COMMENTARIES

Oral Direct Thrombin Inhibitors and Atherosclerosis

Marc Husmann, M.D.1 and Matthias Barton, M.D. 2,
1Department of Angiology, University Hospital Berne and
2Department of Medicine, Internal Medicine I,
Medical Policlinic, University Hospital Zurich,
Switzerland
Please address correspondence to:
Marc Husmann, M.D.
Department of Angiology
University Hospital Bern
CH-3010 Bern, Switzerland
Tel: ++41-31-632-0193
Fax: ++41-31-632-0148
E-mail:husmann@gmx.ch

Atherothrombosis is the most frequent cause of morbidity and mortality in the Western world and is present in all major vascular pathologies, which encompasses myocardial infarction, cerebrovascular disease, and peripheral arterial disease [1-6]. Plaque disruption and subsequent thrombus formation play a critical role in the clinical manifestations of atherothrombosis, such as myocardial infarction or stroke [7,8].

Thrombin is the most potent agonist for platelet activation and aggregation leading to thrombus formation [9]. Antithrombotic therapy with anticoagulant or antiplatelet agents reduces the risk of thrombosis and is recommended for patients at risk of cardiovascular events [10]. Currently, platelet aggregation inhibitors such as aspirin or clopidgrel are recommended for primary or secondary prevention of atherothrombotic diseases such as cerebrovascular, coronary, and peripheral arterial disease. If antiplatelet agents are combined with coumarines, i.e. in a patient with artrial fibrillation and after percutaneous coronary stenting, the risk of bleeding increases two-fold, from 2.0% per year to 3.9% per year [11]. Therefore, current guidelines do not recommend long-term therapy with both antiplatelet and anti-aggregatory agents [12,13].

There is data to suggest that direct thrombin inhibitors (DTIs) are as effective in acute coronary syndromes regarding ischemia, but with a significantly lower rate of major bleeding when compared with heparines in combination with GBIIb/IIIa inhibitors (3.0% versus 5.7%; P < 0.001; relative risk, 0.53; 95% CI, 0.43 to 0.65) [14]. Until recently, direct thrombin inhibitors were administered only intravenously or subcutaneously, and were therefore not a suitable medication for long-term treatment in ambulatory patients. Despite recent drawbacks of ximelagatran, an oral predrug of melagatran, new oral thrombin inhibitors are emerging.

The therapeutic potential of this new class of drugs has not been fully established as it may go far beyond replacing coumarines for the treatment of deep vein thrombosis and atrial fibrillation regarding direct thrombin inhibition in atherothrombosis. Furthermore, the risk of major hemorrhage may possibly be smaller when combined with aspirin compared to coumarines and aspirin.

Recent data suggest that the combination of aspirin with an oral thrombin inhibitor (ximelgatran) has more potent antithrombotic effects and a shorter bleeding time than combination of clopidogrel and aspirin [15]. In this study using a human ex vivo model the combination of ximelagatran with aspirin significantly reduced thrombus formation up to 80% compared to aspirin in combination with clopidogrel for low shear rate conditions and by about 40% for high shear rate conditions. Bleeding time did not change significantly with ximelagatran and aspirin (ratio 1.4 compared to aspirin alone), whereas the combination of clopidogrel with aspirin increased the capillary bleeding time (ratio 1.6 compared to aspirin alone).

The SPORTIF III and IV randomized trials of anticoagulation with warfarin also revealed a smaller risk for bleeding for the combination of aspirin and ximelagatran than for aspirin and warfarin [11,16,17]. Addition of aspirin to either warfarin or ximelagatran was associated with no reduction in stroke or systemic embolism. Major bleeding occurred significantly more often with aspirin plus warfarin (3.9% per year) than with warfarin alone (2.3% per year, P < .01), aspirin plus ximelagatran (2.0% per year), or ximelagatran alone (1.9% per year). The rate of myocardial infarction with aspirin and warfarin (0.6% per year) was not significantly different from that with ximelagatran alone (1.0% per year), warfarin alone (1.0% per year), or aspirin and ximelagatran (1.4% per year) [11]. Taken together, the combination of an oral active thrombin inhibitor alone or in combination with aspirin might prevent atherothrombosis to similar or greater extent by bearing a lower risk of hemorrhages than dual platelet anti-aggregation or the combination of coumarines and aspirin.

