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Management of Non-ST-Segment Elevation
The ACC/AHA and ESC guidelines interpreted these results differently, however, thereby high-
lighting the complexities and pitfalls in the design of such trials and in inferences from subgroup
analyses (Table 2). The ACC/AHA guidelines have given a class I recommendation to each of the
four agents. Given the larger number of available randomized clinical trial data, U
FH and enoxaparin
have a level of evidence A, whereas bivalirudin and fondaparinux – which are supported by only
one trial in the NSTE ACS population – have a level of evidence B. Nonetheless, current guidelines
do not indicate any preference as to which agent should be chosen in patients undergoing an early
invasive strategy. In patients undergoing conservative treatment, the guidelines express a preference for
enoxaparin or fondaparinux (class IIb), with fondaparinux being the agent of choice for patients at risk
of bleeding (class I).
The ESC guidelines indicated a preference for bivalirudin use among patients undergoing an urgent
early invasive strategy (IB), with U
FH as a possible alternative (IC). Enoxaparin has only been attrib-
uted a class IIa, and fondaparinux has not been included as a possible choice in the setting of rapid
cardiac catheterization. In patients who receive a conservative approach or a delayed catheterization,
the
ESC guidelines clearly indicate fondaparinux as the preferred choice (IA), as opposed to enoxaparin
and UFH (IIa and B, respectively).
In our view, there are several factors to be taken into account when deciding which antithrombin
agent should be used.
These include the treatment strategy (invasive vs. conservative), the institutional
standard practice of time to cardiac catheterization (same day vs. next day vs. other), the use of
upstream GP IIb/IIIa inhibitors, the use of clopidogrel as initial medical therapy, the presence of renal
disease, and the overall risk of bleeding. However, none of these factors has been clearly proven to be
critical to predict the benefit/risk of each currently available antithrombotic drug relative to another,
and they mostly derive from informal evaluation of the populations included in trials, the concomitant
medication used, and the treatment strategies adopted.
For high-risk patients requiring a GP IIb/IIIa inhibitor who do not undergo cardiac catheterization
in the first few hours, enoxaparin or UFH may still represent the first choice, particularly if enoxaparin
is used consistently. In patients with renal disease, those at higher risk of bleeding, and those who are
treated conservatively, fondaparinux may be the treatment of choice. Finally, bivalirudin may repre-
Table 2
Class of recommendation and level of evidence regarding NSTE ACS antithrombin therapies in 2007
ACC/AHA and ESC guidelines
Urgent/early invasive strategy Conservative/non-urgent invasive strategy
Class of recommendation,
level of evidence ESC ACC/AHA ESC ACC/AHA
I, A Enoxaparin,
UFH
Fondaparinux Enoxaparin,
UFH
I, B Bivalirudin Bivalirudin,
fondaparinux
Fondaparinux
a
I, C UFH
IIa, B Enoxaparin Enoxaparin
b
, LMWH,
UFH
Enoxaparin,
fondaparinux
c
a
Fondaparinux preferred if there is an increased risk of bleeding
b
Enoxaparin recommended only if the risk of bleeding is low
c
Enoxaparin or fondaparinux preferred over UFH unless CABG is planned <24 h
ACC American College of Cardiology; AHA American
Heart Association; ESC European Society of Cardiology; NSTE
ACS nNon-
ST-segment elevation acute coronary syndromes; UFH unfractionated heparin
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Antithrombotic Drug Therapy in Cardiovascular Disease
sent the optimal choice for those patients undergoing expedited PCI with no planned use of GP IIb/
IIIa inhibitors, in patients not at high risk, or in those pretreated with clopidogrel prior to PCI. As
stated above, those recommendations should be seen more as general criteria from which to choose,
rather than as guidelines supported by scientific evidence from specific randomized clinical investiga-
tions. However, rather than deciding on a case-by-case basis, it is recommended that each hospital
adopt a protocol indicating the antithrombin of choice to be used locally.
