Clinical Cardiology: New Frontiers
Direct Thrombin Inhibitors in Acute Coronary Syndromes
Present and Future
Jeffrey I. Weitz, MD; Harry R. Buller, MD, PhD
M
inhibitors over heparin and low-molecular-weight heparin,
review the clinical data with hirudin, bivalirudin (formerly
known as Hirulog), and argatroban, and outline the opportunities and challenges for direct thrombin inhibitors in the face
of new anticoagulant drugs currently under development.
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ost acute coronary syndromes are caused by intracoronary thrombus superimposed on disrupted atherosclerotic plaque. Platelets adhere to subendothelial proteins exposed at sites of plaque disruption where they become
activated, release vasoactive and procoagulant substances,
and aggregate.1 Tissue factor in the lipid-rich core of the
plaque initiates coagulation, which leads to thrombin generation. A potent platelet agonist, thrombin recruits additional
platelets to the site of vascular injury. Thrombin also converts
fibrinogen to fibrin, which serves to stabilize platelet-rich
thrombi formed at sites of plaque disruption. Depending on
the extent and duration of coronary artery obstruction, clinical
manifestations range from unstable angina to acute myocardial infarction.1
Aspirin and heparin, the cornerstones of therapy for acute
coronary syndromes, reduce the risk of myocardial infarction
and death.2,3 Despite the widespread use of these treatments,
however, patients with unstable angina or acute myocardial
infarction remain at risk for recurrent ischemic events, suggesting that intracoronary thrombus formation is incompletely attenuated by aspirin and heparin. High concentrations
of thrombin are generated by tissue factor exposed at sites of
arterial injury.4 When bound to fibrin,5,6 fibrin degradation
products,7 or subendothelial matrix,8 thrombin is resistant to
inactivation by the heparin/antithrombin complex. Bound
thrombin, which remains enzymatically active, triggers
thrombus growth by activating factors V, VIII, and XI,9
thereby amplifying thrombin generation. Bound thrombin
also activates platelets,10 at least in part, via thromboxane
A2-independent pathways that are not blocked by aspirin.
Because thrombin plays a central role in arterial thrombogenesis, the goal of most treatment regimens is to block
thrombin generation or inhibit its activity. Direct thrombin
inhibitors were developed to overcome the inability of the
heparin/antithrombin complex to inactivate bound thrombin.
In contrast to heparin and low-molecular-weight heparin,
which catalyze the inactivation of thrombin by antithrombin,11,12 direct thrombin inhibitors bind to the enzyme and
block its interaction with its substrates. This paper will
outline the mechanisms responsible for protection of fibrinbound thrombin from inhibition by the heparin/antithrombin
complex, describe the potential advantages of direct thrombin
Mechanisms of Protection of Fibrin-Bound
Thrombin From Inactivation by the
Heparin/Antithrombin Complex
Three distinct domains can be identified on thrombin.13 In
addition to its active site, thrombin possesses 2 exosites, or
positively charged domains located at opposite poles of the
enzyme (Figure 1A). Thrombin uses exosite 1 to dock on its
substrates, thereby orienting the appropriate peptide bonds
into its active site cleft. Exosite 2 serves as the heparinbinding domain. To catalyze the inactivation of thrombin by
antithrombin, heparin bridges the enzyme and the inhibitor by
simultaneously binding to antithrombin and exosite 2 on
thrombin. A unique pentasaccharide sequence found on one
third of the chains of commercial heparin mediates its high
affinity interaction with antithrombin.11
Thrombin binds to fibrin via exosite 1.14,15 By simultaneously binding to exosite 2 on thrombin and to fibrin,
heparin bridges more thrombin to fibrin (Figure 2). Formation
of this ternary heparin/thrombin/fibrin complex heightens the
apparent affinity of the thrombin/fibrin interaction. When
both thrombin exosites are ligated within this ternary complex, the enzyme is relatively protected from inactivation by
the heparin/antithrombin complex.15 This protection reflects,
at least in part, the inaccessibility of exosite 2 on thrombin
within the ternary complex to antithrombin-bound heparin
(Figure 1B). Thus, because exosite 2 is occupied by the
heparin chain that tethers thrombin to fibrin, antithrombinbound heparin is unable to connect the inhibitor to the
enzyme. In contrast to the heparin/antithrombin complex,
direct thrombin inhibitors can inactivate fibrin-bound thrombin (Figure 1C).
Direct Thrombin Inhibitors
Hirudin, bivalirudin, and argatroban are the 3 parenteral
direct thrombin inhibitors currently approved by the US Food
and Drug Administration. Hirudin and argatroban are li-
From McMaster University and Henderson Research Centre, Hamilton, Canada (J.I.W); and Department of Vascular Medicine, Academic Medical
Center, Amsterdam, the Netherlands (H.R.B).
