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The European Society of Cardiology

The re-emergence of anticoagulation in coronary disease

Elliott M Antman*

Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

* Elliott M. Antman, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. Tel.: +1-617-732-7149; fax: +1-617-975-0990
eantman{at}rics.bwh.harvard.edu

Abstract

The underlying pathophysiological process in acute coronary syndromes (ACS) is intracoronary thrombus formation, leading to varying degrees of occlusion of the culprit artery and the resulting clinical manifestations of ST-elevation myocardial infarction (complete occlusion) or unstable angina/non-ST-elevation myocardial infarction (partial occlusion). Given the central role that thrombin plays in the pathogenesis of ACS, antithrombin agents are an important component of treatment. Current antithrombotics, however, have important limitations. Antiplatelet agents such as aspirin or clopidogrel, alone or in combination, fail to suppress activation of the coagulation cascade and thrombin generation in patients with ACS, highlighting the need for more intensive antithrombin therapy. Use of indirect thrombin inhibitors such as the heparins (unfractionated heparin (UFH) or low-molecular weight heparins) are restricted by the need for parenteral administration, risk of thrombocytopenia, inability to inhibit fibrin-bound thrombin, and the potential for rebound activation of the coagulation cascade and further ischaemic events after discontinuation of therapy. Direct thrombin inhibitors are potent inhibitors of both free and fibrin-bound thrombin. Trials of the intravenous direct thrombin inhibitors have shown these agents to be more efficacious than UFH for the prevention of recurrent myocardial infarction with short-term (7 days) use, supporting the rationale for the further development of the direct thrombin inhibitors. The oral anticoagulants, the vitamin K antagonists (VKAs), in combination with low-dose aspirin have demonstrated superior clinical benefits compared with aspirin treatment alone when moderate-intensity anticoagulation (international normalized ratio 2–3) is achieved. Combination antithrombotic therapy with VKAs is, however, associated with an increased risk of bleeding in a relatively high proportion of patients who subsequently have to discontinue therapy, and the complexity of treatment is a significant drawback. The limitations of existing antithrombotic therapies have provided the stimulus for the development of the oral direct thrombin inhibitors. Ximelagatran, the first in this class of agents, has the potential to overcome the limitations of existing antithrombotic therapies and is currently undergoing extensive clinical evaluation in a range of indications, including ACS.

Key Words: Acute coronary syndromes • Antithrombotic agents • Antiplatelet agents • Oral direct thrombin inhibitors • Vitamin K antagonists • Heparins

Introduction

Acute coronary syndromes (ACS) are a major public health problem and are the leading cause of death in the western world. In the United States, for example, ACS accounts for more than 500,000 deaths and for some 1.8 million hospital admissions annually.1 These syndromes, consisting of unstable angina, myocardial infarction (MI) without ST-segment elevation (non-ST-elevation MI [NSTEMI]), and MI with ST-segment elevation (ST-elevation MI [STEMI]), represent a spectrum of increasing severity and are pathophysiologically linked to intracoronary thrombus formation.2,3

Given the critical role that intravascular thrombus formation plays in inciting ACS, antithrombotic therapy is an essential component of the management of patients with these syndromes. This review discusses our current state of understanding of antithrombotic therapy in ACS, particularly of anticoagulant drugs, and examines the rationale behind the development of the oral direct thrombin inhibitors as represented by the first of the class, ximelagatran.4

Clinical recognition of acute coronary syndrome

Fig. 1 illustrates how a patient presenting for the first time with ischaemic discomfort at an emergency department is assessed initially.5–7 The working diagnosis is that the patient has an ACS, but what is unknown at this time is whether the culprit coronary vessel is completely occluded with the thrombus (as shown on the right of Fig. 1) or only partially occluded (as shown on the left of Fig. 1). The 12-lead electrocardiogram (ECG) is used as the decision-making tool to allow the distinction to be made. Specifically, patients who present with STEMI will, in most cases, proceed to the development of Q-wave on their ECGs, particularly if reperfusion through the occluded coronary artery is not achieved. The treatment strategy for this group of patients is administration of thrombolytic therapy or revascularization. In a minority of these STEMI patients, however, no Q-wave development occurs on the ECG as the thrombus lyses spontaneously or there is sufficient collateral circulation to compensate for the blockage.