The protocol should indicate
specific instructions relative to dosing, timing of administration, monitoring (as needed), and manage-
ment of the therapy in case of catheterization, PCI, or CABG.
The protocol should also specify special
situations in which another agent may be preferable.
A protocol-based approach has several potential advantages.
First, it ensures that patients admitted
to the hospital receive consistent treatment, thereby avoiding changes in therapy within the same
hospital.
For the same reason, patients who come from another hospital and have already received an
antithrombin drug should continue the treatment started at the first hospital rather than switching to
accommodate local or personal preferences.
Second, the adoption of a protocol with a “first-choice”
drug increases the familiarity of physicians and other health care professionals with the chosen agent.
Increased familiarity and specific dosing guidelines may decrease the risk of dosing errors and is even
more critical for those therapies with more complex dosing regimens
(64).
In conclusion, despite the developments in new antithrombotic drugs, U
FH and enoxaparin still
represent valuable choices for the treatment of patients with N
STE ACS and retain an ACC/AHA
guideline recommendation of class I, level of evidence A. Appropriate dosing, consistency of therapy,
and adequate management of therapy during invasive procedures are critical to optimize the balance
of efficacy and safety when these drugs are used.
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9 Direct Thrombin Inhibitors
in Acute Coronary Syndromes
Tyler L. Taigen, James E. Harvey,
and A. Michael Lincoff
Co n t e n t s
Introduction
Overview of Direct Thrombin Inhibitors
Specific Direct Thrombin Inhibitors
UA/NSTEMI
STEMI
References
Ab s t r A c t The acute coronary syndromes (ACS) represent a continuum of athereothrombotic diseases
that result from near instantaneous platelet activation and the initiation of the coagulation cascade most
often following plaque erosion/rupture. Due to the central role of thrombin in clot formation, many therapies
have aimed at inhibiting the action of thrombin to slow or reverse the coagulation cascade and to minimize
the morbidity of ACS. While unfractionated heparin has been the stalwart agent for the management of
ACS, several unfavorable characteristics such as the inability to inhibit clot-bound thrombin and a vulner-
ability to circulating inhibitors have prompted the search for alternative agents. Direct thrombin inhibitors
(DTIs) were developed in an effort to effectively block the prothrombotic effects of thrombin without
the associated increase in hemorrhagic events seen with the use of heparin. Early trials evaluating the DTI
hirudin for management of unstable angina (UA) and non-ST-elevation myocardial infarction (NSTEMI)
were largely disappointing. More recent data has demonstrated significantly lower bleeding rates with a
similar effect on ischemic endpoints with the use of the DTI, bivalirudin, across the spectrum of ACS.
As a result, the use of bivalirudin for most patients presenting with UA, NSTEMI, or STEMI is increasing.
In this chapter, the data regarding the use of DTI in ACS will be presented and suggestions for their use
in specific clinical scenarios will be given.
Key words: Direct thrombin inhibitors; bivalirudin; antithrombin; Acute coronary syndromes;
intervention
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_9
© Humana Press, a part of Springer Science+Business Media, LLC 2010
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INTRODUCTION
Acute coronary syndromes (ACS) represent a continuum of atherothrombotic disease and include
unstable angina (UA), non-ST segment elevation myocardial infarction (NSTEMI), and ST-segment-
elevation myocardial infarction (STEMI). Central to the development of an acute coronary syndrome
is atherosclerotic plaque erosion and/or rupture, the mechanism of which remains poorly understood
but involves factors that induce plaque vulnerability. With plaque rupture, subendothelial collagen is
exposed and tissue factor is released resulting in near instantaneous platelet activation and the initia-
tion of the coagulation cascade, respectively.
