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Cardiovascular Research 41 (1999) 418432

Review

Prevention of activation of blood coagulation during acute coronary ischemic syndromes: beyond aspirin and heparin
a b, Shannon M. Bates , Jeffrey I. Weitz *
b a McMaster University and Hamilton Civic Hospitals Research Centre, Hamilton, Ontario, Canada Hamilton Civic Hospitals Research Centre, Henderson General Division, 711 Concession Street, Hamilton, Ontario, Canada L8 V 1 C3

Received 21 August 1998; accepted 8 October 1998

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Abstract Many of the acute coronary ischemic syndromes are triggered by spontaneous or mechanical disruption of atherosclerotic plaques with resultant activation of platelets and coagulation. Given the central role of platelets and thrombin in arterial thrombosis, current strategies for its prevention and treatment focus on both inhibition of platelet aggregation and control of thrombin generation and activity. Although aspirin and unfractionated heparin are the cornerstones of current treatment strategies, both have limitations. This review will describe these limitations and discuss new antithrombotic agents developed for use in acute coronary ischemic syndromes and as adjuncts for percutaneous coronary revascularization procedures. 1999 Elsevier Science B.V. All rights reserved.
Keywords: Coronary ischemic syndromes; Thrombosis; Anticoagulants; Thrombin inhibitors; Antiplatelet therapy; Heparin; Low-molecular-weight heparin; Hirudin

1. Introduction Many of the acute coronary ischemic syndromes are triggered by spontaneous or mechanical disruption of atherosclerotic plaque. Platelets adhere to exposed subendothelial matrix proteins and become activated [1,2]. Platelet activation induces conformational changes in glycoprotein IIb / IIIa (GPIIb / IIIa) which, by binding brinogen, cross-links adjacent platelets [1,2]. Vascular wall damage also exposes tissue factor (TF) which binds activated factor VII (FVIIa) [1,2]. The FVIIa-TF complex then triggers thrombin generation by activating factors IX and X [1,2]. In addition to activating platelets, thrombin converts brinogen to brin, amplies its own generation by activating factors V and VIII, key cofactors in prothrombinase and intrinsic tenase, and activates factor XIII which then stabilizes the brin clot [1,2]. Arterial thrombosis is, therefore, a thrombin- and platelet-dependent process. As a result, current strategies

for its prevention and treatment focus on both the inhibition of platelet aggregation and the control of thrombin generation and activity. While aspirin and unfractionated heparin (UFH) are the cornerstones of current treatment strategies, both have signicant limitations. These limitations have prompted the development of new antithrombotic agents for use in acute coronary syndromes and as adjuncts during percutaneous coronary revascularization procedures.

2. Limitations of aspirin and heparin Arterial thrombosis at sites of atherosclerotic plaque disruption is relatively resistant to inhibition by aspirin and heparin. Aspirin incompletely blocks platelet activation triggered by collagen exposed at sites of vascular injury or by thrombin generated as a consequence of plaque rupture (Fig. 1). The thienopyridine derivatives, ticlopidine and clopidogrel, selectively inhibit the platelet ADP receptor

*Corresponding author. Tel.: 11-905-574-8500; fax: 11-905-5752646; e-mail: weitzj@fhs.mcmaster.ca

Time for primary review 26 days.

0008-6363 / 99 / $ see front matter 1999 Elsevier Science B.V. All rights reserved. PII: S0008-6363( 98 )00323-X

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Fig. 1. Arterial thrombogenesis. Spontaneous or mechanical disruption of atherosclerotic plaque exposes collagen and von Willebrand factor (vWF), to which platelets adhere. Adherent platelets become activated and synthesize thromboxane A 2 (TXA 2 ) and release adenosine diphosphate (ADP), platelet agonists that recruit additional platelets. The coagulation mechanism is activated when tissue factor in the necrotic core of the plaque complexes activated factor VII. Coagulation factor assembly on the surface of activated platelets is responsible for platelet procoagulant activity and results in a burst of thrombin generation. Platelet activation in response to all agonists leads to conformational activation of GPIIb / IIIa, which by binding brinogen, cross-links adjacent platelets. Aspirin inhibits TXA 2 synthesis, whereas ticlopidine and clopidogrel block the platelet ADP receptor. GPIIb / IIIa antagonists block the nal common pathway of platelet aggregation, preventing aggregation in response to TXA 2 , ADP, and thrombin. Direct thrombin inhibitors bind and inactivate thrombin.

[3]. Because platelet activation in response to collagen is mediated by thromboxane A 2 and ADP, the combination of aspirin and a thienopyridine derivative may be better than either agent alone. This combination is widely used in patients undergoing coronary stent insertion where it has been shown to be superior to aspirin alone or aspirin plus warfarin [4]. However, even the combination of aspirin and thienopyridine derivatives does not completely block thrombin-mediated platelet activation. In contrast, because GPIIb / IIIa antagonists block the nal common pathway of platelet aggregation, these agents prevent platelet aggregation in response to both collagen and thrombin [5].

The resistance of arterial thrombosis to heparin largely reects the inability of the heparinantithrombin complex to inactivate thrombin bound to brin [6] and factor Xa bound to activated platelets trapped within the thrombus [7]. By activating prothrombin, platelet-bound factor Xa increases the amount of thrombin available to bind to brin. Because thrombin bound to brin remains enzymatically active and protected from inactivation by uid-phase inhibitors [5,6], the thrombus serves as a reservoir of active thrombin that causes thrombus growth by locally activating platelets [8] and amplifying coagulation [9]. The resistance of brin-bound thrombin to inactivation by the heparinantithrombin complex reects the propensity of heparin to bind simultaneously to brin and thrombin, thereby bridging thrombin to brin [10] (Fig. 2). This tightens the interaction of thrombin with brin and limits access of the heparinantithrombin complex to brin-bound thrombin [11,12]. Only heparin chains with a molecular mass (Mr ).11 200 are long enough to bridge thrombin to brin [13]. With a mean Mr 15 000, most of the chains of UFH are of sufcient length to perform this bridging function. In contrast, with a mean Mr of 5000, only a small fraction of low-molecular-weight heparin (LMWH) chains are long enough to bridge thrombin to brin. Consequently, LMWH may be better than UFH at inactivating brin-bound thrombin. The mechanism by which platelet-bound factor Xa is protected from inactivation by heparinantithrombin is not well established. However, it is likely to be similar to that of brin-bound thrombin because recent evidence suggests that heparin binds factor Xa in the presence of calcium [13,14]. Heparin not only binds brin, but also binds nonspecically to plasma proteins or to proteins released from activated platelets or endothelial cells [1519]. Platelet factor 4 may be a particularly important heparin-binding protein in the setting of arterial thrombosis because large amounts of this protein are likely to be released from platelets activated at sites of vascular injury [20]. Binding of heparin to plasma proteins limits the amount of heparin available to interact with antithrombin, thereby decreasing its anticoagulant activity [21]. Because the levels of heparin-binding proteins vary from patient to patient [21], heparin therapy must be carefully monitored to ensure an adequate anticoagulant response. The limitations of heparin have prompted the development of agents that not only inactivate brin-bound thrombin, but also produce a more predictable anticoagulant response. LMWH produces a more predictable anticoagulant response than UFH and may have slightly greater activity against brin-bound thrombin. Direct thrombin inhibitors, such as hirudin and bivalirudin (formerly known as hirulog), not only inactivate brin-bound thrombin, but also produce a predictable anticoagulant effect because they do not bind to plasma proteins and are not neutralized by platelet-factor 4 [22].