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  		Fig. 1 Initial assessment of patients admitted with a suspected acute coronary syndrome. Adapted with permission from Elsevier.6

 
Patients who present without ST-segment elevation are either experiencing unstable angina or NSTEMI. The correct diagnosis of patients with NSTEMI has been greatly facilitated by the availability of highly specific and sensitive cardiac biochemical markers such as the cardiac-specific troponins. For example, approximately one-third of patients who were previously believed to have unstable angina on the basis of creatine kinase-MB actually had NSTEMI based on serum elevations in cardiac troponin.8,9

Mechanism of action of antithrombotic agents

The underlying pathophysiological process in ACS – intracoronary thrombus formation or thrombogenesis – is usually initiated by arterial plaque rupture, triggering a series of events leading to platelet activation, initiation of the coagulation cascade, and, ultimately, formation of a thrombus comprised of platelets and fibrin.3,10 Looking more closely at the coagulation cascade, initiation of the process occurs after release of tissue factor from the ruptured plaque. Exposed tissue factor then binds to circulating activated Factor VII (Factor VIIa), and the resulting tissue factor/Factor Xa complex catalyses the conversion of Factor IX to Factor IXa and Factor X to Factor Xa. Factor IXa binds to Factor VIIIa on membrane surfaces to form intrinsic tenase, which acts to further activate Factor X to Factor Xa. Factor Xa combines with Factor Va, calcium, and a phospholipid surface, usually activated platelets, to form the prothrombinase complex, which activates prothrombin (Factor ll) to thrombin (Factor lla).

Thrombin cleaves fibrinogen to yield fibrin monomers, which then polymerise. The fibrin polymer is stabilised by Factor XIIIa to insoluble cross-linked fibrin. Other actions of thrombin include amplification of its own generation by feedback activation of Factor XIII, Factor V, Factor VIII, and Factor XI and activation of more platelets, thus further amplifying the coagulation cascade.11

What antithrombotic strategies can be used to reduce the thrombotic burden? As a thrombus consists of platelets and fibrin, antithrombotic strategies are usually directed towards one or both thrombus elements. Fig. 2 summarizes some of the strategies used. Antiplatelet agents include the cyclooxygenase inhibitor, aspirin, the adenosine diphosphate (ADP)-receptor blocker, clopidogrel, and the intravenous glycoprotein (GP) llb/llla receptor antagonists.12 Aspirin, by preventing the production of the platelet agonist thromboxane A2 from arachidonic acid, inhibits platelet aggregation. Clopidogrel, a thienopyridine derivative, blocks ADP-mediated platelet aggregation. Intravenous GP llb/llla receptor antagonists block the platelet GP llb/llla receptors responsible for binding fibrinogen and which serve as the final common pathway for platelet–platelet interaction and thrombus formation.



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  		Fig. 2 Mechanism of action of antiplatelet and anticoagulant agents. ASA, aspirin; UFH, unfractionated heparin; LMWH, low-molecular weight heparin.

 
Given the pivotal role that thrombin plays in thombus formation via fibrin formation and platelet activation, anticoagulant drugs are used to control the generation of thrombin or its activity (Fig. 2). Anticoagulants such as unfractionated heparin (UFH) and low-molecular weight heparins (LMWH) are indirect thrombin inhibitors. Both act by enhancing the activity of the plasma cofactor, antithrombin, which in turn inhibits thrombin, Factor Xa, and several other coagulation enzymes.13 However, the smaller size of LMWHs (4000–6000 Da) relative to UFH (15,000 Da) results in the LMWHs having greater Factor Xa inhibitory activity than thrombin inhibitory activity (LMWH inhibitory ratio of Factor Xa:thrombin 2.1–3.1:1) versus UFHs (UFH inhibitory ratio of Factor Xa:thrombin 1:1).

The LMWHs have several advantages over UFH, including lower plasma protein binding resulting in more predictable anticoagulation that usually does not require monitoring; fewer bleeding complications; and a lower incidence of heparin-induced thrombocytopenia.14,15 Use of both UFH and LMWHs is, however, limited by the need for parenteral administration.

The direct thrombin inhibitors block the catalytic activity of thrombin and/or prevent it from interacting with a range of substrates, including fibrinogen and platelets.11 As such, they have many potential advantages over indirect thrombin inhibitors such as UFH and LMWH, including the lack of protein binding; no thrombocytopenia; and a more predictable anticoagulant response.11,16 Another potential advantage is their ability to inhibit not only free thrombin but also fibrin-bound thrombin.11,16,17 Once a thrombus is formed, thrombin can bind to fibrin and remain active inside the clot, thereby contributing to the extension of the thrombus. The release of fibrin-bound thrombin after the discontinuation of heparin could explain the rebound coagulation and ischaemic events seen in patients with ACS.17–19