Once initiated, the coagulation cascade rapidly facilitates the generation of thrombin which in turn
serves a number of essential functions (Table 1). Thrombin formation induces platelet activation, acti-
vation of factors V, VIII and XI, and the generation of more thrombin. Thrombin triggers
platelet activation by protease-activated receptors (PARs) which leads to the production of thromboxane,
serotonin and ADP. Clot formation is further amplified by thrombin-induced activation of the glyco-
protein IIb/IIIa integrin receptor to bind fibrinogen and the von-Willebrand factor resulting in platelet
aggregation. The intrinsic and extrinsic coagulation cascades unite in the conversion of fibrinogen to
fibrin and cross-linking fibrin, leading to a stable thrombus. In addition, thrombin also plays a role in
endothelial vasoconstriction, smooth muscle cell proliferation, and cytokine release
(1). The final
product is a fibrin-platelet clot which limits or obstructs blood flow through a coronary artery and
results in an acute coronary syndrome.
The central role that thrombin plays in clot formation provides a unique opportunity for therapeutic
intervention. There are two classes of anticoagulants aimed at inhibiting thrombin, the heparins
(unfractionated heparin, low molecular weight heparin (LMWH), and fondaparinux, a synthetic
heparin pentasaccharide) and the direct thrombin inhibitors (DTIs).
Heparins are indirect thrombin inhibitors and require a cofactor, antithrombin (formerly anti-
thrombin III). Upon binding to antithrombin, a conformational change occurs which converts the
enzyme from a slow to a rapid inhibitor of thrombin. The heparin–antithrombin complex inactivates
thrombin, as well as factor VII, IX, and X. This in turn inhibits the activation of factor V and VIII,
and decreases platelet activation and aggregation (Fig. 1).
Notwithstanding the strong anticoagulation properties, there are important intrinsic limitations
associated with the use of heparin (Table 2) (2–4). Perhaps most significant is that the large heparin–
antithrombin complex cannot inactivate thrombin bound within a clot
(2). The thrombin molecule has
three receptors which regulate its enzymatic activity: the catalytic site and two exosites. Exosite-1 is
the substrate binding domain for alignment of the peptide bonds to the catalytic site. Exosite 2 is the
heparin binding site (Fig. 1). Following the attachment of thrombin to fibrin within a clot, exosite 2
is protected from the heparin–antithrombin complex. Thus, clot bound thrombin continues to exert
thrombogenic effects despite the use of heparin. Secondly, heparin is vulnerable to suppression by
circulating inhibitors including platelet factor 4 and heparinase (4). Heparin also exhibits variable
Table 1
Effects of thrombin on coagulation
Effect Mechanism of action
Increased platelet activation Activates platelet protease-activated receptor
Activates platelet Gp IIb/IIIa integrin receptor
Increased generation of thrombin Activates autocatalytic feedback loop
Propagates and stabilizes clot formation Catalyzes cross-link of fibrin clot
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Direct Thrombin Inhibitors in Acute Coronary Syndromes
bioavailability and non-linear pharmacokinetics. The animal source and manufacturing process
results in non-uniform sized molecules, approximately only a third of which have the unique pen-
tasaccharide sequence required to effectively activate antithrombin. Heparin binds numerous tissues
and plasma proteins leading to unpredictable active plasma levels and variable dosing from patient to
patient. Heparin also appears to have an inherent platelet activating effect (5). In addition, extended
heparin use may result in heparin-induced thrombocytopenia (HIT) in 2.5–3% of the patients (6). HIT
is particularly a matter of concern in patients with acute coronary syndrome, as it is results in a pro-
thrombotic state. Lastly, observations from several trials have suggested a potential reactivation of
thrombin leading to coronary ischemia in the hours following heparin discontinuation. (7,8) Another
theoretical limitation is that heparin should have limited effectiveness in patients with antithrombin
deficiency, however, clinically this appears to be irrelevant (9).