Correspondence to Dr Jeffrey Weitz, Henderson Research Centre, 711 Concession St, Hamilton, Ontario L8V 1C3, Canada. E-mail
[email protected]
(Circulation. 2002;105:1004-1011.)
© 2002 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/hc0802.104331
1004
Weitz and Buller
Thrombin Inhibitors in Acute Coronary Syndromes
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Figure 1. Thrombin (IIa) interactions with fibrin. A, In addition to
its active site, thrombin possesses 2 positively charged
exosites; exosite 1 serves as the substrate-binding domain,
whereas exosite 2 binds heparin. B, Thrombin binds to fibrin via
exosite 1. By simultaneously binding to fibrin and exosite 2 on
thrombin, heparin bridges thrombin to fibrin, thereby heightening
the apparent affinity of thrombin for fibrin and inducing 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/AT complex. The conformational changes in the active site of thrombin may also limit
access of AT to the active site of the enzyme. C, Active sitedirected inhibitors, such as argatroban, inhibit fibrin-bound
thrombin without displacing of the enzyme from fibrin, whereas
bivalent inhibitors, such as hirudin or bivalirudin, displace thrombin from fibrin during the inactivation process.
censed for treatment of patients with heparin-induced thrombocytopenia. Bivalirudin is approved as a heparin substitute
in patients undergoing coronary angioplasty.
Hirudin
The prototypical direct thrombin inhibitor hirudin was originally isolated from the salivary glands of the medicinal
leech.16 Composed of 65 or 66 amino acids, hirudin is a
bivalent inhibitor of thrombin. Its globular amino-terminal
domain interacts with the active site of thrombin, whereas the
acidic carboxy-terminal domain binds to exosite 1 (Table 1).
Native hirudin contains a sulfated tyrosine residue at
position 63. Because recombinant hirudins lack this sulfate
group, they are known as desulfatohirudins or desirudins.17
Native and recombinant hirudins bind to thrombin with high
affinity, forming an essentially irreversible 1:1 stoichiometric
complex with thrombin. Although desulfatohirudins bind
thrombin with 10-fold lower affinity than hirudin, they
remain potent inhibitors of thrombin.
The terminal half-life of desulfatohirudins in healthy volunteers is 60 minutes. Desulfatohirudins are cleared via the
kidneys and accumulate in patients with renal insufficiency.
Because no specific antidote is available to reverse their
anticoagulant effect, desulfatohirudins should not be used in
patients with impaired renal function.
Figure 2. Effect of heparin on thrombin binding to fibrin. Binding
of 125I-labeled active-site– blocked thrombin to fibrin monomerSepharose was measured in the absence or presence of heparin at the concentrations indicated. Briefly, suspensions containing 50 nmol/L 125I-labeled active site-blocked thrombin were
added to 9 ␮mol/L fibrin monomer-Sepharose in 0.5 mL buffer
in the absence or presence of heparin. After mixing for 2 minutes, samples were centrifuged and 0.1-mL aliquots of supernatant were counted for radioactivity to calculate the percentage
of bound thrombin. Heparin produces a biphasic response; at
lower concentrations, heparin augments thrombin binding to
fibrin, whereas binding decreases with higher heparin concentrations. This biphasic response is typical of ternary complex
formation. At lower concentrations, heparin bridges thrombin to
fibrin, thereby promoting binding. With high concentrations of
heparin, generation of nonproductive binary heparin/thrombin
and heparin/fibrin complexes prohibits ternary complex formation. The inset table shows the apparent affinity (Kdapp) of thrombin for fibrin as a function of heparin concentration. Five nmol/L
thrombin and 10 mmol/L CaCl2 was clotted with 8 ␮mol/L fibrinogen in the presence of 10 nmol/L 125I-labeled active-site–
blocked thrombin and varying concentrations of heparin. After
centrifugation, an aliquot of supernatant was counted for radioactivity, and the concentration of bound thrombin was calculated by subtraction. At lower concentrations, heparin heightens
the apparent affinity of thrombin for fibrin, whereas at higher
heparin concentrations, the apparent affinity of thrombin for
fibrin is similar to that measured in the absence of heparin.
bivalirudin forms a 1:1 stoichiometric complex with thrombin. Once bound, however, the Arg-Pro bond at the aminoterminal of bivalirudin is cleaved by thrombin, thereby
restoring active site functions of the enzyme.19
Bivalirudin has a half-life of 25 minutes.20 In contrast to
hirudin, renal excretion is not the major route of bivalirudin
clearance.21 Instead, it is likely that bivalirudin is degraded by
endogenous peptidases. Consequently, bivalirudin may be
safer than hirudin in patients with renal impairment.