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Fig. 2. Inactivation of brin-bound thrombin by indirect and direct thrombin inhibitors. Thrombin binds to brin via exosite 1. Heparin tightens the interaction of thrombin with brin by simultaneously binding to brin and exosite 2, the heparin-binding domain, on thrombin. Thrombin within this ternary complex is protected from inactivation by the heparin-antithrombin complex (A). In contrast, active-site-directed thrombin inhibitors can access brin-bound thrombin (B). By competing with brin for exosite 1 on thrombin, bivalent thrombin inhibitors, such as hirudin or bivalirudin, also can inactivate brin-bound thrombin (C).

3. New antithrombotic agents The limitations of both aspirin and heparin have prompted the development of new antithrombotic agents that target platelets or various steps in the coagulation pathway. The most extensively studied are GPIIb / IIIa antagonists and direct thrombin inhibitors.

3.1. Platelet glycoprotein IIb / IIIa antagonists


Ligation of brinogen by conformationally activated GPIIb / IIIa is the nal common pathway in platelet aggregation. Consequently, GPIIb / IIIa is an attractive target for antithrombotic therapy of acute coronary syndromes. This new class of platelet inhibitors, which includes monoclonal antibodies against GPIIb / IIIa and a variety of low-molecular-weight synthetic inhibitors [23], has been evaluated in patients undergoing coronary angioplasty and in those with unstable angina or non-Q-wave myocardial infarction.

whether inhibition of a v b 3 contributes to the effectiveness of abciximab in humans, but in laboratory animals a v b 3 blockade attenuates injury-induced smooth muscle migration and neointimal hyperplasia [25]. While its free levels decrease rapidly when the drug is stopped, abciximab redistributes to new platelets entering the circulation and platelet-associated antibody persists in the circulation for greater than 14 days [26]. Rare complications of therapy include reversible thrombocytopenia and the development of human antichimeric antibodies that may preclude readministration of abciximab.

3.1.1. Monoclonal antibodies against glycoprotein IIb / IIIa Abciximab (ReoPro) is a recombinant monoclonal chimeric antibody fragment against GPIIb / IIIa consisting of the murine variable portion of the Fab fragment combined with the human constant region [24]. A potent inhibitor of platelet aggregation, abciximab prolongs the template bleeding time when given in doses that produce greater than 80% receptor blockade [24]. In addition to inhibiting GPIIb / IIIa, abciximab also blocks the closely related vitronectin receptor (a v b 3 ) [24]. It is uncertain

3.1.2. Synthetic glycoprotein IIb / IIIa antagonists Most of the synthetic GPIIb / IIIa antagonists are peptide or nonpeptide mimetic analogues of ArgGlyAsp (RGD) or LysGlyAsp (KGD), the minimal sequence required for GPIIb / IIIa recognition. Eptibatide (Integrelin), a cyclic heptapeptide KGD analogue that is highly selective for GPIIb / IIIa, exhibits minimal cross-reactivity with a v b 3 [27]. Tiroban (Aggrastat) and lamiban, nonpeptide RGD mimetics, also are specic inhibitors of GPIIb / IIIa [27]. Although these agents are given parenterally, xemiloban, oroban, and sibraban are examples of prodrugs that are metabolised to active forms after oral ingestion [28]. The synthetic antagonists have been associated with a low rate of reversible thrombocytopenia (approximately 1%). Thrombocytopenia is likely to be immune-mediated and caused by preformed antibodies that bind to neoepitopes on GPIIb / IIIa exposed when the inhibitor binds to the receptor (so-called ligand-induced binding sites).

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3.2. Thrombin inhibitors


The procoagulant effects of thrombin can be blocked either by inactivating the enzyme or by preventing its generation from precursor coagulation proteins. Indirect thrombin inhibitors, such as UFH and LMWH, activate the naturally occurring thrombin inhibitor, antithrombin. Direct thrombin inhibitors act in an antithrombin-independent manner by binding directly to thrombin and blocking its interaction with its substrates. Among the theoretical advantages of direct thrombin inhibitors over heparin is their ability to inactivate brin-bound thrombin in addition to free thrombin [5]. Moreover, they produce a more predictable anticoagulant response than heparin [22]. The most extensively studied direct thrombin inhibitors are hirudin and bivalirudin, both of which are administered parenterally.

