The re-emergence of anticoagulation in coronary disease

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.