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The European Society of Cardiology

Oral direct thrombin inhibition for anticoagulation in coronary artery disease – focus on the ESTEEM trial

L Wallentin*

Department of Cardiology, Uppsala Clinical Research Centre, University Hospital, Uppsala, Sweden

* L. Wallentin, Department of Cardiology, Uppsala Clinical Research Centre, University Hospital, S751 85 Uppsala, Sweden. Tel.: +46-70-631-35-66; fax: +46-18-50-66-38
lars.wallentin{at}ucr.uu.se

Abstract

Long-term treatment with anticoagulation agents in combination with aspirin can be beneficial for the prevention of recurrent thrombotic events, although the limitations of current agents make their use far from ideal. In contrast, the oral direct thrombin inhibitor, ximelagatran, has considerable therapeutic potential in this disease area because it has predictable pharmacokinetics and dynamics and therefore can be used at a fixed dose, does not require coagulation monitoring and has a low potential for drug and food interactions.

The ESTEEM trial, a randomised, placebo-controlled phase II dose-ranging study in 1883 patients with recent myocardial infarction, is the first study to investigate the efficacy of ximelagatran in the prevention of atherothrombotic events. Patients were randomised to 6 months of treatment with twice-daily tablets of ximelagatran 24, 36, 48, or 60 mg or placebo in addition to aspirin 160 mg daily. Ximelagatran was significantly more effective than placebo in reducing the composite endpoint of death, non-fatal myocardial reinfarction, and severe recurrent ischaemia (), resulting in a mean 24% reduction in relative risk for the combined ximelagatran groups versus placebo. The efficacy of ximelagatran was not dose-dependent; the 24-mg dose was as effective as the 60-mg dose. Major bleeds were rare with ximelagatran and not significantly different from placebo (1.8% combined ximelagatran groups versus 0.9% placebo). Ximelagatran was associated with transient elevations in liver enzymes, which did not result in clinical complications. Discontinuation due to adverse experiences with the lowest dose of ximelagatran tested (24 mg bid) was not different from placebo. Therefore, treatment with ximelagatran 24 mg twice daily in combination with aspirin achieved optimal efficacy with an acceptable safety profile. The ESTEEM trial results highlight the potential for ximelagatran in combination with aspirin as a convenient and well-tolerated, long-term treatment for prevention of arterial thrombotic events.

Key Words: Myocardial infarction • Oral direct thrombin inhibitors • Ximelagatran • ESTEEM • Anticoagulation • Coronary arterial disease

Introduction

The importance of thrombosis in the pathogenesis of acute myocardial infarction (MI) is well established, and antithrombotic drugs remain an important therapy for the reduction of recurrent events and death after MI.1–3 The two main long-term antithrombotic therapies are anticoagulants and platelet-inhibiting drugs. Long-term aspirin is the major antiplatelet therapy; but although aspirin is effective, patients remain at a high risk for subsequent events.4 Currently available anticoagulants, such as the indirect thrombin inhibitors warfarin and the heparins (unfractionated heparin [UFH] and low-molecular-weight heparins [LMWHs]), are proven to be effective at reducing ischaemic complications after myocardial events both alone and in combination with aspirin, but their use as long-term therapy is restricted by several inherent limitations. The anticoagulant effect of warfarin is unpredictable because of its narrow therapeutic window, multiple drug and food interactions, and there is an increased risk of bleeding.5 As a result, warfarin therapy requires close coagulation monitoring and dose adjustment. The heparins are also associated with an increased risk of bleeding,6 as well as heparin-induced thrombocytopenia.7 Moreover, the response to fixed doses of UFH is unpredictable because of the binding of plasma proteins.8 Also, the subcutaneous administration of LMWH makes them inconvenient for long-term treatment outside of the hospital. Such limitations has prompted the quest to identify oral antithrombotic drugs that are safer, more effective, and predictable, and therefore potentially more appropriate for long-term use.

Rationale for direct thrombin inhibitors in coronary artery disease

The rationale behind the development of direct thrombin inhibitors for the treatment of coronary artery disease resides in three main observations: (1) thrombus material remains at the coronary lesion for several months after an acute MI;9 (2) the coagulation system remains activated for 3–6 months after an acute event;10 and (3) when anticoagulant treatment with indirect thrombin inhibitors is stopped, patients often experience re-activation of the coagulation system and rebound ischaemic events.11–13

These observations have not only highlighted the need for more prolonged anticoagulation treatment in addition to aspirin, but also the inability of indirect thrombin inhibitors to inhibit clot-bound thrombin, which is protected from inhibition and remains enzymatically active.14

In contrast to the indirect thrombin inhibitors, direct thrombin inhibitors are small molecules that inhibit thrombin by directly binding to the active catalytic site, which allows them to function independently of antithrombin and they can therefore inhibit clot-bound as well as free thrombin.15 Furthermore, they do not bind plasma proteins, producing a more consistent anticoagulant response.16