Table 2
Comparison of heparin and direct thrombin inhibitors
Unfractionated heparin Direct thrombin inhibitors
Unable to inhibit thrombin bound to fibrin clot due to
steric hindrance
Inhibits thrombin bound to fibrin clot
Indirectly inhibits thrombin through antithrombin
cofactor
Directly inhibits thrombin without cofactor
Reduced potency with antithrombin cofactor deficiency No dependence upon cofactor
Unpredictable bioavailability due to non-specific binding
to circulating or vascular proteins
Little or no non-specific binding
Variable potency depending upon distribution
of molecular size in natural mixture
Consistent potency
Inhibited by platelet factor 4 and other circulating
inhibitors
No circulating inhibitors
Activates platelets No platelet activation. Inhibits thrombin-mediated
pathway of platelet activation
Antibody-mediated heparin-induced thrombocytopenia
syndrome (HITS)
No heparin-induced thrombocytopenia
or cross-reaction with HITS antibodies
Unfractionated
heparin
Pentasaccharide
sequence
Antithrombin
Factor Xa
Thrombin
Fig. 1. Schematic representation of the interaction between antithrombin and heparin and its effect on the binding of
antithrombin with factor Xa and thrombin. Heparin binds with antithrombin via a specific pentasaccharide binding site.
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Antithrombotic Drug Therapy in Cardiovascular Disease
In an effort to overcome some of the unfavorable pharmacokinetic and pharmacodynamic
characteristics of UFH, LMWH was developed. LMWHs are approximately 5,000 dalton heparin
fragments produced through the enzymatic or chemical depolymerization of UFH
(10). Whether
injected IV or SC, LMWHs have a more predictable onset of action than does UFH and LMWHs
have a decreased propensity to bind to plasma proteins and platelets
(11,12). This is believed to
explain the greater bioavailability and diminished platelet activation and incidence of HIT observed
with the use of LMWHs as compared to UFH. Like UFH, LMWH binds with AT through a unique
pentasaccharide segment resulting in the accelerated AT-mediated inactivation of factor Xa, thus
inhibiting the coagulation cascade. LMWH also inactivates thrombin, however, it does so to a lesser
degree than does UFH. Different LMWH preparations have varying ratios of polysaccharide chain
lengths, the majority of which are less than 18 units in length. Because the inactivation of thrombin
requires the heparin molecule to have at least 18 saccharide units, the anticoagulant effects LMWH
are predominantly due to its inhibition of factor X and less so to its inhibition of thrombin
(13). The
overall result is a longer and a more predictable anticoagulation effect that does not require frequent
monitoring or dose adjustment and is feasible for SC delivery
(14). Early trials comparing the
LMWH enoxaparin to UFH among patients with UA/NSTEMI treated with aspirin and conserva-
tive management revealed a decrease in ischemic events with no difference in hemorrhagic compli-
cations
(15–17). While these data were promising, they had significant limitations. Most importantly,
these trials did not employ an early invasive strategy or the adjunctive use of Gp IIbIIIa inhibitors
in the treatment of ACS and thus, it was not possible to extrapolate these trials to include contem-
porary practice patterns
(18). To resolve this, the SYNERGY trial randomized 10,000 high-risk
patients with ACS to receive either enoxaparin or UFH with concomitant Gp IIbIIIa inhibitor as per
the physician’s discretion and an early invasive strategy of catheterization and revascularization
(19,20). There was no statistically-significant difference between the two groups in the primary
endpoint of death or MI (14.5% vs. 14.0% in the UFH and enoxaparin arms, respectively, p
= 0.4);
however, major bleeding occurred more frequently among patients in the enoxaparin arm (7.6% vs.
9.1% respectively, p = 0.008). Similarly, multiple studies comparing the use of enoxaparin vs. UFH
in patients presenting with STEMI and undergoing fibrinolytic therapy were performed
(21–23).
While each of these trials showed enoxaparin to have similar or improved efficacy in reducing death
and MI when compared to UFH, they also revealed significantly increased risk of hemorrhagic
complications. The use of enoxaparin compared to UFH in patients with STEMI and primary PCI
has not been well evaluated.