4.1. Acute myocardial infarction with thrombolysis


Modern thrombolytic regimens remain suboptimal in that patency of the infarct-related coronary artery (thrombolysis in myocardial infarction [TIMI]-2 or TIMI-3 ow) is restored in only 6080% of patients at 90 min, and normal antegrade ow (TIMI-3 ow) is established in only 5560% of patients at the same time point [34]. Failure to restore ow may reect the relative proportions of platelets and brin in the thrombus because brin-rich thrombi are most susceptible to thrombolytic therapy. Reocclusion of initially successfully reperfused vessels occurs in up to 25% of patients [34,35] and may be associated with recurrent infarction and an increased risk of mortality and morbidity [35]. Failure to achieve or maintain patency of the infarct-related artery may reect the procoagulant state induced by thrombolytic therapy. After thrombolysis, additional thrombin is generated, in part because plasmin formed during the thrombolytic process activates contact factors [36], factor V [37], and possibly prothrombin [38,39]. Additional brin-bound thrombin is exposed when the thrombus undergoes lysis [40], and soluble brin degradation products bind thrombin and protect it from inactivation by uid-phase inhibitors [41]. Thrombin thus generated may also activate a latent carboxypeptidase B (thrombin activatable brinolysis inhibitor or TAFI), that attenuates brinolysis, presumably by removing carboxyterminal lysine residues from brin, thereby preventing plasminogen and plasmin binding [42,43]. The goal of adjunctive treatment in patients with acute myocardial infarction receiving thrombolytic therapy, therefore, is to accelerate restoration of anterograde ow and to help maintain patency of the infarct-related artery. The substantial value of aspirin in patients with acute myocardial infarction, regardless of electrocardiographic ndings on presentation or the use of reperfusion therapy, was conclusively demonstrated by the International Study of Infarct Survival (ISIS)-2 [44]. The role of subcutaneous UFH given after thrombolysis in patients receiving aspirin has been examined in three large multicentre randomized trials [4547]. Taken together, the results of the Italian portion of the Gruppo Italiano per lo Studio della Sopravvivenza nel-Infarto Miocardico (GISSI)-2 trial [45], the international extension of the GISSI-2 trial [46], and the ISIS-3 trial [47] indicate that no signicant mortality or other clinical benet is associated with the use of high doses of subcutaneous UFH (12 500 units twice daily, beginning 412 h after initiation of thrombolysis) in patients receiving aspirin. Moreover, subcutaneous UFH was associated with a small, but statistically signicant, excess in major hemorrhage. Critics of these studies have, however, argued that delayed administration and the inferior efcacy of subcutaneous UFH minimized potential clinical benet. The results of small patency trials [4850] and the rst Global Utilization of Strategies to Open Occluded Cor-

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3.2.1. Hirudin Hirudin, a 65-amino acid polypeptide originally isolated from the saliva of the medicinal leech, is a potent and specic inhibitor of thrombin. It binds to both thrombins active site and its substrate recognition site [29,30]. Recombinant hirudin, unlike natural hirudin, lacks a sulphate group on the tyrosine residue at position 63. While this results in a 10-fold reduction in its afnity for thrombin, recombinant hirudin still binds tightly to the enzyme forming a slowly reversible complex [31]. The almost irreversible nature of this complex may be considered a relative weakness, as there is no available antidote should bleeding occur. 3.2.2. Bivalirudin This synthetic 20-amino acid polypeptide also acts as a bivalent inhibitor of thrombin [32]. Its amino-terminal segment is linked to a dodecapeptide analogue of hirudins carboxy-terminal by four glycine residues [32]. Thrombin cleavage of a peptide bond within the amino-terminal segment of bivalirudin results in only transient active site inhibition [33]. Although the carboxy-terminal portion of bivalirudin remains bound to thrombins substrate recognition site, without its amino-terminal segment, it is a much weaker thrombin inhibitor [33]. Its shorter half-life may confer this agent with a better safety prole than hirudin.

4. Clinical evaluation of new antithrombotics The new antiplatelet agents and antithrombins have been evaluated both in patients with acute coronary ischemic syndromes and in those undergoing interventions such as coronary angioplasty and coronary artery stenting. The results of their use in specic clinical settings will be discussed in turn.

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onary Arteries (GUSTO-1) trial [51] have been invoked to support the routine administration of early intravenous UFH, especially when used with tissue plasminogen activator (t-PA). Recent meta-analyses have, however, shown no net mortality benet associated with intravenous UFH when used in conjunction with thrombolytics and full-dose aspirin [52,53]. Moreover, the early termination of both the TIMI-9A [54] and GUSTO-IIa [55] trials because of excessive major bleeding in patients receiving intravenous UFH (despite the fact that the heparin dose was only 20% higher than that used in previous trials), emphasizes the potential hazards of high-dose UFH in this situation.

4.1.1. Antiplatelet agents 4.1.1.1. Glycoprotein IIb / IIIa antagonists In laboratory animals, the dose of thrombolytic agent can be substantially reduced, and the rate and durability of reperfusion increased, when thrombolytic therapy is combined with GPIIb / IIIa antagonist [5666]. This combination of therapies has been evaluated in three small pilot studies. The Thrombolysis and Angioplasty in Myocardial Infarction (TAMI)-8 pilot study [67], the Integrelin to Manage Platelet Aggregation to Prevent Coronary Thrombosis (IMPACT)-AMI trial [68], and the PARADIGM trial [69] demonstrated improved coronary reperfusion by either angiography or continuous electrocardiography when GPIIb / IIIa antagonists were added to full-dose thrombolytic therapy. Further clinical studies are required to determine the efcacy and safety of GPIIb / IIIa inhibition in this setting. 4.1.2. Thrombin inhibitors 4.1.2.1. Hirudin Promising results from phase II trials that used patency of the infarct-related artery as a surrogate endpoint [7072], prompted phase III clinical trials of hirudin. Both the TIMI-9A [54] and GUSTO-IIa [55] trials comparing intravenous hirudin with dose-adjusted intravenous UFH as adjunctive therapy to thrombolysis and aspirin in patients with acute myocardial infarction were temporarily halted because of unacceptably high rates of intracranial hemorrhage in patients receiving either therapy. The trials were restarted with lower doses of UFH and hirudin. As an additional safety measure, both agents were titrated to achieve an activated partial thromboplastin time (aPTT) in the range of 5585 s. The TIMI-9B [73] and GUSTO-IIb [74] trials together randomized over 7000 patients with ST-segment elevation myocardial infarction, all of whom received aspirin and either streptokinase or tissue-plasminogen activator (t-PA), to adjunctive treatment with either intravenous hirudin or heparin. Overall, there was no signicant difference in 30-day mortality or mortality and reinfarction between the two groups. A subgroup analysis of results in 1082 patients

