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Antithrombotic Drug Therapy in Cardiovascular Disease
Table 3
Select major trials of GP IIb/IIIa inhibitors in acute coronary syndromes and elective PCI
Trial
GP IIb/IIIa
inibitor Design
# of
patients Results Comments
EPIC (78) Abciximab Prospective, double blind, high
risk pts (ACS, or high risk
anatomy) on ASA and heparin
randomized to abciximab vs.
placebo
2,099 At 30 days, 35% reduction in pri-
mary endpoint of death, nonfatal
MI, unplanned surg. revasc, or
refractory ischemia req. IABP or
unplanned percutaneous proce-
dure
The benefits of treatment were noted out
to 6 months and 3 years with regards to
the primary composite endpoint
EPILOG (79) Abciximab Prospective double blind trial of
elective or urgent PCI of abcix-
imab vs. placebo
2,792 At 30 days, significant reduction in
primary endpoint noted in abcixi-
mab group
The benefit comes at no increased risk of
bleeding. Furthermore, the benefits of
treatment noted out to 1 year (80)
CAPTURE (81) Abciximab Prospective double blind ran-
domized to abciximab vs.
placebo after angiography
and prior to PCI for ACS not
responsive to medications
1,265 At 30 days, composite endpoint of
death, MI, or urgent intervention
was lower in the treatment group
(p = 0.012)
Major bleeding was more frequent in the
treatment group
ADMIRAL
(82) Abciximab Prospective, double blind, rand-
omized to abciximab vs. pla-
cebo at time of PCI for STEMI
400 At 30 days and 6 months, primary
endpoint (death, MI, urgent TVR)
was lower in the treatment group
Angiographic analysis at 30 days and
6
months revealed more TIMI 3 flow in
the treatment group vs. placebo
RAPPORT (83) Abciximab Prospective double blind, rand-
omized to placebo vs. abcixi-
mab prior to PCI for STEMI
(<12
h)
483 At 6 months, no difference in pri-
mary efficacy endpoint (death,
MI or any TVR) between the two
groups
At 7 days and at 30 days, early death, any
TVR or re-infarction were significantly
reduced. At 6 months, treatment group
had significant reduction in death, MI or
urgent TVR
CADILLAC
(84) Abciximab Prospective, 2 × 2 factorial, testing
combination of PTCA vs. stent-
ing and abciximab vs. placebo
2,082 At 6 months, the difference in the
primary endpoint was noted in
those with stents, irrespective of
abciximab status
The reduction in the composite endpoint
at 6
months was driven by a significant
reduction in rates of ischemia driven
TVR
EPISTENT
(85) Abciximab Prospective, examining stenting
with placebo, stenting with
abciximab, or PTCA with
abciximab
2,399 At both 30 days and 6 months, the
primary endpoint (death, MI,
urgent revasc) was lower in stent-
ing and abciximab group
The benefit was observed at 1 year in the
stenting and abciximab group. The ben-
efit was noted regardless of whether the
patients had elective PCI or urgent PCI
GUSTO IV ACS
(86)
Abciximab Prospective, ACS pts randomized
to placebo vs. abciximab bolus
and 24 h infusion or abciximab
bolus and 48
h infusion with no
planned intervention
7,800 Primary endpoint of death or MI at
30 days was no different between
the three groups
No added benefit in patients with positive
biomarkers of myonecrosis
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Antiplatelet Therapies in Unstable Angina and Non-ST Segment Elevation Myocardial Infarction
PURSUIT (87) Eptifibatide Pts w. UA/NSTEMI randomized
to eptifibatide vs. placebo for
up to 72 h
10,948 At 30 days, primary composite end-
point of death, non fatal MI was
lower in the eptifibatide group
The benefit of eptifibatide was noted in
patients treated with only medical man-
agement or early revascularization
ESPRIT (88) Eptifibatide Prospective, elective PCI, rand-
omized to eptifibatide or pla-
cebo in addition to asa, heparin
and thienopyridine
2,064 Primary endpoint at 30 days of
death, MI, urgent TVR and bail-
out therapy was significantly
lower in the treatment arm
Major bleeding was higher in the treatment
arm (p = 0.027). At 1 year the benefits of
eptifibatide treatment were still present
IMPACT II (89) Eptifibatide Prospective, prior to PCI, rand-
