ximelagatran and Coronary-Thrombosis

Fibrinolysis is the reference treatment for most myocardial infarctions with ST-segment elevation; alternatives are angioplasty, with or without stent. The earlier fibrinolysis is performed (preferably before hospitalization), the more effective it is. It can be optimized by adjuvant antiplatelet therapy, such as aspirin, and probably by anticoagulant treatment as well. Because fibrinolytic therapy is accompanied by intensive thrombin generation and activation, immediate and continuous adjunctive simultaneous heparin therapy is recommended. The efficacy of subcutaneous low-molecular-weight heparin (LMWH) HBPM) is at least equivalent to that of intravenous unfractionated heparin (UFH), but its risk of severe (but not cerebral) hemorrhage is greater. Bolus LMWH on the other hand is associated with an increased risk of cerebral hemorrhage. Antithrombotic treatment thus appears optimal with bolus UFH at fibrinolysis and for at least 48 hours afterwards. An alternative after this bolus might be subcutaneous enoxaparin until discharge. Because the major drawback of both types of heparin is their rebound activation of thrombosis, oral anticoagulants are recommended thereafter. The combination of anticoagulant treatment + (low-dose) aspirin is not superior to aspirin alone when the target INR is below 2. Adequate anticoagulation with INRs greater than 2.0 consistently improves angiographic and clinical outcome. Bleeding (except intracerebral) is significantly increased whether the INR is greater than or less than 2.0. Other treatments are being investigated. Pentasaccharide (anti-Xa) combined with fibrinolysis seems to reduce reocclusion more effectively than UFH. Oral postinfarction treatment with ximelagatran (a thrombin inhibitor), combined with aspirin, is associated with fewer cardiovascular events than aspirin alone. More studies are needed.

Topics: Anticoagulants; Aspirin; Azetidines; Benzylamines; Cerebral Hemorrhage; Coronary Thrombosis; Drug Therapy, Combination; Factor Xa; Fibrinolytic Agents; Follow-Up Studies; Forecasting; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Injections, Intravenous; Injections, Subcutaneous; Myocardial Infarction; Myocardial Ischemia; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Risk Factors; Time Factors; Treatment Outcome

Two new classes of anticoagulants are actually developed which would change in the near future our strategies for the prevention and the treatment of venous thromboembolic events. These two classes are the anti-factor Xa and anti-factor IIa (direct antithrombin) agents. Among the anti factor Xa, the pentasaccharides are initiating their clinical use. Fondaparinux is a synthetic form of the natural pentasaccharide, its pharmacokinetics allows one s.c. administration/24 hours. It is active in prevention and treatment of venous thromboembolic and coronary thrombotic events. A modified form (idraparinux) whose pharmacokinetics allows one administration only once a week should have the same type of efficacy. Among direct antithrombin agents, hirudin and derivatives have been developed in the past decade with a limited use due to several drawback. More recently synthetic direct antithrombins modified to allow oral route have been developed, the most advanced in development, melagatran, is active in the prevention and treatment of venous thromboembolic and coronary thrombotic events. It could allow (if confirmed by clinical trials) a complete oral treatment of deep vein thrombosis without any biological monitoring. Melagatran is also active in the prevention of arterial thromboembolic events on atrial fibrillation. But other molecular forms of synthetic orally active direct antithrombin are also in development. Besides these important changes in our therapeutics which should appear in a near future, molecules aimed at other target are also tested: the most advanced are those antagonizing the initial phase of tissue factor activation of factor VII but other strategies are being tested such as stimulation of fibrinolysis. These new drugs at our disposal to treat venous thromboembolism should modify completely our handling of the patients. But additionally the numerous clinical trials necessary to prove the efficacy of the drugs, modify our understanding in the implication of the coagulation and in the physiopathogeny of thrombotic events.

Topics: Administration, Oral; Azetidines; Benzylamines; Clinical Trials as Topic; Coronary Thrombosis; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Glycine; Hirudin Therapy; Humans; Orthopedics; Polysaccharides; Prodrugs; Prothrombin; Research; Thrombin; Thromboembolism; Time Factors; Venous Thrombosis