Argatroban
A synthetic small molecule, argatroban acts as a competitive
inhibitor of thrombin. An arginine derivative, argatroban
TABLE 1. Comparison of the Properties of Hirudin, Bivalirudin,
and Argatroban
Hirudin
Bivalirudin
7000
1980
527
Active site and
exosite 1
Active site and
exosite 1
Active site
Renal clearance
Yes
No
No
Hepatic metabolism
No
No
Yes
Plasma half-life, min
60
25
45
Molecular mass
Bivalirudin
A 20 amino acid polypeptide,18 bivalirudin is a synthetic
version of hirudin (Table 1). Its amino-terminal D-Phe-ProArg-Pro domain, which interacts with the active site of
thrombin, is linked via 4 Gly residues to a dodecapeptide
analogue of the carboxy-terminal of hirudin. Like hirudin,
1005
Site(s) of interaction with
thrombin
Argatroban
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February 26, 2002
TABLE 2. Potential Advantages of Direct Thrombin Inhibitors
Over Heparin
Advantage
No binding to plasma proteins
Not neutralized by platelet factor 4
Inhibition of fibrin-bound thrombin
as well as fluid-phase thrombin
TABLE 3. Comparison of Hirudin Doses Used in Clinical Trials
Evaluating its Utility in Acute Coronary Syndromes
Consequence
Predictable anticoagulant
response
Trial
OASIS-128
Bolus,
mg/kg
Infusion,
mg/kg per h
0.2
0.10
0.4
0.15
Maintained anticoagulant
activity in the vicinity of
platelet-rich thrombi
OASIS-2
0.4
0.15
Greater attenuation of thrombus
growth
HIT-III31
0.4
0.15
TIMI-9A30
0.6
0.20
GUSTO-2A32
0.6
0.20
TIMI-9B
0.1
0.10
GUSTO-2B34
0.1
0.10
29
35
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interacts only with the active site of thrombin.22 Argatroban is
metabolized in the liver, a process that generates at least 3
active intermediates. The half-life of argatroban is 45 minutes, but the half-life is prolonged in patients with hepatic
dysfunction.23
Other active site-directed inhibitors of thrombin that have
been evaluated in patients with acute coronary syndromes
include efegatran24,25 and inogatran.26
Potential Advantages of Direct Thrombin
Inhibitors Over Heparin
Direct thrombin inhibitors have potential advantages over
heparin (Table 2). Because heparin binds to plasma proteins,
some of which are acute phase reactants and others of which
are released from platelets or endothelial cells activated by
products of clotting, the anticoagulant response to heparin
varies among patients.11,12 Careful laboratory monitoring is
therefore necessary to ensure that a therapeutic anticoagulant
effect is obtained. In contrast, direct thrombin inhibitors
produce a more predictable anticoagulant response because
they do not bind to plasma proteins.
Platelet factor 4, a cationic protein released from activated
platelets, binds heparin with high affinity. Consequently,
platelet factor 4 released in the vicinity of platelet-rich
thrombi can locally abrogate heparin activity. In contrast,
platelet factor 4 does not affect direct thrombin inhibitors.
Thrombin bound to fibrin or fibrin degradation products is
resistant to inhibition by the heparin/antithrombin complex,
but is susceptible to inactivation by direct thrombin inhibitors.6,7 Because the active site of thrombin is not involved in
the interaction of the enzyme with fibrin, it remains accessible to active site-directed thrombin inhibitors, even when
thrombin is bound to fibrin. Consequently, these agents
inactivate fibrin-bound thrombin without displacing the enzyme from fibrin. In contrast, bivalent thrombin inhibitors,
such as hirudin and bivalirudin, displace bound thrombin
during the inhibition reaction by competing with fibrin for
access to exosite 1 on thrombin (Figure 1C).
Lower molecular-weight direct thrombin inhibitors, such
as bivalirudin and argatroban, are better able to inhibit
thrombin bound to fibrin clots than hirudin.6,7,27 This ability
likely reflects size-restricted diffusion of hirudin into intact
thrombi because once thrombi are solubilized, hirudin and
smaller inhibitors have equivalent activity against bound
thrombin.7
The potential advantages of direct thrombin inhibitors over
heparin prompted comparisons of these agents for treatment
of acute coronary syndromes. This review will primarily
focus on Phase III trials with hirudin and bivalirudin. To
provide perspective, Phase II trial results with argatroban and
other active site-directed thrombin inhibitors also will be
briefly discussed.