Ximelagatran

Ximelagatran (AstraZeneca, Mölndal, Sweden) is the first oral agent in the new class of direct thrombin inhibitors under investigation for the prevention and treatment of thromboembolic events. After oral administration, ximelagatran is rapidly and completely bioconverted to the active form melagatran (Fig. 1) which exerts antithrombotic effects.17 Ximelagatran is less charged and more lipophilic than melagatran, and thus better absorbed orally.18 Melagatran is not metabolised, and its excretion is predominately (80%) via the kidneys.19 Ximelagatran is administered twice daily and has a rapid onset of action, achieving peak melagatran concentrations within 2 h, with a half-life of between 4 and 5 h.20–23 This pharmocokinetic profile of melagatran is predictable and is not affected by age, weight, or ethnic origin.21,22 Furthermore, it is not affected by food intake,22 and because it is not metabolised by the cytochrome P450 system, there is a low potential for drug–drug interactions.24



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  		Fig. 1 Profile of ximelagatran.

 
Ximelagatran in the treatment of acute coronary syndromes

Clinical data have demonstrated the efficacy of ximelagatran in the prevention of venous thromboembolism in orthopedic surgery patients25–27 and, as discussed elsewhere in this supplement, atrial fibrillation.28 Here, I review the results from the phase II ESTEEM (Efficacy and Safety of the oral direct Thrombin inhibitor ximelagatran in patiEnts with rEcent and Myocardial damage) trial, the first study that attempts to support the concept that ximelagatran could prevent coronary thrombotic events.29

ESTEEM trial

The objective of the ESTEEM trial was to determine the efficacy of ximelagatran in combination with aspirin in the long-term treatment of post-MI patients, a population with a high risk of arterial thrombotic events. ESTEEM also provided important information about the optimum dose selection-range to use in the for a future phase III programme.

Study design and procedure

Patients were randomized within 14 days after an acute event. As ESTEEM involves a high-risk population, the trial inclusion criteria required patients to have at least one of the following risk factors: age 65 years or older, diabetes mellitus, previous MI, multivessel coronary disease at coronary angiography, previous ischaemic stroke (confirmed by CT/MRI), peripheral arterial occlusive disease, symptomatic congestive heart failure, new or previously unknown left bundle branch block, new or previously unknown ST-segment depression, or history of hypertension. Exclusion criteria included patients who had a planned revascularization procedure within the next 60 days, active liver disease (alanine transaminase [ALAT] greater than two times the upper limit of normal), anaemia, persistently high systolic and diastolic blood pressure, or an increased risk of bleeding, such as patients with recent stroke or patients who were taking other oral anticoagulant or oral antiplatelet drugs. As the drug is renally excreted, patients with severe renal impairment (Clcr30 ml/min) were also excluded.

Patients were randomised to one of four doses (24, 36, 48, or 60 mg) of ximelagatran or placebo twice daily in addition to aspirin 160 mg once daily for 6 months (Fig. 2). Of 1883 patients, 683 patients were treated with placebo, approximately twice as many compared with each of the four arms of ximelagatran treatment. Clinical assessments and blood sampling (haematology and clinical chemistry) were performed at monthly intervals for the 6 months of treatment and again 2 weeks after cessation of treatment.



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  		Fig. 2 ESTEEM study design. AMI, acute myocardial infarction; ASA, aspirin; R, randomization; ITT, intention-to-treat.

 
There were no significant differences between the baseline characteristics of the different treatment groups. Due to the inclusion criteria, the average age of the intention-to-treat population was 69 years, around 5–8 years older than the mean age of patients enrolled in most clinical trials of acute coronary syndromes. Before randomization, 99% of patients were taking aspirin and 90% were treated with UFH or LMWH. MI with ST-segment elevation on the electrocardiogram (ST-elevation MI) was the index event for two thirds of patients, and half of these patients had been treated with (fibrinolytic)thrombolytic therapy. Patients with non-ST-elevation MI were included at an average time of 6 days after the index event with the aim of inclusion at the same time as cessation of heparin and LMWH treatment. In this way, the new treatment was used as a protection against rebound events, which are commonly associated with discontinuation of these treatments.30

ESTEEM outcome measures

The primary composite endpoint was death, MI, and severe recurrent ischaemia. Additional analyses were the clinical composite endpoints of cardiovascular death, MI, ischaemic stroke, severe recurrent ischaemia, and death. The safety and tolerability of the four ximelagatran doses compared with placebo (aspirin) were assessed, with special regard to bleeding and biochemical changes. Liver enzymes were carefully monitored, and if ALAT was two times the upper limit of normal, weekly testing of liver enzymes was initiated. If ALAT was more than three times the upper limit of normal, additional tests of liver function were carried out, and if the level did not return to normal within 4 weeks, treatment was terminated. If at any time ALAT was above five times the upper limit of normal, the study drug was withdrawn.

Results

Ximelagatran was significantly more effective than placebo in reducing the composite endpoint of death, non-fatal reinfarction, and severe recurrent ischaemia among patients () (Figs. 3 and 4). The reduced risk was observed within the first month and the difference was maintained, or even increased, over the 6 months of treatment (Fig. 3). These results provide clear evidence that direct thrombin inhibition with an oral agent such as ximelagatran prevents new coronary events. There was no dose response for ximelagatran; the lowest dose (24 mg bid) was as effective as the highest dose (60 mg bid) for reduction of coronary events (Fig. 4). When the data for all the ximelagatran treatment groups were combined, the event rate is 12.7% versus 16.3% for placebo, a 24% relative reduction in risk over 6 months (Figs. 3 and 4). A post hoc analysis revealed a 34% relative risk reduction for the thrombotic events of death, MI, and stroke () (Fig. 5). Again, the event curve demonstrated an early treatment benefit in the first month, which seemed to increase with continuation of treatment.