omized to placebo, eptifibatide
bolus +0.5 mg/kg/min infusion,
or eptifibatide bolus +0.75 mg/
kg/min infusion
4,010 Composite endpoint at 30 days of
death, MI or unplanned or repeat
revascularization was no different
between the groups
By treatment-received analysis, the bolus
+0.5 mg/kg/min infusion group had a
significant reduction in the compos-
ite endpoint (p = 0.04). There was no
increase in the rates of major bleeding
noted
PRISM
(90) Tirofiban Prospective, double blind, ACS
pts randomized to IV heparin
vs. tirofiban for 48 h
3,232 Primary endpt of death, MI or
refractory ischemia at 48 h was
significantly lower in the tirofiban
group
The benefits of tirofiban at 30
days from
randomization were in those high risk
patients with positive troponin values
(91)
PRISM-PLUS
(92)
Tirofiban Prospective , double blind, ACS
pts randomized to either IV
heparin, tirofiban or tirofiban
and IV heparin prior to PCI
1,915 7
day composite primary endpt of
death, MI or refractory ischemia
was lower in group with the
combination of IV heparin and
tirofiban
The benefit of the combination of heparin
and tirofiban remained at 30
days and
there was no increase in major bleeding
in the combination therapy group
EPIC Evaluation of c7E3 to prevent ischemic complications; EPILOG platelet glycoprotein IIb/IIIa receptor blockade and low dose heparin during percutaneous
coronary revascularization; CAPTURE c7E3 fab antiplatelet therapy in unstable refractory angina; ADMIRAL abxicimab before direct angioplasty and stenting in
myocardial infarction regarding acute and long term follow up; RAPPORT ReoPro and primary PTCA organization and randomization trial; CADILLAC controlled
abciximab and device investigation to lower late angioplasty complications trial; EPISTENT evaluation of platelet IIb/IIIa inhibitor for stenting trial; GUSTO IV ACS
global utilization strategies to open occluded coronary arteries trial IV in acute coronary syndromes; PURSUIT platelet glycoprotein IIb/IIIA in unstable angina:
receptor suppression using integrelin therapy; ESPRIT enhanced suppression of the platelet IIb/IIIa receptor with integrellin therapy; IMPACT II integrellin to
minimize platelet aggregation and coroanry thrombosis II; PRISM platelet receptor inhibition in ischemic syndrome management; PRISM-PLUS platelet receptor
inhibition in ischemic syndrome management limited by unstable signs and symptoms; ACS acute coronary syndrome; MI myocardial infarction; IABP intraaortic
balloon pump counterpulsation; PCI percutaneous coronary intervention; STEMI ST elevation myocardial infarction; TVR target vessel revascularization; TIMI throm-
bolysis in myocardial infarction; PTCA percutaneous transluminal coronary angioplasty; UA/NSTEMI unstable angina, non-ST elevation myocardial infarction; IV
intravenous
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Antithrombotic Drug Therapy in Cardiovascular Disease
GLYCOPROTEIN IIB/IIIA INHIBITORS IN ACUTE CORONARY SYNDROMES
The role of the GP IIb/IIIa receptor in platelet aggregation and thrombus stability has led to the use
of glycoprotein IIb/IIIa inhibitors in the setting of PCI and ACS. The rationale in the use of the inhibi-
tors is to prevent the binding of the GP IIb/IIIa receptor to fibrinogen or circulating vWF, thus prevent-
ing platelet aggregation and formation and stabilization of the thrombus.
There are three forms of intravenous GP IIb/IIIa inhibitiors available and approved for clinical use.
Those are eptifibatide, abciximab, and tirofiban. There has been investigational work done in the area
of oral GP IIb/IIIa inhibitors, which have not demonstrated any benefit and will not be expounded
upon at this time. The intravenous GP IIb/IIIa inhibitors have been assessed in both the context of
ACS and elective PCI. Table 3 discusses the important studies of glycoprotein IIb/IIIa inhibitors for
ACS and for elective PCI. It is important to carefully understand the indications and the populations
studied in each of these large trials as these may account for the noted differences in results.