Clinical Trials
Hirudin
Unstable Angina
The largest phase II study to compare hirudin with heparin,
the Organization to Assess Strategies for Ischemic Syndromes (OASIS)-1 pilot trial, randomized 909 with unstable
angina or non–ST-elevation myocardial infarction to a 72hour infusion of hirudin, in either low or medium dose, or to
heparin.28 Doses of hirudin and heparin were adjusted to
maintain the activated partial thromboplastin time (APTT)
between 60 and 100 sec. Compared with heparin, hirudin
produced a promising reduction in the primary outcome, a
composite of cardiovascular death, myocardial infarction, or
refractory angina at 7 days (OR 0.57, 95% CI: 0.32 to 1.02)
and a significant reduction in the secondary outcome, a
composite of death, myocardial infarction, or refractory or
severe angina requiring revascularization at 7 days (OR 0.49,
95% CI: 0.27 to 0.86). Major bleeding occurred in about 1%
of patients in both treatment groups and was not significantly
higher in those given hirudin (OR 0.86, 95% CI: 0.23 to
3.19). Minor bleeding, however, was more frequent in patients given medium or low dose hirudin than in those treated
with heparin (21.3%, 16.2%, and 10.5%, respectively), differences that were statistically significant (P⫽0.033 and
0.001, respectively).
The results of the OASIS-1 trial prompted OASIS-2,29 a
phase III trial that randomized 10,141 patients with unstable
angina or non–ST-elevation myocardial infarction to a 72hour infusion of either medium-dose hirudin (Table 3) or
heparin. During treatment, hirudin produced a significant
reduction in the composite endpoint of death or myocardial
infarction compared with heparin (2.0% and 2.6%, respectively; OR 0.76, 95% CI: 0.59 to 0.99). Although the primary
outcomes, a composite of death or myocardial infarction at 7
days (3.6% and 4.2%, respectively; OR 0.84, 95% CI: 0.69 to
1.02) and 35 days (6.8% and 7.7%, respectively; OR 0.87,
95% CI: 0.75 to 1.01) were not significantly different
Weitz and Buller
Thrombin Inhibitors in Acute Coronary Syndromes
between the two groups, the absolute risk reduction in death
or myocardial infarction produced by hirudin during the
72-hour treatment period was maintained at 7 and 35 days.
Major bleeding occurred more frequently with hirudin than
with heparin (1.2% and 0.7%, respectively; OR 1.73, 95% CI:
1.13 to 2.63), but rates of life-threatening bleeding were
similar (0.4% in both groups).
When the results of the OASIS-1 and OASIS-2 trials are
combined,29 hirudin shows a significant reduction in the
composite outcome of death or myocardial infarction at 35
days compared with heparin (6.7% and 7.7%, respectively;
OR 0.86, 95% CI: 0.74 to 0.99). Thus, the early treatment
benefits of hirudin observed in both trials were maintained at
least for 1 month.
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Adjunct to Thrombolytic Therapy
Hirudin was compared with heparin as adjuncts to
thrombolytic therapy in 3 trials. The Thrombolysis in Myocardial Infarction (TIMI)-9A and Hirudin for Improvement of
Thrombolysis (HIT)-III trials only enrolled patients with
acute myocardial infarction,30,31 whereas the Global Use of
Strategies to Open Occluded Coronary Arteries (GUSTO)-2A
trial also included patients with unstable angina and those
with myocardial infarction who were ineligible for
thrombolytic therapy.32 The doses of hirudin given in the
TIMI-9A and GUSTO-2A studies, which are illustrated in
Table 3, were higher than that used in the OASIS-2 trial. In
contrast, the HIT-III trial used a hirudin regimen identical to
that used in the OASIS-2 study.
All 3 initial phase III trials were stopped prematurely
because of unacceptably high rates of major hemorrhage.
Although the rate of major bleeding was higher with hirudin
than with heparin in the TIMI-9A trial30 and there was a trend
for more intracranial bleeding with hirudin in the GUSTO-2A
and HIT-III trials,31,32 the rates of major bleeding with
heparin also were higher in the GUSTO-2A and TIMI-9A
trials than that observed in the GUSTO-1 study. Consequently, the TIMI-9B and GUSTO-2B trials were restarted
with doses of hirudin lower than that used in the OASIS-2
trial (Table 3), and the hirudin dose was adjusted to achieve
a target APTT of 55 to 85 sec in the TIMI-9B and 60 to 85
sec in GUSTO-2B trials. The dose of heparin also was
reduced to more closely match that used in the GUSTO-1
trial. With lower doses of anticoagulants, both trials completed their planned enrollment.