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  		Fig. 3 Cumulative risk of death, myocardial infarction, and severe recurrent ischaemia. Analysis by intention-to-treat; HR, hazard ratio. Adapted with permission from Elsevier (The Lancet 2003;362:789–797).

 


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  		Fig. 4 Ximelagatran dose response of the cumulative risk of death, myocardial infarction, and severe recurrent ischaemia. Analysis by intention-to-treat; MI, myocardial infarction; SRI, severe recurrent ischaemia; HR, hazard ratio.

 


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  		Fig. 5 Cumulative risk of death, myocardial infarction, and stroke. Post-hoc analysis; Intention-to-treat; HR, hazard ratio. Adapted with permission from Elsevier (The Lancet 2003;362:789–797).

 
Analyses of the pre-defined secondary endpoint, the composite of cardiovascular death, MI, ischaemic stroke, and severe recurrent ischaemia, demonstrated a significant 29% relative risk reduction with ximelagatran at the end of 6 months () (Fig. 6). This result indicates that ximelagatran treatment on top of aspirin prevents 1 of these ischemic events for every 21 patients treated, an impressive result for this type of treatment.



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  		Fig. 6 Cumulative risk of cardiovascular death, myocardial infarction, ischaemic stroke, and severe recurrent ischaemia. Pre-defined analysis, intention-to-treat.

 
Safety

Major bleeding, defined as fatal or clinically overt bleeding associated with a fall in haemoglobin of at least 20 g/l, was not significantly increased in the individual or combined ximelagatran groups relative to placebo (e.g., 1.8% combined ximelagatran versus 0.9% placebo), although the cumulative risk for total bleeding (major and minor) was higher in the ximelagatran groups (21.9% combined ximelagatran versus 13.2% placebo).

With respect to liver enzymes, a transient increase in ALAT levels (greater than three times the upper limit of normal) was observed (Fig. 7). The elevated levels of ALAT were generally detected after 2–6 months of treatment, peaked after 60–120 days, and returned towards normal, irrespective of whether the patient continued or stopped treatment.



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  		Fig. 7 Proportion of patients with elevated alanine transaminase levels. ALAT, alanine aminotransferase; ULN, upper limit of normal.

 
No significant differences were found between the ximelagatran group and the placebo group for any adverse events or serious adverse events (Fig. 8). Discontinuation of treatment was higher in the ximelagatran group relative to placebo, mainly because of ALAT elevations greater than five times the upper limit of normal leading to immediate discontinuation of treatment. In contrast, there were fewer ischaemic/cardiac events in the ximelagatran group.



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  		Fig. 8 All adverse events. AE, adverse event; SAE, serious adverse event; CAD, coronary artery disease.

 
Summary

Ximelagatran in combination with aspirin is significantly more effective than aspirin alone in preventing the composite endpoint of death, non-fatal MI, and severe recurrent ischaemia, amounting to a 24% relative risk reduction over 6 months. The clinical significance of the effect of ximelagatran was further supported by the 34% relative risk reduction in the composite endpoint of death, MI, and stroke. This relative risk reduction by ximelagatran is at least of a similar magnitude to that observed previously in trials of well-controlled warfarin31 or clopidogrel32 in combination with aspirin in patients with MI.

The efficacy of ximelagatran was not related to dose, whereas the total bleeding events increased with increasing doses. While the cumulative risk of total bleeding was higher in the ximelagatran treatment groups, it is worth noting that there was no significant difference between ximelagatran and placebo in major bleeds or the frequency of bleeding in critical regions such as the pericardial, intracranial, or ocular regions. There was an increase in ALAT levels three times the upper limit of normal in 6.5% of patients treated with the lowest dose of ximelagatran (24 mg bid) and 12–13% treated with the highest dose (60 mg bid) compared with 1.3% on placebo. However, these elevations were transient whether ximelagatran was continued or not and typically asymptomatic.

Conclusions

The use of currently available anticoagulants as long-term therapy for the prevention of recurrent events is restricted by several inherent limitations. This has prompted the development of new and improved anticoagulants, such as ximelagatran, which produce inhibition of clot-bound and free thrombin and has a low potential for drug and food interactions, allowing fixed dosing without the need for coagulation monitoring. The ESTEEM trial provides the first clinical evidence that ximelagatran, the first of the oral direct thrombin inhibitors, is effective and well tolerated as a long-term treatment for the prevention of arterial thrombotic events. The lowest dose of ximelagatran, 24 mg bid, achieved optimal efficacy at an acceptable safety profile under the conditions studied in ESTEEM. Future phase III trials will expand the evidence base about the clinical benefits of ximelagatran in acute and chronic arterial disease.

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