Meta-analyses of some of these large trials of GP IIb/IIIa inhibitors have reinforced the benefit of
these agents in both the UA/NSTEMI
(49) and ST STEMI populations (50).
The relative benefits of each of these antiplatelet agents may vary significantly based on the context
in which the medication is being administered. In the modern era, with the use of aspirin, heparin (or
LMWH), and clopidogrel in the setting of ACS, the concomitant use of a GP IIb/IIIa inhibitor has
been questioned. The Intracoronary Stenting and Antithrombotic Regimen: Rapid and Early Action
for Coronary Treatment 2 (ISAR-REACT-2) examined this question in the setting of PCI for ACS. In
higher risk patients undergoing PCI for NSTEMI, this study examined the utility of adding abciximab
to aspirin, IV heparin, and 600 mg of clopidogrel. At total of 2,022 patients were randomized to
abciximab or placebo and while there were no significant differences between the groups in terms of
bleeding, there was a significant reduction in the primary composite endpoint of death, myocardial
infarction, or urgent TVR noted in troponin positive patients in favor of abciximab
(51).
GP IIb/IIIa inhibitors have demonstrated utility across the broad spectrum of ACS patients, particu-
larly in the higher risk troponin positive patients, as shown in post-hoc analyses. Furthermore, the
benefit of this drug is really observed in the context of undergoing PCI while receiving the drug.
Although no data has demonstrated the benefit of the combination of GP IIb/IIIa inhibitors and
thienopyridine therapy over either therapy alone in the medical management of ACS patients, the com-
bination of these medications appears to be more potent than a single agent during PCI for ACS.
NOVEL ANTIPLATELET THERAPIES ON THE HORIZON
Many new antiplatelet agents are currently under investigation for use in ACS and elective PCI.
The hope is to achieve more rapid and more sustained platelet inhibition with less inconsistency than
with currently available agents. There are several new ADP receptor antagonists currently being
examined in clinical trials.
Cangrelor is an intravenous ADP P2Y
12
receptor subtype inhibitor that is direct acting and does not
require conversion to an active form. Phase II clinical studies in the setting of elective PCI have shown
cangrelor to be efficacious (100% inhibition of platelet aggregation at 4 mg/kg dose) yet safe when
compared with standard medical therapies. Furthermore, in addition to achieving rapid and reversible
inhibition of platelet function, there is a more rapid return to baseline bleeding times in comparison to
abciximab (52). Phase II clinical studies in the setting of ACS have clearly demonstrated the safety of
this agent as an adjunct to aspirin and heparin therapy without an increase in serious bleeding events
(53). The Clinical Trial Comparing Cangrelor to Clopidogrel in Subjects who Require Percutaneous
Coronary Intervention (CHAMPION-PCI) (54) is a mutli-center clinical trial currently enrolling
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Antiplatelet Therapies in Unstable Angina and Non-ST Segment Elevation Myocardial Infarction
patients to demonstrate either superiority or non-inferiority of cangrelor to clopidogrel in the setting of
PCI. The Clinical Trial Comparing Treatment with Cangrelor (In Combination With Usual Care), to
Usual Care in Subjects Who Require Percutaneous Coronary Intervention (CHAMPION-PLATFORM)
(55) will measure the composite of all cause mortality, myocardial ischemia, and ischemia driven
revascularization as an assessment of cangrelor vs. usual care in patients undergoing PCI.
Prasugrel is an ADP P2Y
12
receptor irreversible antagonist, which like the currently available
thienopyridines, requires conversion to an active prodrug form. The potential advantage of this ADP
receptor antagonist is the potent antiplatelet effect
(56) and more rapid onset of action demonstrated in
comparison to currently available thienoyridines
(57). These effects are a result of enzymatic transfor-
mation of the prodrug to an active metabolite in the plasma phase – not dependent upon hepatic function.
