The European Society of Cardiology
Introduction
a Department of Cardiology, Heart Centre, University Medical Centre, P.O. Box 9101, St. Radboud, Nijmegen, The Netherlands
b Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
* Tel.: +31-24-361-4220; fax: +31-24-354-0537
f.verheugt{at}cardio.umcn.nl
eantman{at}rics.bwh.harvard.edu
Arterial thrombosis is the underlying pathophysiological cause behind coronary arterial disease and ischaemic stroke, and arises as a result of a complex interplay between the ruptured arterial plaque, activation of platelets, and the coagulation cascade. Given the central role that coagulation factor thrombin (Factor ll) plays in thombus formation via fibrin formation and platelet activation, anticoagulant drugs are used to control its generation or its activity.
The most commonly used anticoagulant agents are the indirect thrombin inhibitors heparin (unfractionated heparin and the low-molecular-weight heparins) and vitamin K antagonists such as warfarin. These agents, while efficacious, have several drawbacks that limit their use in the treatment and prevention of thromboembolism, particularly with long-term use. The heparins require parenteral administration, are associated with the development of heparin-induced thrombocytopenia, and their inability to inhibit clot-bound thrombin may explain the phenomenon of rebound activation of the coagulation cascade and recurrence of thrombotic events after discontinuation of treatment.
The vitamin K antagonists block the vitamin K-dependent liver production of the plasma clotting factors prothrombin (Factor II) and Factors VII, IX, and X. While they are administered orally, they have a slow onset of action and a relatively narrow therapeutic window that requires close anticoagulation monitoring using the international normalized ratio (INR); overdosing may result in life-threatening bleeding while underdosing can result in lack of efficacy. In the setting of stroke prevention in patients with artial fibrillation, the fear of bleeding with the vitamin K antagonists, specifically intracranial bleeding, has resulted in their underutilization, where the overall use of anticoagulation in eligible patients is approximately half of what it should be.
There have been some major improvements recently in the monitoring of vitamin K antagonists, i.e., maximizing efficacy and safety through achievement of target INR values in trials of patients with atrial fibrillation, with artificial heart valves and after myocardial infarction, and the finding that INR self-monitoring by patients may potentially be more efficient than laboratory monitoring. However, their use remains laborious, and their therapeutic response remains poorly predictable.
Against this background of unmet treatment needs, the oral direct thrombin inhibitors are being developed. These agents could potentially be the first new oral anticoagulants in more than 50 years. The first oral agent of this class is ximelagatran, which in its active form, melagatran, inhibits clot-bound as well as free thrombin, has a predictable pharmacokinetic profile that does not require coagulation monitoring, and has a fixed dosing regimen. This agent is currently in late stage clinical development, and has been evaluated in clinical trials of coronary artery disease (in the ESTEEM phase II trial)1 and stroke prevention in atrial fibrillation (in the SPORTIF trial programme)2. If ximelagatran is shown to fulfil its potential in its clinical trial programme, it will be a valuable addition to our therapeutic armamentarium, providing clinicians and patients alike with a more predictable and convenient anticoagulant treatment option.
Footnotes
1 ESTEEM (Efficacy and Safety of 6-month treatment with the oral direct thrombin inhibitor, ximelagatran, in combination with acetylsalicylic acid, in patients with a recent Myocardial infarction) phase II trial. Published in September 2003: Wallentin L, Wilcox RG, Weaver WD, et al. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomized controlled trial. Lancet 2003; 362:789–797. 
2 SPORTIF (Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation) trials. Lancet (2003), in press
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