In GUSTO-2B,33 hirudin produced a modest reduction in
the primary outcome, a composite of death or myocardial
infarction at 30 days, compared with heparin (OR 0.89; 95%
CI: 0.79 to 1.00). During the initial 24 hours of treatment,
hirudin produced a significant reduction in death or myocardial infarction compared with heparin (1.3% and 2.1%,
respectively; OR 0.61, 95% CI: 0.46 to 0.81). Retrospective
subgroup analysis34 suggested that when used as adjuncts to
streptokinase, hirudin produced a 39% greater reduction in
death or myocardial infarction at 30 days than did heparin
(9.1% and 14.9%, respectively; OR 0.57, 95% CI: 0.38 to
0.87). In contrast, hirudin was not superior to heparin in
patients given tissue-type plasminogen activator (t-PA).
1007
Hirudin was no better than heparin in the TIMI-9B trial.35
Thus, the primary outcome, a composite of death, myocardial
infarction, cardiac failure, or cardiogenic shock at 30 days,
was similar in the hirudin and heparin groups (OR 1.09, 95%
CI: 0.88 to 1.36), as was the composite of death or myocardial
infarction at 30 days (OR 1.02, 95% CI: 0.80 to 1.31). There
was a trend for a reduction in non-fatal myocardial infarction
with hirudin during hospitalization (OR 0.65, 95% CI: 0.42 to
1.01) and at 30 days (OR 0.81, 95% CI: 0.56 to 1.18). Rates
of major bleeding and intracranial hemorrhage were similar
with hirudin and heparin in both the TIMI-9B35 and
GUSTO-2B trials.33
Taken together, the TIMI-9B and GUSTO-2B trials suggest that hirudin is at least as effective as heparin when used
as an adjunct to thrombolytic therapy. When the results of
these trials are pooled with those of the OASIS-2 study,
hirudin produces a 10% reduction in the risk of death or
myocardial infarction at 30 to 35 days compared with
heparin.29 However, the lack of a clear benefit of hirudin over
heparin at 30 days in the GUSTO-2B and TIMI-9B trials
limits the strength of this conclusion in patients with acute
myocardial infarction.
There are several potential explanations for the disappointing results of the GUSTO-2B and TIMI-9B trials. One
possibility is that the hirudin dose was too low. Support for
this concept comes from the results of the OASIS-1 and
OASIS-2 trials. When used at a slightly higher dose, hirudin
was more effective than heparin. Based on the results of the
HIT-III trial,31 however, it is unlikely that this medium-dose
hirudin regimen would be safe in conjunction with
thrombolytic agents.
Another potential explanation for the disappointing results
of the GUSTO-2B and TIMI-9B trials relates to the timing of
initiation of anticoagulant therapy. In these trials, hirudin or
heparin therapy was initiated 30 to 40 minutes after starting
thrombolytic therapy.33,35 Because more thrombin is exposed
during the thrombolytic process,7,36 concomitant anticoagulant therapy may be necessary for optimal efficacy.
Finally, the duration of anticoagulant therapy also may be
important. There is biochemical evidence that activation of
coagulation persists for at least 6 months after onset of acute
coronary syndromes,37 suggesting that the disrupted plaque is
slow to heal. Although short-term treatment with heparin or
hirudin suppresses coagulation, rebound activation occurs
once therapy is stopped.38 This phenomenon likely reflects
the inability of direct thrombin inhibitors to block thrombin
generation, which can trigger ongoing clotting once the
thrombin inhibitor is cleared. These observations suggest that
long-term anticoagulant treatment may be better than shortterm therapy.
Hirudin for Coronary Angioplasty
Hirudin was compared with heparin for prevention of
restenosis after percutaneous coronary angioplasty in the
Hirudin in a European restenosis prevention trial, VErsus
heparin Treatment In PTCA patients (HELVETICA) study.39
A total of 1141 patients scheduled for coronary angioplasty
were randomized to either hirudin given as a bolus plus
infusion for 24 hours, followed by subcutaneous hirudin or
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February 26, 2002
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placebo for an additional 72 hours, or to heparin given as a
bolus plus infusion for 24 hours, followed by subcutaneous
placebo injections for 72 hours. An additional bolus of
placebo (in the hirudin group) or heparin (in those randomized to heparin) could be given if the procedure lasted longer
than 1 hour, but no subsequent dose adjustments were
allowed. The primary outcome was event-free survival at 30
weeks, defined as absence of death, myocardial infarction,
coronary artery bypass grafting, or bailout angioplasty with or
without coronary stenting at the previous angioplasty site.
At 7 months, event-free survival was similar in those given
heparin, intravenous hirudin, or intravenous hirudin followed
by subcutaneous hirudin (67.3%, 63.5%, and 68.0%, respectively). Likewise, on repeat angiography at 6 months, there
was no significant difference in mean luminal diameter of the
dilated vessel among the 3 groups. Compared with heparin,
however, hirudin produced a significant reduction in the
primary composite outcome at 96 hours (OR 0.61, 95% CI:
0.41 to 0.90) that was preserved at 30 days. The time-to-event
curves converged thereafter, possibly reflecting the development of restenosis in both groups. No excess bleeding was
seen with hirudin.