All of the direct thrombin inhibitors currently approved for clinical use require intravenous administration. They include hirudin, the semi-synthetic analog of hirudin, bivalirudin, and the small peptide molecule, argatroban. The first oral direct thrombin inhibitor, ximelagatran, is in advanced clinical testing20–23 and data evaluating the potential of ximelagatran for use in ACS are discussed further in this supplement.24

Antiplatelet therapy

Aspirin remains a fundamental element in the management of patients with ACS and coronary artery disease in general, a view supported by the recently published meta-analysis from the Antithrombotic Trialists Collaboration.25 This meta-analysis provides information on more than 144,000 patients who received antiplatelet therapy or control therapy; in most cases, the antiplatelet therapy was aspirin. The main study finding was that antiplatelet therapy significantly reduced the risk of serious vascular events (defined as non-fatal MI, non-fatal stroke, or vascular death) by approximately one quarter in high-risk patients, including those with acute MI, ischaemic stroke, coronary artery disease, peripheral arterial disease, and atrial fibrillation.

An important observation from the meta-analysis was the optimum dose range of aspirin to use during long-term treatment. Daily doses of 75–150 mg of aspirin were found to be as effective as higher aspirin doses (500–1500 mg/day), which were more poorly tolerated by the GI tract. However, in acute settings, an initial loading dose of at least 150 mg of aspirin may be required.25 Support for this dose-range for aspirin was provided from data from the aspirin control arm of the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study.26 This study found that the risk of bleeding increased with increasing aspirin dose, with or without clopidogrel, without any increase in efficacy. The optimal daily dose of aspirin was considered to be between 75 and 100 mg/day. Such observations have led many clinicians to select an aspirin dose between 75 and 150 mg/day, which provides the same efficacy as higher aspirin doses, but with a lower risk of bleeding. I use 81 mg/day of enteric-coated aspirin, a formulation available in the United States.

Turning briefly to the intravenous GP llb/llla receptor antagonists, these agents have shown particular benefit in patients undergoing percutaneous coronary intervention (PCI).27,28 However, their duration of benefit is less clear, as is their efficacy in patients with ACS who do not undergo PCI.27,29 Results with the oral GP IIb/IIIa inhibitors in patients after coronary intervention or with ACS have been disappointing30 and none have received regulatory approval to date.

Dual antiplatelet therapy
What happens when two antiplatelet agents with different mechanisms of action are combined? The combination of the platelet ADP-receptor blocker, clopidogrel, and the cyclooxygenase inhibitor, aspirin, was evaluated in the CURE study of patients with ACS without ST-segment elevation.31 Patients were randomised to receive either clopidogrel (300-mg loading dose, then 75 mg/day) or placebo in addition to aspirin (75–350 mg/day) for 3–12 months (mean follow-up was 9 months). At the end of the study, patients who received clopidogrel and aspirin had a statistically significant 20% reduction in risk of cardiovascular death, MI, or stroke relative to patients receiving only aspirin (Relative Risk [RR] 0.80; 95% CI: 0.72–0.90; . Moreover, the beneficial effect of clopidogrel in combination with aspirin was evident as early as 30 days into treatment, continuing through to the end of the study. Thus, not only did the CURE study lay the foundation for using clopidogrel in the long-term management of patients with ACS, it also demonstrated the clinical benefits of combining antiplatelet agents targeting different pathways of platelet activation.

Prevention of coagulation activation during acute coronary syndrome

A number of studies have shown that patients presenting with an ACS display biochemical evidence of coagulation activation and thrombin generation several weeks to months after the initial episode.32–34 This raises the possibility that intensive antithrombotic therapy may be required to suppress the prothrombotic/procoagulant state found in patients with ACS. In this respect, a sub-study from the main CURE trial demonstrated that dual antiplatelet therapy is unable to suppress coagulation activation.35 This study found significant and persistent increases in plasma markers of coagulation activation (D-dimer) and thrombin generation (prothrombin fragment F1–2) despite long-term clopidogrel and aspirin therapy (Fig. 3). These results support the theory that even more intensive antithrombotic therapy than that provided by dual antiplatelet therapy might be required in patients with ACS, particularly targeting the prothrombotic/procoagulant activities of thrombin.



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  		Fig. 3 Antiplatelet agents and coagulation cascade activation. Adapted from Eikelboom et al.35 Clopidogrel does not suppress blood markers of coagulation activation in aspirin-treated patients with non-ST-elevation acute coronary syndromes. 1771–1779. Copyright 2002, with permission from The European Society of Cardiology.