who received streptokinase in the GUSTO-IIb trial demonstrated a 34% reduction in the rate of death and reinfarction at 30 days in patients randomized to hirudin compared with those given heparin (9.6 vs. 14.7%, respectively; P 50.01) [75]. No such favorable interaction was seen in patients receiving hirudin as an adjunct to t-PA. Critics of these studies have suggested that the hirudin dose was too low and treatment duration too short to obtain evidence of clinical efcacy. In addition, the delay in initiation of hirudin may have permitted the development of a procoagulant state and subsequent TAFI activation after thrombolysis. Nonetheless, in this population of patients treated with hirudin in the manner described above, therapy with hirudin is no better than heparin in preventing adverse clinical outcomes.
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4.1.2.2. Bivalirudin While bivalirudin has shown promise in patency trials involving patients with ST-segment elevation myocardial infarction treated with thrombolytics and aspirin [7678], its clinical superiority over UFH remains to be tested in large-scale trials. 4.2. Unstable angina / non-ST segment elevation myocardial infarction
Although the role of aspirin in patients with unstable angina or non-ST-segment elevation myocardial infarction [79,80] appears well-dened, there is considerable confusion and controversy regarding recommendations for the use of UFH in this patient population. Interpretation of these data is difcult due to variations in treatment, patient population heterogeneity, and small trial size. A number of small trials have shown limited benet to the addition of heparin to aspirin in this patient population [8183]. Moreover, pooled data in a recent meta-analysis showed no statistically signicant difference between the use of intravenous UFH with aspirin compared with aspirin alone in patients with unstable angina, although there was a trend towards a reduction in the relative risk of myocardial infarction or death with added intravenous UFH (95% CI 0.441.02, P 5NS) [84]. Oral anticoagulants were widely used for the treatment of patients with acute myocardial infarction soon after their introduction in the 1940s. This practice changed after several critical reviews, published in the 1970s, questioned the utility of oral anticoagulants in this patient population. The issue has now resurfaced based on the positive ndings in three recent, well designed, placebo-controlled randomized trials. In the Sixty Plus trial [85], patients greater than 60 years of age who had been receiving oral anticoagulants (acenocoumarol or phenprocoumon) for a mean of 6 years after myocardial infarction were randomized to placebo or to continued anticoagulant therapy at doses sufcient to achieve an International Normalized Ratio (INR) of 2.7 4.5. Those who continued on treatment had signicantly

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fewer recurrent myocardial infarctions and strokes. This study, however, provided no evidence that initiation of oral anticoagulant therapy soon after myocardial infarction was benecial. The Warfarin Re-Infarction Study (WARIS) [86] randomized 1214 patients recovering from acute myocardial infarction to treatment with warfarin (target INR of 2.8 4.8) or placebo a mean of 27 days after onset of symptoms. Patients were treated for an average of 37 months. Warfarin produced a 24% reduction in mortality (P 5 0.027), a 34% reduction in recurrent infarction (P 50.007), and a 55% reduction in the number of total cerebrovascular accidents (P 50.0015), including hemorrhages. Serious bleeding was noted in 0.6% of the warfarin-treated patients per year. The Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis (ASPECT) [87] study randomized 3404 patients with anterior myocardial infarction within the past 6 weeks to oral anticoagulants (nicoumalone or phenprocoumon) with a target INR of 2.84.8 or placebo. Approximately 25% of patients had received thrombolytic therapy. Over a mean follow-up of 37 months, oral anticoagulants produced statistically signicant reductions in recurrent myocardial infarction (53%), cerebrovascular events (40%), and all vascular events (35%). There was a statistically insignicant 10% reduction in all-cause mortality. Although major bleeding complications were more common with anticoagulants (Hazard Ratio:3.87, 95% CI:2.336.41), at 3 years, 83% of those in the anticoagulant group were event-free (including major hemorrhage), compared with 76% of those in the placebo group (P ,0.0001). Overall, these trials suggest that oral anticoagulant treatment after myocardial infarction produces a reduction in clinically important vascular outcomes. While the efcacy of long-term oral anticoagulant therapy after myocardial infarction has been directly compared [88,89] with that of aspirin, poor study design and small sample size limit interpretation of results. Aspirin (150 mg / day) was compared with anticoagulation (intravenous UFH, followed by oral anticoagulation with a target INR of 2.02.5) in 1036 patients who received anistreplase thrombolysis for myocardial infarction in the unblinded AFTER study [90]. No difference in the incidence of cardiac death or reinfarction at 30 days or 3 months was found. The trial was, however, too small to condently claim treatment equivalence. Patients receiving anticoagulation were more likely than those receiving aspirin to have a stroke or severe bleeding by 3 months (3.9 vs. 1.7%, respectively, P 5 0.04). The Coumadin Aspirin Reinfarction Study (CARS) [91], in which 8803 patients were randomized to either 160 mg of aspirin daily, 1 mg warfarin with 80 mg aspirin daily, or 3 mg warfarin with 80 mg aspirin daily, demonstrated that low, xed-dose warfarin therapy combined with low-dose aspirin did not provide clinical benet beyond that achiev-

able with 160 mg aspirin alone. Fixed low-dose warfarin in combination with aspirin cannot, therefore, be recommended after myocardial infarction. While both aspirin and oral anticoagulants are more efcacious than placebo after myocardial infarction, the increased rate of non-fatal major hemorrhage and the greater cost and complexity of oral anticoagulant therapy make aspirin a better choice.

4.2.1. Antiplatelet agents 4.2.1.1. Glycoprotein IIb / IIIa antagonists Tiroban has been studied in aspirin-treated patient with unstable angina or non-Q-wave myocardial infarction in two recent trials [92,93]. In the Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) study [92], in which tiroban was compared with UFH, tiroban produced a 32% reduction in the incidence of death, myocardial infarction, or refractory angina at 48 h (P 50.01); a benet not sustained at 7 days. In the PRISM in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial [93], the combination of tiroban and intravenous UFH reduced the incidence of death, myocardial infarction, or refractory ischemia by 27% at 48 h compared with UFH alone (P 50.08). Moreover, this benet was sustained at 6 months. The study was stopped prematurely in the tiroban-alone group because of excess mortality at 7 days compared with that in the groups given heparin alone or combined tiroban and heparin. The reason for the differences in results between these two studies is unclear. While it is possible that the excess mortality in patients receiving tiroban alone in the PRISM-PLUS trial was the result of chance, this study included higher risk patients. More than 90% had ST-segment changes on their presenting electrocardiogram compared with 33% in the PRISM study. In addition, 45% had evidence of non-Q-wave myocardial infarction while only 25% of those in the PRISM study had similar ndings. Higher risk patients may require higher doses of GPIIb / IIIa antagonists or longer duration of therapy for treatment to be effective. The durable benets seen in the PRISM-PLUS study may be the result of tiroban addition to UFH, the increased use of revascularization therapy in this trial, or the continuation of antithrombotic therapy during revascularization. In the Platelet Glycoprotein IIb / IIIa in Unstable Angina: Receptor Suppression Using Integrelin Therapy (PURSUIT) trial, 10 948 patients with acute coronary syndromes but no persistent ST-segment elevation on electrocardiogram were randomized to receive a bolus and infusion of either eptibatide or placebo, in addition to aspirin and heparin [94]. As in the PRISM-PLUS trial, in approximately 45% of patients the index episode was classied as a myocardial infarction. The addition of eptibatide resulted in a 1.5% absolute reduction in the incidence of the primary endpoint of death or nonfatal myocardial infarction occurring up to 30 days after the index event (14.2 vs. 15.7%, P 50.04). Major or severe