It is not surprising that hirudin failed to prevent restenosis
because none of the antithrombotic agents tested to-date has
influenced this process.40 The observation that hirudin was
superior to heparin at 96 hours, and that this benefit was
maintained at 30 days, is consistent with the results of other
studies. In the OASIS-2 trial, 117 patients randomized to
hirudin or heparin for unstable angina underwent percutaneous coronary intervention. At 35 days, hirudin produced a
significant reduction in death or myocardial infarction compared with heparin (6.4% and 22.9%, respectively; OR 0.25,
95% CI: 0.07 to 0.86). Likewise, in the GUSTO-2B trial,
1404 patients received hirudin or heparin during percutaneous coronary interventions and for 72 hours thereafter. The
risk of death or myocardial infarction was lower in the hirudin
group than in those given heparin (2.1% and 3.8%, respectively; P⫽0.05). Thus, hirudin produces a greater reduction in
death or myocardial infarction than heparin in patients undergoing coronary angioplasty, suggesting that potent antithrombotic drugs are needed to prevent thrombosis after
mechanical injury to the coronary artery.
Bivalirudin
Bivalirudin for Coronary Angioplasty
Bivalirudin was compared with heparin in 4,098 patients
undergoing coronary angioplasty for unstable or postinfarction angina.41 Bivalirudin did not reduce the primary endpoint, a composite of in-hospital death, myocardial infarction,
abrupt vessel closure, or clinical deterioration of cardiac
origin necessitating coronary intervention (OR 0.9, 95% CI:
0.8 to 1.1). Major bleeding, however, was significantly less
frequent in patients randomized to bivalirudin than in those
given heparin (3.8% and 9.8%, respectively; P⬍0.001). In a
prospectively stratified subgroup of 704 patients with postinfarction angina, the primary endpoint occurred in significantly fewer patients receiving bivalirudin (OR 0.6, 95% CI:
0.40 to 0.90, P⫽0.004). Bleeding rates in this group were
significantly lower with bivalirudin than with heparin (3.0%
and 11.1%, respectively, P⬍0.001).
Despite these promising results, development of bivalirudin was temporarily halted. This decision was based on lack
of clear evidence of superior efficacy in lower-risk patients.
Although bivalirudin was safer than heparin, the initial
process used to manufacture bivalirudin was complex, resulting in an expensive product. Consequently, there was an
impression that the high cost of bivalirudin would limit its use
in all but the highest risk patients.
A number of factors have changed the outlook for bivalirudin. By streamlining the manufacturing process, the cost
of bivalirudin has now been reduced. Moreover, the decision
to stop the development of bivalirudin was based on analysis
of an incomplete data set because the original publication
lacked information on some patients and follow-up was
limited. A recent reanalysis of the results of the angioplasty
trial suggests that bivalirudin is not only of benefit in the
high-risk population, but also is superior to heparin in those at
lower risk. Using the same closed database as the initial
study, this reanalysis includes results on the entire intentionto-treat cohort of 4312 patients, as was specified in the initial
protocol. In addition, it provides complete follow-up information and a more contemporary definition of myocardial
infarction.42 When this additional information is included,
bivalirudin significantly reduced the combined endpoint of
death, myocardial infarction, or repeat revascularization in
the entire cohort at 7 days (OR 0.78, 95% CI: 0.62 to 0.99,
P⫽0.04) and at 90 days (OR 0.82, 95% CI: 0.70 to 0.96,
P⫽0.01). Although the absolute risk reduction with bivalirudin at 180 days was similar to that at 7 days, the difference
was no longer significant (OR 0.9, 95% CI: 0.78 to 1.04,
P⫽0.15). Major bleeding events were significantly less frequent with bivalirudin than with heparin (3.5% and 9.3%,
respectively; P⬍0.001).