Early phase clinical trials have demonstrated the safety and efficacy of prasugrel
(58–60). The Phase III
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-
Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) examined the efficacy of prasugrel in
comparison to clopidogrel in patients with ACS undergoing PCI. A total of 13,608 patients with ACS
were randomized to loading and maintenance dosing of either prasugrel or clopidogrel. While there was
a 19% reduction in the primary efficacy end point of cardiovascular death, non fatal myocardial infarc-
tion or nonfatal stroke with prasugrel (p < 0.001), this was counterbalanced by an increase in the rate of
life threatening bleeding (p
= 0.01) (61). Furthermore, among those patients with an initial primary end-
point event, those treated with prasugrel had fewer recurrent events (p
= 0.016) and less cardiovascular
mortality (p
= 0.008) when compared to the clopidogrel treatment arm (62). Although the overall clinical
efficacy appears to favor prasugrel over clopidogrel in ACS, the increased rates of major bleeding events
with prasugrel are cause for concern. The Prasugrel in Comparison to Clopidogrel for Inhibition of
Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 (PRINCIPLE-TIMI 44)
examined the question of dosing with regard to both prasugrel and clopidogrel
(63).
AZD6140 is a novel, non-thienopyridine ADP P2Y
12
receptor inhibitor. This oral reversible ADP
receptor inhibitor belongs to a class of agents termed cyclopentyltriazolopyrimidines that do not
require metabolism to an active state. In a double blind, parallel group study, 200 patients with athero-
sclerosis were randomized to either 50, 100, or 200
mg twice daily, or 400 mg once daily or clopidogrel
75
mg. Nearly complete platelet inhibition was achieved with AZD6140 doses greater than 100 mg bid.
At higher dose ranges of AZD6140, there were slightly higher rates of minor/mild bleeding and one
reported major bleeding event at a dose of 400 mg once daily. Furthermore, there was a slight increase
in non-heart failure or bronchospasm related symptoms of dyspnea with increasing doses of AZD6140
(64). The Phase III Platelet Inhibition and Patient Outcomes (PLATO) trial will compare the effective-
ness of AZD6140 against clopidogrel in patients with acute coronary syndromes (65).
CONCLUSION
The ability to modulate platelet activity effectively and safely has proved to be an advantage in many
different types of cardiovascular disease. Platelet inhibition has improved outcomes in both elective PCI
and, especially, in ACS. Activated platelets appear to provide a key link between inflammation and
thrombosis. As such, inhibiting platelet activation by one of many pathways serves not only to inhibit
thrombus formation, but also appears to temper the inflammatory component in ACS and in the setting
of PCI. Effective antiplatelet therapy has also been shown to be of primary importance in the prevention
of stent thrombosis following PCI with drug eluting stents. The goal of newer agents is to improve effi-
cacy, to reduce time to peak platelet inhibition, and to provide a more uniform response among patients.
There are several new agents, which are currently under investigation to answer questions on efficacy
and safety. Time will tell whether these agents will significantly alter practice and outcomes. What is
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Antithrombotic Drug Therapy in Cardiovascular Disease
certain is that an improved understanding of platelet function will allow for the development of more
specific therapies that will likely enhance our ability to safely and effectively control platelets.
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8 Unfractionated Heparin and Enoxaparin
for the Management of Non-ST-Segment
Elevation Acute Coronary Syndromes
Pierluigi Tricoci and Kenneth W. Mahaffey
Co n t e n t s
Structure and Mechanism of Action
Pharmacokinetics
Heparin Monitoring and Dosing
Clinical Trials of UFH in NSTE A
CS
Clinical Trials of LMWH in NSTE A
CS
Overview of Trials Comparing Lmwh and UFH in NSTE ACS
Management of Antithrombin Therapy During PCI in NSTE ACS
Patients
Clinical Perspective and Current Guideline Recommendations
References
Ab s t r A c t Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are anti-
thrombin agents used to treat patients with non-ST-segment elevation acute coronary syndromes
(NSTE ACS). Among LMWH agents, enoxaparin has the strongest evidence for use in NSTE ACS.
While heparins were the only antithrombin drugs recommended for NSTE ACS treatment during the
last decade, new developments in antithrombotic drugs – particularly bivalirudin and fondaparinux – have
broadened the list of agents from which physicians may choose.
This chapter will focus on pharmacology and clinical data for enoxaparin and UFH in the management
of patients with N
STE ACS, while clinical trials comparing heparins with new antithrombin agents will
be described in detail in other chapters.