Patients with atrial fibrillation and evidence of atherosclerotic vascular disease (carotid artery disease, coronary artery disease, and/or peripheral arterial disease) are requiring both coumarine and aspirin. Often the combination is not prescribed because of the increased risk of major hemorrhage. However, these patients will potentially profit from a lower risk of major hemorrhages as well as from reduced risk of vascular event rate when the combination of thrombin inhibitor and aspirin is given. Any additional antithrombotic effect (on top of the proven anti-embolic effect) will need to be addressed in ongoing and future phase III trials. One group of atherosclerotic patients is likely to have the greatest benefit: patients with peripheral arterial disease (PAD). PAD patients are at highest risk for future cerebrovascular, cardiovascular, and peripheral arterial atherothrombosis and have been shown to undergo most vascular interventions [18,19].

Despite the significant advances over the last 50 years with regard to anticoagulant therapy, warfarin remains the definitive standard for the long-term prevention of thromboembolic events in at-risk patients, except those with acute coronary syndromes, in which antiplatelets are preferred. So far, the therapeutical potential OTIs has been investigated for ximelagatran in venous thromboembolism, acute coronary syndromes and prevention of stroke in patients with atrial fibrillation [16,20-22]. Clinical studies have demonstrated ximelagatran to be comparable in efficacy to the oral vitamin K antagonist warfarin and low molecular weight heparin for prevention of venous thromboembolism, comparable to warfarin for stroke prevention in the setting of atrial fibrillation, and, when combined with aspirin, more effective than aspirin alone in preventing major adverse cardiovascular events in patients with a recent myocardial infarction [11]. These randomized trials have also revealed the efficacy of ximelagatran in the secondary prevention of venous thromboembolism and shown the agent to be as effective as enoxaparin/warfarin in treating patients with acute deep vein thrombosis. Adverse effects with ximelagatran include elevations in alanine transaminase (ALT), which may require monitoring, and as for all anticoagulants, bleeding complications [23]. Bleeding complications appear to be less than or at least comparable to those occurring with standard anticoagulant treatments like warfarin or low molecular weight heparin [11,24]. In addition to its favorable efficacy and safety profile in comparison with standard anticoagulant therapy, the convenience of its oral, fixed-dose administration without the need for anticoagulation monitoring and its independence from vitamin K synthesis might help encourage a wider use of appropriate anticoagulation using the new oral active thrombin inhibitors across the population at risk, reducing the incidence of cardiovascular events.

Considering that atherothrombosis is the most frequent cause of morbidity and mortality in the increasing size of the aged western population with different vascular beds involved, optimized and tailored antithrombotic and anticoagulant therapy is needed for primary and secondary prevention. The therapeutic success of antithrombotic and anticoagulant therapy depends on its effect and side effects as well on the wide or narrow therapeutic window. In the aged population, multiple co-morbidities often exist and require complex medication. Especially in obstructive vascular disease a combination of a long-term oral antithrombotic and anticoagulant therapy might be indicated but not be implemented due to the increased risk of major hemorrhages. Oral thrombin inhibitors seem to have a potent antithrombotic effect while simultaneously also being as effective in preventing embolism as coumarines. Large trials have already shown that the risk of major bleeding is lower when oral thrombin inhibitors are combined with antithrombotic drugs compared to the combination of aspirin and coumarines. If this is a pharmacodynamic or a pharmocokinetic effect is not yet known. Possibly, the thrombotic and antithrombotic balance is more stable with oral thrombin inhibitors than with coumarines, which are known for their very variable and dependent pharmacodynamic characteristics requiring a strict monitoring and constant new adjusting. Oral thrombin inhibitors are fixed dosed and show relatively stable plasma levels. This not only reduces obviously the risk of major bleedings but also eases medications in elderly people. However, not all problems have been solved, as this new class of oral anticoagulant has been shown to have serious side effects in terms of liver enzyme elevation, which have to be monitored as well and can cause substantial harm. Furthermore, renal function has to be considered and patients with severe renal insufficiency are not candidates for these drugs. The current ReLy Trial investigates the effect of dabigatran extexilate, an oral thrombin inhibitor, in atrial fibrillation, and aims to include 15,000 patients. The analysis of the effect of dabigatran etexilate on atherothrombotic events as well as of the combination of dabigatran etexilate with aspirin regarding major hemorrhages will answer in part this topic.

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