Like hirudin,39 bivalirudin appears to be more effective
than heparin in patients undergoing coronary angioplasty.41,42
However, bivalirudin produces a 50% reduction in major
bleeding compared with heparin. Some investigators have
suggested that the dose of heparin used in the bivalirudin
angioplasty trial was excessive, resulting in a higher than
usual rate of bleeding in the control arm. Heparin was given
as a 175 U/kg bolus followed by an infusion of 15 U · kg⫺1 ·
h⫺1 so as to achieve an activated clotting time (ACT) over 350
sec. An additional 60 U/kg heparin bolus was administered if
the ACT was below this target. With this heparin regimen, the
median ACT was 383 sec and the interquartile range was 332
to 450 sec.49 This result is close to ideal anticoagulation
because a recent pooled analysis of data from 6 contemporary
randomized trials indicates that an ACT of 350 to 375 sec
with heparin produces the lowest rate of ischemic events at 7
days in coronary angioplasty patients not receiving glycoprotein (GP) IIb/IIIa antagonists. Moreover, the rates of major
bleeding are not significantly greater in patients with a higher
ACT than in those with a lower ACT.43
Argatroban and Other Active Site-directed
Thrombin Inhibitors
None of the active site-directed thrombin inhibitors has yet to
undergo Phase III testing. In Phase II evaluation, argatroban
Weitz and Buller
Thrombin Inhibitors in Acute Coronary Syndromes
1009
has been compared with heparin as an adjunct to t-PA in
patients with acute myocardial infarction,44 whereas efegatran
and inogatran have been compared with heparin in patients
with unstable angina,24,26 and efegatran has been compared
with heparin as an adjunct to thrombolytic therapy.25 In
contrast to the promising Phase II results with hirudin or
bivalirudin, none of the active site-directed thrombin inhibitors tested to-date appears to be superior to heparin. Further
trials are needed to determine whether this reflects inappropriate dosing or an intrinsic problem with this type of
inhibitor.
Conclusions and Future Directions
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Based on randomized trials, hirudin appears to be superior to
heparin in patients with unstable angina,29 and both hirudin
and bivalirudin are at least as effective as heparin in patients
undergoing coronary angioplasty.39,41,42 Despite these data,
however, the role of hirudin in acute coronary syndromes has
yet to be established. In patients with unstable angina, hirudin
and GPIIb/IIIa antagonists produce similar reductions in the
risk of recurrent ischemia.29,41 The major concerns about the
use of hirudin in acute coronary syndromes relate to its safety
and cost. Although safety is an issue, the relative increase in
bleeding with hirudin compared with heparin29 is similar to
that produced by addition of a GPIIb/IIIa antagonist to
heparin.45 Furthermore, it is possible that the safety of hirudin
could be improved by monitoring its anticoagulant effect and
adjusting the dose accordingly. Cost of goods also is an issue
with hirudin. Because it is considerably more expensive than
heparin, hirudin would need to be reserved for high-risk
patients.
Despite its promise, further development of hirudin is
unlikely. The disappointing experience with hirudin highlights the need for adequately powered phase II trials when
selecting appropriate doses for phase III evaluation.46
Currently, bivalirudin is the only direct thrombin inhibitor
with an established indication in acute coronary syndromes.
Bivalirudin is safer and more effective than heparin in
patients undergoing coronary angioplasty for post-infarction
angina41,42 and, based on reanalysis of the Phase III data,42
may also be advantageous in lower-risk individuals. Consequently, bivalirudin may provide a safer platform on which to
add other antithrombotic agents, such as GPIIb/IIIa antagonists. Alternatively, by better inhibiting thrombin-mediated
platelet aggregation, bivalirudin may obviate the need for
additional therapy. These concepts are currently under investigation in patients undergoing coronary artery stenting.
In patients with a history of heparin-induced thrombocytopenia, direct thrombin inhibitors can be used for anticoagulation during percutaneous coronary interventions. Bivalirudin is the only agent licensed for this indication, although the
others have been used. Bivalirudin is given as an intravenous
bolus followed by a 4-hour infusion, and its short half-life
facilitates early sheath removal. When used for treatment of
patients with established heparin-induced thrombocytopenia
and thrombosis, direct thrombin inhibitors are given by
continuous intravenous infusion until the platelet count rises,
at which time warfarin therapy can be initiated.
Figure 3. Steps in blood coagulation and sites of action of new
anticoagulants. Initiation of coagulation is triggered by the tissue
factor/factor VIIa complex (TF/VIIa), which activates factor IX (IX)
and factor X (X). Activated factor IX (IXa) propagates coagulation
by activating factor X in a reaction that utilizes activated factor
VIII (VIIIa) as a cofactor. Activated factor X (Xa), with activated
factor V (Va) as a cofactor, converts prothrombin (II) to thrombin
(IIa). Thrombin then converts fibrinogen to fibrin. Active siteblocked VIIa (VIIai) competes with VIIa for TF, whereas tissue
factor pathway inhibitor (TFPI) and nematode anticoagulant peptide (NAPc2) target VIIa bound to TF. Synthetic pentasaccharide
and DX-9065a inactivate Xa and activated protein C (APC) inactivates Va and VIIIa, whereas hirudin, bivalirudin, argatroban,
and ximelagatran target thrombin.