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bleeding was, however, signicantly more frequent in patients receiving eptibatide.

4.2.1.2. Thienopyridine derivatives Ticlopidine has been studied in patients with unstable angina in a multicentre, randomized trial of 625 patients [95]. Compared with placebo, ticlopidine produced a greater than 40% reduction in mortality and nonfatal myocardial infarction at 6 months. However, as ticlopidine has not been directly compared with aspirin, and appears to have a delayed onset of peak action, there is insufcient evidence to recommend its general use in the acute setting. Clopidogrel has not been evaluated in this situation. 4.2.2. Thrombin inhibitors 4.2.2.1. Low-molecular-weight heparin One of the rst studies to compare LMWH with intravenous UFH was a small, randomized, single-blinded, placebo-controlled trial in patients with unstable angina, all of whom were treated with aspirin. Those receiving LMWH (nadroparin) were less likely than those receiving adjusted-dose UFH or

aspirin alone to develop recurrent angina or myocardial infarction [83]. These results prompted three large randomized trials of LMWH in aspirin-treated patients with unstable angina (Table 1): the Fragmin During Instability in Coronary Disease (FRISC) trial [96], the Fragmin in Unstable Coronary Artery Disease (FRIC) study [97], and the Efcacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE) trial [98]. While the addition of subcutaneous dalteparin (Fragmin) to aspirin therapy in this patient population reduced the incidence of death or myocardial infarction at 6 days compared with placebo [96], it did not provide any benet beyond that produced by UFH [97]. Moreover, with reduction of the dalteparin dose from 120 anti-Xa units / kg twice daily to 7500 anti-Xa units once daily at 6 days, there was an apparent reactivation of disease, especially among smokers [96], suggesting a need for long-term treatment at the higher dose. In contrast, treatment with 1 mg / kg of enoxaparin for 2 to 8 days resulted in a signicant decrease in the number of events at 14 days compared with UFH therapy [98]. More importantly, this difference was sustained through 30 days. Thus, on the

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Table 1 LMWH in patients with unstable angina or non-q-wave myocardial infarction receiving aspirin therapy FRISC [96] Number enrolled LMWH Dose of LMWH 1506 Dalteparin (Fragmin) 120 anti-Xa units / kg twice daily to a maximum of 10 000 units for 6 days then 7500 anti-Xa units once daily to day 3545) Placebo FRIC [97] 1499 Dalteparin (Fragmin) 120 anti-Xa units / kg twice daily to a maximum of 10 000 units for 6 days then 7500 anti-Xa units once daily to day 45 Adjusted-dose intravenous UFH to day 6, placebo to day 45 (chronic phase) ESSENCE [98] 3171 Enoxaparin (Lovenox) 100 anti-Xa units / kg twice daily for 28 days

Comparison group

Adjusted-dose intravenous UFH for 2 to 8 days placebo to day 30 (chronic phase) NA

Death / MI at 6 days LMWH Placebo / UFH Death / MI / recurrent angina at 6 days LMWH Placebo / UFH Death / MI / recurrent angina at 14 days LMWH Placebo / UFH Death / MI during chronic phase LMWH Placebo / UFH Death / MI / recurrent angina during chronic phase LMWH Placebo / UFH Bleeding (acute phase) LMWH Placebo / UFH Bleeding (chronic phase) LMWH Placebo / UFH

1.8% * 4.8% ** NA

3.9% 3.6% 9.3% * 7.6% NA

NA

NA

16.6% * 19.8% NA

8.0% 10.7%

4.3% 4.7%

NA

12.3% 12.3% 1.1% 1.0% 1.1% 1.0%

23.3% 19.8% ***

0.8% 0.5% 0.3% 0.3%

6.5% 7.0%

Chronic phase: FRISC5640 days, FRIC5645 days, ESSENCE, to day 30. * Primary endpoint; ** P 50.001; *** P 50.02; remainder of comparisons P .0.05. Abbreviations: NA, not available; UFH, unfractionated heparin; LMWH, low-molecular weight heparin.

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basis of these three studies, it appears that LMWH is at least as effective as UFH in patients with unstable angina. The former is, however, more convenient, as it can be given subcutaneously and requires no monitoring. In all three trials, there was no association between the use of LMWH and major bleeding [9698]. In the TIMI11A trial, a multicentre randomized double-blind dosending study, patients receiving more than 1 mg / kg of enoxaparin subcutaneously twice-daily were more likely to develop major hemorrhage [99]. These ndings suggest that 1 mg / kg of enoxaparin (which is equivalent to approximately 100 anti-Xa units / kg) subcutaneously twice-daily represents the maximum dose that can safely be given in this setting.

