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IMPORTANCIA DA TROMBOSE
J Thromb Thrombolysis
Highlights from the III International Symposium of Thrombosis
and Anticoagulation (ISTA), October 14–16, 2010, São Paulo, Brazil
“Venous and arterial thrombosis remains the most frequent cause of death in western countries. Cardiovascular disease, including heart attack and stroke, accounts for more than 50% of deaths. Additionally, the presence of thromboembolism is an adverse prognostic indicator in patients with cancer, which is the second most common cause of death. As a result, there is great interest in the development of novel anticoagulant agents designed to reduce the risk of first or recurrent thrombotic event while minimizing the risk of bleeding. Arterial thrombosis is generally due to platelet activation occurring at sites of vascular injury in high-flow and high-sheer vessels. Generally, antiplatelet agents are preferred for primary or secondary prevention of arterial thrombosis because they inhibit platelet activation induced by platelet binding at sites of vascular injury and mediated by von Willebrand factor. Recent interest has focused on the development of new and more potent antiplatelet agents with special characteristics including rapid on- and off-set of action, shorter half-lives, and more potent inhibition of specific self-surface receptors including the thrombin receptor.
Venous thrombosis is generally thought to be due to activation of soluble coagulation proteins in low-flow areas of the venous system. There are some parallels in the left atrium of patients with atrial fibrillation (AF), suggesting that treatments that are effective for prevention of venous thrombosis will also be effective for prevention of systemic embolization in patients with AF. Traditional agents for prevention and treatment of venous thrombosis include heparins, low-molecular-weight heparins (LMWH), pentasaccharides, and a variety of parenteral anticoagulants used infrequently in specific circumstances such as patients with heparin-induced thrombocytopenia. Long-term therapy has traditionally been provided by warfarin administered to achieve an international normalized ratio (INR) of 2.0–3.0. The limitations of warfarin—including drug and food interactions, variability within and between patients in dosing requirements, a narrow therapeutic window, and the need for frequent INR monitoring—have led to the development of novel agents that lack some or all of these characteristics. Dabigatran and rivaroxaban are two agents that have been approved for several indications. Dabigatran recently was approved in Canada and the United States for prevention of systemic embolization in patients with AF. These agents, if proven safe in phase IV studies, offer significant advantages over warfarin for prevention of systemic embolization. They are also the subject of studies for secondary prevention of venous thrombosis. In this setting, efficacy of both agents is comparable to warfarin.
Intensification of antithrombotic therapy has a cost. There is clear evidence that bleeding rates increase as patients are treated with more aggressive antithrombotic regimens. Thus, when compared with warfarin alone, bleeding risks increase in patients treated with aspirin and warfarin, and further increase in patients treated with socalled ‘‘triple therapy.’’ Risks of bleeding will undoubtedly be even higher in patients who are treated with ‘‘quadruple therapy,’’ as novel antiplatelet and antithrombotic agents are brought to market.
There is also evidence that a therapeutic effect can be achieved at lower doses of antithrombotic medications than are currently employed for many indications. Thus, prophylactic doses of pentasaccharide are as effective as therapeutic doses of enoxaparin for prevention of thrombotic and other vascular complications in patients with unstable coronary syndromes. At prophylactic doses, fondaparinux produces less bleeding than enoxaparin, suggesting it may be a preferred agent for treatment in this setting. The pentasaccharide study highlights current thoughts suggesting that ‘‘de-intensification’’ should be considered in selected patients because currently available antithrombotics may maintain their ‘‘therapeutic effect’’ at levels that are associated with a lower rate of ‘‘toxicity,’’ predominantly bleeding.
In summary, cardiovascular disease remains a leading cause of death. Significant resources have been invested in the design and evaluation of novel antithrombotic agents, which are now being evaluated for prevention of both first and recurrent thrombotic events in high-risk patients. Demonstration that intensification of anticoagulation is associated with enhanced bleeding risk has led to studies that attempt to de-intensify antithrombotic therapy. Novel agents offer the hope of simplicity of treatment with reduced toxicity; however, their safety must be proven in large patient groups”.