Key words:
Acute coronary syndromes; Unfractionated heparin; Enoxaparin; Antithrombin; NSTE ACS
From: Contemporary Cardiology: Antithrombotic Drug Therapy in Cardiovascular Disease
Edited by: A.T. Askari and A.M. Lincoff (eds.), DOI 10.1007/978-1-60327-235-3_8
© Humana Press, a part of Springer Science+Business Media, LLC 2010
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Antithrombotic Drug Therapy in Cardiovascular Disease
STRUCTURE AND MECHANISM OF ACTION
Unfractionated heparin (UFH) is a mixture of heparins, which are highly sulfated, negatively
charged glycosaminoglycans.
The molecules in the mixture are heterogeneous in molecular weight
ranging from 3,000 to 30,000
Da (1). Heparins act as indirect inhibitors of coagulation factors, because
antithrombin, a natural regulator of the coagulation cascade, is required as a cofactor for the anticoagulant
effect. Antithrombin and heparins form a complex that inhibits thrombin (factor IIa), factors Xa, IXa,
XIa, and XIIa
(1). Among those factors, thrombin and factor Xa are the most sensitive to antithrombin/
heparin inhibition
(1). UFH has a more potent effect on thrombin than on factor Xa, with an anti-IIa/
anti-Xa activity ratio of approximately ten
(1). The weight of the heparin molecules determines the
capability to inhibit factor IIa and the anti-IIa/anti-Xa ratio. In fact, the inhibitory effect on thrombin
requires that a heparin molecule binds antithrombin and thrombin simultaneously.
This complex can
be formed only by heparin molecules with at least 18 saccharides
(1). The inhibition of factor Xa
requires a heparin molecule to contain a specific pentasaccharidic sequence
(2). The pentasaccharide
is a heparin sequence that binds antithrombin, producing a high anti-Xa effect without anti-IIa effect.
Therefore, small heparin molecules containing pentasaccharide are highly selective in inhibiting factor
Xa
(2). Approximately 30% of UFH molecules contain the requisite pentasaccharide (1).
Low-molecular-weight heparins (L
MWHs) are derived from depolymerization of UFH resulting in
an average molecular weight that is approximately one-third of U
FH (2,000–9,000 Da) (3). The various
L
MWH agents commercially available differ in the method adopted to achieve depolymerization.
Enoxaparin is obtained by alkaline depolymerization of heparin benzyl ester. Enoxaparin has an average
molecular weight of approximately 4,500
Da (4). Given their smaller size, LMWHs are less capable
of inhibiting thrombin and therefore act more specifically as factor Xa inhibitors
(1). The anti-IIa/
anti-Xa ratio for commercially available L
MWH is typically from 1:2 to 1:4, and 1:3 for enoxaparin
(5). Selective factor Xa inhibition has been proposed as a potential pharmacological advantage of
L
MWH over UFH because factor Xa is located upstream in the coagulation cascade. However, no
evidence confirms that anti-Xa activity is clinically superior to anti-IIa activity, or that anti-Xa selectivity
represents a clinical advantage.
PHARMACOKINETICS
Circulating molecules contained in UFH mixtures bind to several plasma proteins and only 30%
bind antithrombin, thus producing an actual anticoagulant effect
(1). Heparin molecules also bind
endothelial cells and macrophages. These nonspecific protein- and cell-binding properties of heparin
render its anticoagulant effect unpredictable (1). The clearance of heparin from plasma occurs in two
phases. The first, rapid, saturable phase is the consequence of the cell-binding properties of heparin.
The second, slow, nonsaturable mechanism is mediated by renal clearance. As a consequence of this
complex elimination, the anticoagulant effect of heparin is not linear at therapeutic doses (1).
The most recognized pharmacologic advantage of LMWH over UFH is the pharmacokinetic
profile. In fact, the lower molecular size of LMWH results in limited binding to plasma protein and
cells (4). This has two main reported consequences. First, the dose–response relationship is more
predictable for L
MWH, eliminating the need for monitoring in most clinical situations. Second,
because of the lack of a rapid cell-mediated clearance mechanism, LMWH has a longer half-life and
therefore can be administered at longer intervals without continuous infusion. Moreover, the higher
subcutaneous bioavailability of LMWH obviates the need for intravenous infusion. The main elimination
mechanism for LMWH is renal, with potential risk of accumulation in patients with renal insufficiency
and need for dose adjustment (1).
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