4.2.2.2. Hirudin Promising results have been obtained from phase-II studies comparing hirudin with UFH in patients with unstable angina, using angiographic endpoints [100]. However, among those patients enrolled in the GUSTO-IIb trial who presented without ST-segment elevation and, therefore, did not receive thrombolytic therapy, there was no signicant difference in the rate of death or myocardial infarction between those receiving intravenous UFH (9.1%) and those treated with hirudin (8.3%) (OR: 0.90, 95% CI: 0.781.06, P 50.22) [74]. Intracranial hemorrhage occurred in 0.02% and 0.2% of patients, respectively (P 50.06). In the pilot Organization to Assess Strategies for Ischemic Syndromes (OASIS) study, the primary outcome of cardiovascular death, new myocardial infarction, or refractory angina at 7 days occurred in 3.0% of patients randomized to high-dose hirudin (0.4 mg / kg / bolus followed by a 72-h infusion at 0.15 mg / kg / h), 4.4% of those allocated to low-dose hirudin (0.2 mg / kg bolus followed by a 72-h infusion at 0.1 mg / kg / h), and 6.5% of those treated with intravenous UFH (UFH compared with high-dose and low-dose hirudin, P 50.045 and P 50.267, respectively) [101]. There was no signicant increase in major bleeding (1.1, 0.7 and 1.1% of the UFH, low-dose hirudin, and high-dose hirudin groups, respectively). The OASIS-II trial, which uses a 232 factorial design to assess the effects of hirudin compared with UFH, and warfarin compared with placebo in patients with unstable angina, is ongoing. 4.2.2.3. Bivalirudin The use of bivalirudin in patients with unstable angina has been evaluated in pilot studies [102104]. The promising results obtained require conrmation in large clinical studies. 4.3. Percutaneous coronary interventions
Interventional coronary revascularization procedures produce damage to the vascular endothelium and, to varying degrees, the underlying arterial wall. Formation of arterial thrombus at the site of vessel injury contributes to early complications including peri-procedural death, acute

myocardial infarction, and recurrent ischemia [105108]. Moreover, delayed vascular reocclusion, reecting intimal hyperplasia and vascular remodelling at the treatment site, occurs in up to 30% of patients after coronary angioplasty [109111]. A number of studies have demonstrated that, compared with balloon angioplasty, stent placement reduces the rate of clinical and angiographic restenosis in selected patients [112114]. In the past, however, stent use was complicated by subacute thrombosis in 3.58.6% of stent-treated patients [113115]. Initially, aggressive anticoagulant regimens were used to prevent this complication [113115]. The use of improved stent deployment techniques with attendant reductions in the frequency of subacute thrombosis [116] has allowed the evaluation of less aggressive anticoagulant regimens. Small studies have shown that peri-procedural dextran-40 and dipyridamole provide little incremental benet over aspirin and intravenous UFH given in doses similar to those used during conventional coronary angioplasty [116].

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4.3.1. Antiplatelet agents 4.3.1.1. Glycoprotein IIb / IIIa antagonists Despite aspirin therapy, early ischemic events occur in 3.012.8% of patients undergoing coronary angioplasty [106,107,117]. Because GPIIb / IIIa antagonists inhibit platelet aggregation in response to all agonists, they have been extensively investigated in this setting (Table 2). The Evaluation of c7E3 for the Prevention of Ischemic Complications (EPIC) trial demonstrated the efcacy of abciximab in reducing ischemic complications after high-risk coronary interventions [117]. More importantly, the benets seen at 30 days were sustained for at least 3 years after the procedure [118]. However, the use abciximab was associated with a signicant increase in major bleeding. The Evaluation of PTCA to Improve Long-term Outcome by Abciximab GPIIb / IIIa Receptor Blockade (EPILOG) trial was designed to determine whether the use of low-dose UFH and early sheath removal would reduce the risk of bleeding in patients receiving abciximab [119]. The trial was terminated after the rst interim analysis because of a highly signicant 55% decrease in the primary efcacy endpoint of death, myocardial infarction, or need for revascularization at 30 days in patients receiving abciximab. Each of the components of the composite endpoint was similarly reduced. The reduction in acute ischemic complications was maintained throughout the 6-month follow-up period. Moreover, the clinical benet derived from the inhibition of platelet thrombus formation by GPIIb / IIIa receptor blockade was uncoupled from the risk of hemorrhage. A retrospective analysis of patients enrolled in studies evaluating the use of abciximab in coronary angioplasty indicates that, compared with placebo, the prophylactic use of this agent in those undergoing bailout stent implantation reduces the risk of death and myocardial infarction 30

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Table 2 Effect of adding GPIIB / IIIA antagonists to UFH and aspirin in patients undergoing percutaneous coronary interventions
EPIC [117] Population High-risk patients EPILOG [119] Low-risk patients IMPACT-II [122]) Patients undergoing elective, urgent, or emergent coronary intervention 4010 Eptibatide Bolus of 135 mg/kg followed by a 2024-h low-dose infusion (0.5 mg/kg/min) or Bolus of 135 mg/kg followed by a 2024 h high dose infusion (0.75 mg/kg/min) 100 units/kg bolus prior to procedure with incremental boluses to maintain ACT 300350 s during procedure (standard UFH) RESTORE [123] High-risk patients undergoing coronary interventions within 27 h of presenting with unstable angina or acute myocardial infarction 2212 Tiroban Bolus of 10 mg/kg followed by a 36-h infusion at 0.15 mg/kg/min CAPTURE [124] Patients with refractory unstable angina

No. enrolled Agent GP IIb/ IIIa antagonist regime

2099 Abciximab Bolus of 0.25 mg/kg or Bolus of 0.25 mg/kg followed by 12-h infusion at 10 mg/min

2973 Abciximab Bolus of 0.25 mg/kg followed by 12-h infusion at 0.125 mg/kg/min

1265 Abciximab Bolus of 0.25 mg/kg starting 1824 h prior to procedure followed by a continuous infusion of 10 mg/min until 1 h after procedure 100 units/kg bolus (to maximum of 10 000 units) prior to procedure with boluses to achieve ACT of 300 s during procedure Heparin administered until at least 1 h after PTCA

UFH regimen

10 00012 000 units as a bolus prior to procedure with incremental boluses to maintain ACT 300350 s during procedure After angioplasty adjusted to maintain aPTT 1.523 control for 12 h until sheaths removed

100 units/kg bolus prior to procedure with incremental boluses to maintain ACT 300350 s during procedure (standard UFH) or 70 units/kg bolus prior to procedure with incremental boluses to maintain ACT 200300 s during procedure; early removal of sheath (low dose UFH) Placebo with standard-dose UFH

150 units/kg bolus prior to procedure to maximum of 10 000 units with incremental boluses to maintain ACT 300400 s during procedure

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Comparison group

Placebo with UFH

Placebo with UFH

Placebo with UFH

Placebo with UFH

Death/Nonfatal MI/need for urgent coronary intervention at 30 days Placebo 12.8% 11.7% Bolus 11.4% Bolus1infusion 8.3% ** Bolus1standard-dose UFH 5.4% *** Bolus1low-dose UFH 5.2% *** Low-dose infusion High-dose infusion