OVERVIEW OF DIRECT THROMBIN INHIBITORS
The inherent limitations of heparins led to the investigation of alternative strategies to inhibit
thrombin. DTIs bind directly to the catalytic and/or substrate recognition (exosite 1) sites of thrombin,
in contrast to heparin which binds antithrombin (1). Hirudin, the prototype DTI, and other recently
developed synthetic analogues are potent anticoagulants with different pharmacokinetic and pharma-
codynamic properties. Bivalent DTIs bind the catalytic site and the substrate binding site (exosite 1)
whereas univalent DTIs only bind the catalytic site (Fig.
2). DTIs have several important advantages
over heparin (Table 2). In contrast to heparin, DTIs are not subject to steric hindrance and are able to
inactivate thrombin bound within a clot. DTIs do not require a cofactor and there are no circulating
inhibitors. DTIs have more reliable therapeutic responses as in general they do not bind plasma pro-
teins. They do not cause the immune-mediated syndrome of HIT. Finally, whereas heparin has been
shown to intrinsically activate platelets (3), DTIs do not share this effect and actually inhibit the
thrombin-mediated pathway of platelet aggregation (Table 2).
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Direct Thrombin Inhibitors in Acute Coronary Syndromes
Initial studies using animal models to compare DTIs to heparin in suppression of arterial and
venous thrombosis suggested a possible benefit with DTIs. Enthusiasm for their use however was
tempered by the results of several large trials in the 1990s. It appeared that DTIs, primarily hirudin,
provided only minimal benefit beyond that of heparin in protection against ischemic events, and yet
increased hemorrhagic events. More recent evidence has suggested the therapeutic benefit of synthetic
analogues, in particular bivalirudin, initially in the attenuation of peri-procedural ischemic complica-
tions of percutaneous intervention and later in the treatment of ACS.
SPECIFIC DIRECT THROMBIN INHIBITORS
Hirudin
Hirudin is a naturally occurring molecule originally isolated from the saliva of the medicinal leech
(Hirudo medicinalis) over 30 years ago (Table
3). It is a 65-amino-acid polypeptide which bivalently
and irreversibly binds thrombin with high affinity
(24). Hirudin can be administered intravenously or
subcutaneously and is almost exclusively excreted by the kidneys. The half-life of hirudin is approxi-
mately 60 min; however this can be significantly prolonged in the presence of renal dysfunction. Hirudin
is contraindicated for patients with a creatinine clearance <15
ml/min. Formation of antibodies directed
against hirudin may occur in up to 40% of patients, and anaphylactic reactions have been reported
(25,26). Moreover, anti-hirudin antibodies may lead to an increased half-life and subsequent drug
accumulation
(27). Plasma levels of partial thromboplastin times (PTT) increase proportionally with
dosing over a range of 0.1–0.4
mg/kg. Dosing adjustments should be made until a steady state aPTT
of 1.5–2.5 times the initial baseline value is achieved. Hirudin is FDA-approved for treatment of HIT.
Lepirudin is a recombinant form of hirudin derived from yeast cells with virtually the same pharma-
cokinetic and pharmacodynamic properties.
Table 3
Properties and FDA indications for use of parenteral DTIs : Hirudin, Bivalirudin, and Argatroban
Hirudin Bivalirudin Argatroban
Type of molecule 65 amino acid
polypeptide
20 amino acid peptide Synthetic arginine
derivative
Mass (daltons) 7,000 1,980 527
Thrombin binding
sites
Catalytic, exosite I Catalytic, exosite I Catalytic
Thrombin binding
kinetics
Irreversible Reversible on proteolytic cleavage Reversible,
competitive
Clearance Renal Predominantly endogenous
circulating peptidases,
minor renal
Hepatic
Elimination half-life 60 min 25 min 54 min
Produces antibodies? Yes No No
FDA indication(s) Treatment of HIT 1. AC in patients undergoing PCI.
2. ACS (with ASA) undergoing
PTCA
1. Treatment of HIT
2. During PCI in patients
who have or are at risk
for HIT
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