 
Anticoagulation therapy
Heparins
Both UFH and the LMWHs have shown efficacy in ACS.13 Of the LMWHs, enoxaparin has been most extensively studied against UFH and shown to be superior.36,37 In support of this, a meta-analysis of four trials involving almost 12,000 patients with ACS – the Thrombolysis In Myocardial Infarction (TIMI)-llB trial,36 the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group (ESSENCE) trial,37 the Integrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment (INTERACT) trial,38 and the A–Z trial39 – has shown that the odds ratio for death, death or MI, and the triple endpoint of death, MI, and recurrent ischaemia or recurrent ischaemia driving urgent revascularisation significantly favours treatment with enoxaparin over UFH.

LMWHs such as enoxaparin are increasingly being used in the management of patients with ACS and could potentially replace UFHs in this setting.15 However, the data on the long-term use of the LMWHs is less favourable.15,36,40 For example, in the TIMI 11B study, use of enoxaparin after hospital discharge was not found to be beneficial, possibly because relatively low-risk patients entered the chronic phase of treatment, whereas higher-risk patients underwent revascularisation procedures during the index hospitalisation.36 Prolonged treatment with the LMWH, dalteparin, in the Fragmin during Instability in Coronary Artery Disease II (FRISC II) trial resulted in a significant reduction in rates of death, MI, and revascularization after 30 days and 3 months but not after 6 months.41

Direct thrombin inhibitors
The efficacy of the intravenous direct thrombin inhibitors in the treatment of ACS has been evaluated in a meta-analysis of 11 randomised controlled trials involving some 36,000 patients with ACS.25 These patients received up to 7 days' treatment with an intravenous direct thrombin inhibitor or UFH and were then followed up for at least 30 days. Compared with UFH, direct thrombin inhibitors had no significant effect on mortality at the end of treatment or at follow-up at 7 days or 30 days. In contrast, the intravenous direct thrombin inhibitors were associated with a significant reduction in recurrent MI at all three timepoints. They also carried a significantly lower risk of bleeding relative to UFH. However, extensive heterogeneity was found between the different direct thrombin inhibitors; for example, hirudin had a higher rate of major bleeding than UFH, whereas bivalirudin had lower rates of major bleeding. Overall, the short-term administration of the intravenous direct thrombin inhibitors (for several days) appears more efficacious than UFH for the prevention of recurrent MI.

While the intravenous direct thrombin inhibitors have not become a major therapeutic option in the treatment of patients with ACS, results from the Direct Thrombin Inhibitor Trialists' Collaborative Group study25 and other recent trials of intravenous direct thrombin inhibitors42 have supported the rationale for the further development of the direct thrombin inhibitors for the treatment of ACS.

Oral anticoagulants: vitamin K antagonists
VKAs inhibit the synthesis of the vitamin K-dependent coagulation proteins, prothrombin, and Factors VII, IX, and X.43 The VKAs, of which the most commonly used is warfarin, have many limitations, including a narrow therapeutic window; slow onset of action; risk of bleeding; and multiple food and drug interactions. Because of these limitations, their anticoagulant effects are unpredictable, necessitating frequent monitoring to ensure that their anticoagulation activity (international normalized ratio, INR) is within the therapeutic range.43,44

As the VKAs target several procoagulant processes, anticoagulation with warfarin in combination with antiplatelet therapy with aspirin in the treatment of ACS has been evaluated in a number of studies.45–49 For example, the Coumadin Aspirin Reinfarction Study (CARS) tested whether a combination of low-dose warfarin and low-dose aspirin in patients who had had an MI was superior to aspirin monotherapy, without excessive bleeding or complexity of treatment.46 The trial involved about 8800 patients, enrolled 3–21 days after an MI, who were randomized to aspirin 160 mg, aspirin 80 mg plus warfarin 1 mg, or aspirin 80 mg plus warfarin 3 mg. Patients were followed up for a maximum of 33 months (median 14 months). Themedian INRs at 6 months were 1.02, 1.04, and 1.19, respectively, all well below the normal therapeutic range. CARS found no difference among the groups in the 1-year life table estimate for the primary end-point of cardiovascular death, MI, or non-fatal ischaemic stroke or on the individual components of cardiovascular death, MI, or non-fatal ischaemic stroke. The rate of major bleeding was also similar between the three groups.

Similar findings were reported in the Combination Hemotherapy and Mortality Prevention (CHAMP) trial.48 CHAMPS evaluated over 5000 patients within 2 weeks of infarction and compared two regimens, aspirin 160 mg/day versus warfarin with an INR of 1.5–2.5 and a reduced dose of aspirin 81 mg/day. No significant differences in mortality, recurrent MI, or stroke were found between the aspirin group and the combination therapy group. Major bleeding was, however, significantly higher in the combination therapy group, at 1.28 events per 100 person years, compared with 0.72 events per 100 person years with aspirin alone (). CHAMPS, as well as CARS,46 concluded that low intensity, fixed-dose warfarin (INR2) in combination with low-dose aspirin had no clinical benefit over that obtained with aspirin monotherapy.