11.4%

12.2% 10.3%

15.9% 11.35% *

9.25% 9.95%

All patients received 325 mg of aspirin prior to procedure and then daily. UFH, unfractionated heparin. * P ,0.05; ** P 50.050.001; *** P ,0.001; remainder of comparisons P .0.05.

days and 6 months after the procedure [120]. These results have been conrmed in a recent trial assessing the efcacy of abciximab in patients undergoing elective coronary artery stenting. The addition of abciximab to aspirin, intravenous heparin, and ticlopidine reduced the rate of death, myocardial infarction, or need for urgent revascularization in the rst 30 days from 10.8 to 5.3% (hazard ration 0.48, 95% CI: 0.330.69, P ,0.001) [121]. Rates of death or large myocardial infarction were signicantly lower among patients assigned stent plus abciximab (3.0%) than among those assigned stent plus placebo (7.8%) (P ,0.001). Major bleeding complications occurred in 2.2% of patients assigned stent plus placebo and 1.5% assigned sent plus abciximab (P 50.38) The Integrelin to Manage Platelet Aggregation to Pre-

vent Coronary Thrombosis (IMPACT)-II [122] and the Randomized Efcacy Study of Tiroban for Outcomes and Restenosis (RESTORE) [123] trials investigated the role of two synthetic GPIIb / IIIa antagonists in patients undergoing coronary intervention. In both studies, treatment with these agents protected against early adverse events. However, the difference in the primary (30-day) endpoint event rate between the placebo and treatment groups, when analyzed in an intention-to-treat manner, was not statistically signicant in either study. Thus, in contrast to the long-term benets obtained with abciximab in the EPIC study [118], the synthetic GPIIb / IIIa antagonists tested to date have not reduced the frequency of long-term ischemic events after coronary angioplasty. While inadequate dosing of the synthetic

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antagonists may be to blame, it is possible that the longterm effects of abciximab are the result of its prolonged circulating half-life and its ability to block the vitronectin receptor. The c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) study was designed to assess whether abciximab, given during the 1824 h before percutaneous coronary angiography and continued until 1 h after the procedure, could improve outcome in patients with refractory unstable angina [124]. The primary endpoint of 30-day death, myocardial infarction, or urgent intervention for recurrent ischemia occurred in 11.3% of those who received abciximab compared with 15.9% of placebo recipients (P 50.012). This difference was due mainly to a difference in the proportion with myocardial infarction (4.1% and 8.2%, respectively, P 50.002). At 6 months, however, the composite endpoint of death, myocardial infarction, or urgent intervention for recurrent ischemia had occurred in 31.0% of those who had received abciximab and 30.8% of those randomized to placebo. Major bleeding was uncommon but occurred more often with abciximab than with placebo (3.8 vs. 1.9%, P 5 0.043).

anticoagulant group (RR: 0.14, 95% CI: 0.020.62, P 5 0.004). Hemorrhagic complications occurred only in those receiving anticoagulants (6.5%) (RR: 0, 95% CI: 00.19, P ,0.001).

4.3.2. Thrombin inhibitors 4.3.2.1. Hirudin The Hirudin in a European Trial Versus Heparin in the Prevention of Restenosis after PTCA (HELVETICA) study was a multicentre double-blind randomized trial involving 1141 patients with unstable angina and one or more clinically important coronary narrowings suitable for treatment with percutaneous coronary angioplasty [126]. Participants were randomized to receive UFH (bolus of 10 000 units, followed by an infusion of 14 units / kg for 24 h) or one of two hirudin regimens (40 mg bolus, followed by an intravenous infusion of 0.2 mg / kg for 24 h or the same regimen, followed by twice daily 40 mg hirudin injections subcutaneously for 3 days). All patients received 100 to 500 mg of aspirin on the day of angioplasty and then daily for at least 14 days. While there was a reduction in the composite endpoint of death, nonfatal myocardial infarction, coronary bypass surgery, stenting, or second angioplasty at 96 h in patients receiving hirudin (7.9% of patients randomized to intravenous hirudin and 5.6% of those allocated to intravenous and subcutaneous hirudin) compared with patients in the UFH group (11.0%) (combined RR with hirudin: 0.61, 95% CI: 0.410.90, P 50.023), there was no signicant difference between the groups with respect to the primary endpoint. That is, the proportion of patients event-free at 7 months was similar in all three treatment arms (67.3% of those receiving UFH, 63.5% of those randomized to intravenous hirudin, and 68.0% of those in the group receiving both intravenous and subcutaneous hirudin (P 50.61)). There was no signicant difference with respect to major bleeding among the groups. 4.3.2.2. Bivalirudin In a multicentre randomized doubleblind trial, the Hirulog Angioplasty Study Investigators compared UFH (175 units / kg bolus, followed by an 18 to 24-h infusion at 15 units / h) and bivalirudin (1.0 mg / kg intravenous bolus, followed by a 4-h infusion at 2.5 mg / kg / h and then a 14 to 20-h infusion at 0.2 mg / kg / h) in 4098 patients undergoing angioplasty for unstable or postinfarction angina [127]. All patients received 300 to 325 mg of aspirin daily. Bivalirudin did not reduce the primary endpoint of in-hospital death, myocardial infarction, abrupt closure, or rapid clinical deterioration of cardiac origin requiring coronary intervention (OR: 0.9, 95% CI: 0.81.1, P 50.44). Major bleeding was, however, signicantly less frequent in those randomized to bivalirudin compared with those receiving UFH (3.8 and 9.8%, respectively, P ,0.001). In a prospectively stratied subgroup of 704 patients with post-infarction angina, the primary endpoint occurred in signicantly fewer patients

