination with tirofiban. Platelet activation status was determined
by measuring surface expression of P-selectin (CD62) and generation of platelet aggre-
gates. Of the low-molecular-weight heparins tested, enoxaparin produced the best concen-
tration-dependent inhibition of P-selectin expression and platelet aggregation; enoxaparin
at therapeutic concentrations was able to inhibit tissue factor-mediated platelet activa-
tion by >70%. Unlike enoxaparin, tirofiban alone produced weak concentration-dependent
inhibition of P-selectin and platelet aggregation. Additive effects on inhibition of platelet
activation and inhibition between tirofiban and enoxaparin were only noted at lower doses.
At therapeutic concentrations of these drugs, the additive effects were no longer present.
Although these findings are in large part dependent on the model selected, the assumption
that this combination of drugs will necessarily be an improvement over current therapy
requires clinical testing.
LOW-MOLECULAR-WEIGHT
HEPARIN IN ACUTE CORONARY SYNDROMES
Studies of low-molecular-weight heparins in patients with acute coronary syndromes
have produced varying results. Two trials of the global management of patients with acute
coronary syndromes have studied enoxaparin in comparison with unfractionated hepa-
rin. The ESSENCE (48) (3171 patients) and TIMI 11B (68) (3910 patients) trials demon-
strated that enoxaparin given as a dose of 1 mg/kg bid (initiated as a 30-mg/kg bolus in
TIMI 11B) for 3 d was superior to unfractionated heparin in reducing a composite end-
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Chapter 16 / Interaction of GPIIb/IIIa Antagonists with Thrombin Inhibitors 349
point of death, myocardial infarction, and recurrent ischemia. The findings of studies
with other low-molecular-weight heparins have been less robust, although it is not clear
whether these differences are caused solely by differences in the acuity of patients enrolled
in the trials, or by differences between the low-molecular-weight heparins themselves,
or by differences in the doses selected (Table 1).
LOW-MOLECULAR-WEIGHT HEPARINS
IN PERCUTANEOUS CORONARY INTERVENTION
Hematologic Considerations
The low-molecular-weight heparins are attractive as anticoagulants during percutane-
ous coronary intervention for several reasons. First, the pharmacodynamic properties of
these compounds, as discussed previously, are favorable. Second, the use of low-molecular-
weight heparins in patients with acute coronary syndromes is increasing, and logistic con-
siderations would strongly favor their use during percutaneous coronary intervention
within the hospital stay. On the other hand, monitoring the level of anticoagulation during
treatment with low-molecular weight heparins poses a considerable challenge since the
usual measure of anticoagulant response to heparin, the ACT, is relatively insensitive to
low-molecular-weight heparins.
No data currently exist to indicate what levels of anticoagulation are optimal when low-
molecular-weight heparins are used as anticoagulants during percutaneous coronary inter-
vention. Given the pleiotropic activity of these molecules, it is not at all clear that any single
measure will be able to provide a precise indication of antithrombotic activity. Data from
animal models of arterial injury indicate that higher concentrations of unfractionated hep-
arin are associated with reduced thrombus deposition on injured arterial surfaces (69).
However, the low-molecular-weight heparins in animal models appear to confer an advantage
over unfractionated heparin. Reviparine, a low-molecular-weight heparin, was administered
Table 1
Trials of Low-Molecular-Weight
Heparins vs Unfractionated Heparin in Patients with Acute Coronary Syndromes
Heparin (%)
Low
No. of Composite molecular
Study patients endpoints Unfractionated weight p value
ESSENCE 3171 14-d endpoint 19.8 16.6 0.019
(enoxaparin) (D, MI, RA)
TIMI 11B 3910 8-d endpoint 14.5 12.4 0.048
(enoxaparin) (D, MI, UTVR)
FRIC 1482 6-d endpoint 7.6 9.3 0.96
(dalteparin) (D, MI, RA)
FRAXIS 3468 6-d endpoint 18.1 17.8 0.85
(nadroparin) (D, MI, RA)
Abbreviations: D, death; MI, myocardial infarction; RA, recurrent angina; RI, recurrent ischemia; UTVR,
urgent target vessel revascularization.
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