In contrast to CHAMPS and CARS, trials in which the intensity of anticoagulation was increased to an INR of 2–3 in combination with low-dose aspirin, such as that seen in the Antithrombotics in the Prevention of Reocclusion In Coronary Thrombolysis (APRICOT-2) trial,45 the Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis-2 (ASPECT-2) trial49 and the Warfarin-Aspirin Reinfarction (WARIS-2) Study47 have collectively shown that moderate intensity anticoagulation in combination with low-dose aspirin has superior clinical benefits compared with aspirin monotherapy.

In WARIS-ll, for example, 3630 patients (75 years old) with a recent MI were randomized to receive treatment with either warfarin, aimed at a therapeutic INR level of 2.8–4.2, aspirin 160 mg/day, or the combination of warfarin at an INR of 2.0–2.5 and aspirin 75 mg/day.47 Over a mean duration of follow-up of 4 years, the primary endpoint, a composite of death, non-fatal MI, or thromboembolic stroke, was significantly lower in the two warfarin arms compared with aspirin alone (Fig. 4). There were significant reductions in relative risk with warfarin alone versus aspirin alone (19%, ) and with combination therapy versus aspirin alone (29%, ). No significant differences in the primary endpoint were seen between the two warfarin arms. The beneficial effect of warfarin, alone or in combination with aspirin, was limited to a reduction in MI and thromboembolic stroke, as evidenced by the rate ratio values compared with aspirin alone (Table 1). Moreover, major bleeding episodes were nearly four times as frequent with warfarin alone or in combination with aspirin compared with aspirin alone (0.68% per year, 0.57% per year, and 0.17% per year, respectively), while the discontinuation rate was two-fold higher – nearly two-fold higher discontinuation rates were also reported in the CHAMPS and ASPECT-ll trials on the warfarin arms.48,49



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  		Fig. 4 WARIS-ll: event-free survival curves for the composite end point of death, non-fatal MI, or thromboembolic stroke. Reproduced with permission from Hurlen et al.47 Copyright © 2002 Massachusetts Medical Society. All rights reserved.

 

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  		Table 1 WARIS-ll: distribution of death, myocardial infarction, and thromboembolic stroke according to treatment group

 
In general, in the treatment of ACS moderate intensity anticoagulation with warfarin at an INR of 2–3 in combination with low-dose aspirin provides therapeutic benefits greater than aspirin monotherapy. Anticoagulation with warfarin, however, comes at a price – increased risk of bleeding, high discontinuation rates, and a need for close INR monitoring/complexity of treatment.

Conclusion

In summary, in considering long-term antithrombotic therapy after an ACS, antiplatelet therapy in the form of aspirin should be given to virtually all patients. Clopidogrel, at a dose of 75 mg/day, should be considered for aspirin-intolerant patients and for patients who present with unstable angina or non-ST-segment elevation for a minimum treatment duration of 1 month and up to 9 months. Whether clopidogrel is of benefit in patients with STEMI is currently being evaluated in clinical trials and the data are awaited. The oral GP llb/llla inhibitors have not proved useful from a therapeutic perspective and they have not become a part of our clinical armamentarium.

Combining antiplatetet therapy in the form of low-dose aspirin with anticoagulation, in the form of the VKA agonist, warfarin, can provide long-term therapeutic benefit after an ACS. However, this benefit is only achieved if the dose of warfarin is maintained at an INR range of 2–3. The need for close INR monitoring along with the high discontinuation rate, risk of bleeding, and other complications of treatment limit the use of VKAs in the setting of ACS.

With the complexities and limitations of treatment with the VKAs and the heparins, there is a need for new improved and more convenient therapeutic options. Ximegalatran, the first oral agent in the new class of direct thrombin inhibitors50 is currently undergoing evaluation in an extensive clinical trial programme,20–22 including use in the treatment of ACS.23 With its favourable pharmacokinetic and pharmacodynamic properties, ability to inhibit fibrin-bound thrombin, wide therapeutic window, low potential for drug or food interactions, and no requirement for coagulation monitoring,50 ximelagatran represents an exciting new oral agent in the class of direct thrombin inhibitor. As such, ximelagatran has the potential to overcome the limitations of existing anticoagulant therapies in the treatment of ACS.

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