Although a meta-analysis suggests that bivalirudin is safer
than heparin for all clinical indications in which the 2 agents
were compared,47 recent data from the Hirulog Early Reperfusion Occlusion (HERO)-2 trial indicate that bivalirudin
produces more bleeding than heparin when used in conjunction with streptokinase. Post hoc analysis suggests that the
excess bleeding can be explained by the fact that bivalirudin
produced a higher APTT than heparin. These data indicate
that, like hirudin, bivalirudin needs careful monitoring when
used as an adjunct to thrombolytic therapy. In contrast,
unmonitored enoxaparin appears to be better than heparin as
an adjunct to coronary thrombolysis with tenectaplase.48
Consequently, low–molecular-weight heparin may be a more
useful and less costly adjunct to plasminogen activators than
direct thrombin inhibitors.
The advantages of hirudin and bivalirudin over heparin
have prompted development of orally bioavailable direct
thrombin inhibitors. The drug in most advanced development
is ximelagatran, a prodrug form of melagatran that targets the
active site of thrombin. With predictable pharmacokinetics
and no food or drug interactions,49 ximelagatran may not
require laboratory monitoring, thereby rendering it more
convenient than warfarin. Based on promising phase II data,
a phase III trial comparing ximelagatran with warfarin in
patients with atrial fibrillation has been initiated. To explore
the possibility that long-term anticoagulant therapy may be of
benefit in patients with unstable angina, a phase II trial
comparing ximelagatran with placebo is underway.
Recent attention has focused on blocking coagulation
above the level of thrombin.50 Indirect and direct inhibitors of
factor Xa are under investigation (Figure 3). Synthetic pen-
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February 26, 2002
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tasaccharide, an analogue of the pentasaccharide sequence of
heparin that mediates its interaction with antithrombin, catalyzes the inhibition of factor Xa by antithrombin. Phase III
clinical trials indicate that synthetic pentasaccharide is superior to low-molecular-weight heparin for thromboprophylaxis
after major orthopedic surgery when given once-daily subcutaneously.51,52 A phase II trial comparing pentasaccharide
with low–molecular-weight heparin for unstable angina is
underway.
DX9065a is a direct factor Xa inhibitor that blocks the
active site of the enzyme.50 Given intravenously, DX9065a is
undergoing phase III evaluation in patients with coronary
artery disease. Several orally bioavailable agents that target
the active site of factor Xa will soon be entering phase II
evaluation.
Drugs that block the initiation of coagulation are under
development. A recombinant analogue of a protein initially
isolated from the canine hookworm, nematode anticoagulant
protein-2 (NAPc2), inhibits factor VIIa bound to tissue factor
in a factor X/Xa-dependent fashion. Given subcutaneously on
alternate days, NAPc2 produces a dose-dependent reduction
in venographically-detected deep vein thrombosis in patients
undergoing elective knee arthroplasty.53 An ongoing phase II
trial in patients undergoing coronary angioplasty is comparing NAPc2 with placebo as adjuncts to heparin and aspirin.
Other inhibitors of the factor VIIa/tissue factor complex
include active site-blocked factor VIIa (factor VIIai) which
competes with factor VIIa for tissue factor binding,51 and
tissue factor pathway inhibitor (TFPI), which, like NAPc2,
blocks factor VIIa in factor Xa-dependent fashion. Factor
VIIai is under evaluation as an alternative to heparin in
patients undergoing coronary angioplasty. A phase III trial
comparing TFPI with placebo in patients with sepsis is
underway. This trial is predicated by the results of a recent
study demonstrating a reduction in mortality in sepsis patients
given recombinant activated protein C (APC).51
Parenteral and orally active drugs that target clotting
enzymes above the level of thrombin block the initiation or
propagation of coagulation. Clinical trials will be needed to
determine whether agents that inhibit thrombin generation are
better than those that directly block thrombin activity.
Acknowledgments
This work was supported by grants from the Heart and Stroke
Foundation of Canada, Canadian Institutes of Health Research, and
the Ontario Research and Development Challenge Fund. Dr Weitz is
the recipient of a Career Investigator Award from the Heart and
Stroke Foundation of Canada and holds the Heart and Stroke
Foundation of Ontario/J. Fraser Mustard Chair and the Canada
Research Chair in Cardiovascular Research at McMaster University.
Dr Buller is an Established Investigator of the Dutch Heart Foundation. The authors are indebted to Sue Crnic for excellent secretarial
support.
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KEY WORDS: thrombin
䡲
inhibitors
䡲
coronary disease
Direct Thrombin Inhibitors in Acute Coronary Syndromes: Present and Future
Jeffrey I. Weitz and Harry R. Buller
Circulation. 2002;105:1004-1011
doi: 10.1161/hc0802.104331
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