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4.3.1.2. Thienopyridine derivatives Ticlopidine has been shown to prevent early complications after coronary angioplasty, but has not been shown to be superior to aspirin [125]. Given its delayed onset of action, ticlopidine should, whenever possible, be started at least 24 h prior to angioplasty. Clopidogrel has yet to be tested in this setting, but is likely to show similar benets when combined with aspirin. As an adjunct to aspirin, ticlopidine has been shown to reduce the frequency of subacute thrombosis after stent placement. Two different antithrombotic regimens were evaluated in a single centre randomized trial of 517 patients undergoing coronary artery stent placement [4]. After successful placement of coronary artery stents following acute myocardial infarction or suboptimal angioplasty, patients were randomly assigned to receive either 4 weeks of antiplatelet therapy (aspirin 100 mg twice daily and ticlopidine 250 mg twice daily) or 4 weeks of anticoagulant therapy (intravenous UFH adjusted to maintain an aPTT of 80100 s for 510 days, phenprocoumon in doses to attain a target INR of 3.54.5, and aspirin 100 mg twice daily). The primary endpoint of cardiac death, myocardial infarction, coronary bypass surgery, or repeated angioplasty occurred in 1.6% of those receiving antiplatelet therapy and 6.2% of those given anticoagulant therapy (RR: 0.25, 95% CI: 0.060.77, P 50.01). Compared with patients receiving anticoagulant therapy, those receiving antiplatelet agents had an 82% lower risk of myocardial infarction (P 50.02) and a 78% lower requirement for repeated intervention (P 50.01). Occlusion of the stented vessel by thrombus or dissection occurred in 0.8% of those receiving antiplatelet therapy and 5.4% of the

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receiving bivalirudin (OR: 0.60, 95% CI: 0.400.90, P 5 0.04). In this group of patients, bleeding rates also were signicantly decreased in those receiving bivalirudin (3.0% compared with 11.1%, P ,0.001). Thus, both hirudin and bivalirudin appear to have shortterm benets over heparin in patients undergoing angioplasty, especially in high-risk groups. The short-term benets of the direct thrombin inhibitors appear to be lost over time, suggesting the presence of an ongoing thrombogenic stimulus after angioplasty. Consequently, the sole use of these agents in this setting cannot be recommended. Further studies are needed to dene the role of these agents in patients undergoing percutaneous interventions and their utility as adjuncts to GPIIb / IIIa antagonists.

5. Conclusion Platelet deposition and thrombin generation at sites of plaque rupture lead to the formation of platelet-rich thrombi. Aspirin and UFH are limited in their ability to attenuate this process. New antithrombotic agents have been extensively evaluated in patients with acute coronary ischemic syndromes and in those undergoing coronary interventions. On the basis of currently available data, LMWH appears to be at least as effective as UFH in patients with unstable angina, but LMWH is more convenient, because it can be given subcutaneously and no monitoring is necessary. The dose of LMWH should not exceed 100 anti-Xa units per kilogram of body weight, because higher doses appear to cause excessive bleeding. The results of the EPIC and EPILOG trials highlight the importance of platelets in the pathogenesis of both shortand long-term complications after coronary angioplasty and the limitations of aspirin in this setting. These studies indicate that both low-risk and high-risk patients benet from peri-procedural abciximab. Given the high cost of this agent, further economic analysis is necessary before its use can be endorsed in all patients. In the interim, its use is most easily justied in high-risk patients. The CAPTURE study suggests that a longer pretreatment period may be benecial in patients with refractory unstable angina. Abciximabs hemorrhagic complications can be attenuated, without diminishing its efcacy, by early sheath removal and by lowering the dose of heparin given at angioplasty. It is unlikely that the use concomitant use of heparin can be eliminated completely, as abciximab does not block thrombin generation that occurs at sites of vascular injury. In contrast to abciximab, the synthetic GPIIb / IIIa antagonists tested to date have not reduced the frequency of long-term ischemic events after coronary angioplasty. Possible explanations for the apparent superiority of abciximab over synthetic agents include inadequate dosing of the synthetic antagonists, abciximabs longer half-life, and abciximabs ability to block the vitronectin receptor in

addition to GPIIb / IIIa. The signicance of the shorter half-life of these agents may be overcome by the development of oral synthetic GPIIb / IIIa antagonists that could be given long-term. Thus, while abciximab has already established its niche in the setting of coronary angioplasty, further studies are required to determine the role of synthetic GPIIb / IIIa antagonists. The role of synthetic agents in other coronary interventions (such as stent insertion) and most GPIIb / IIIa antagonists in unstable angina, and acute myocardial infarction remains to be established. The results of the PRISM-Plus study suggest that high risk patients with unstable angina may benet from the addition of tiroban to heparin. Further studies are needed to determine the role and optimal dosing regimens for other GPIIb / IIIa antagonists in this setting. The role for aspirin in acute myocardial infarction and unstable angina is clear. For patients who cannot tolerate aspirin, treatment with ticlopidine is reasonable. Clopidogrel can be given to patients with a history of complications with ticlopidine and is likely to supplant ticlopidine because of its superior safety prole. Ticlopidine and aspirin should be administered to patients undergoing stent implantation. While oral anticoagulant therapy with a target INR of 2.84.8 after myocardial infarction results in a reduction in clinically important vascular outcomes, the rate of nonfatal hemorrhage is increased. CARS demonstrated the lack of efcacy of xed-low dose warfarin in this patient population. Information on the use of low-intensity warfarin (target INR 2.03.0) in this setting is lacking. Studies with direct thrombin inhibitors indicate that thrombin plays an important role in platelet-dependent thrombosis associated with acute coronary ischemic syndromes. The short-term benets of hirudin and bivalirudin over heparin appear to be lost over time, suggesting that there is reactivation of the procoagulant state once treatment stops. These ndings suggest that long-term therapy, preferably with orally administered agents, may be needed. In addition, it appears that the therapeutic window for hirudin is narrower than that for bivalirudin, at least when the agents are used in conjunction with thrombolytic therapy. Given that direct thrombin inhibitors only block thrombin activation and have no effect on thrombin generation, high doses are required to prevent thrombin-mediated feedback amplication of coagulation or activation of platelets. Bivalirudins wider therapeutic window may allow it to be given in doses necessary to block arterial thrombogenesis. Generally, however, the results with these agents have been somewhat disappointing and further studies will be necessary to dene their role in this patient population. The rather discouraging results with direct thrombin inhibitors have prompted interest in agents that inhibit clotting enzymes higher up in the coagulation cascade, thereby blocking thrombin generation. Direct inhibitors of

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factor Xa and inhibitors of the factor VIIa / tissue factor pathway, which initiates coagulation at sites of vascular injury, are currently under development.

Acknowledgements This paper was supported by grants from the Medical Research Council of Canada and the Heart and Stroke Foundation of Ontario. Dr. Bates is a recipient of a Research Fellowship Award and Dr. Weitz is the recipient of a Career Investigator Award from the Heart and Stroke Foundation of Ontario.

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