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Jan 1, 2011 (Vol. 31, No. 1)

Solving the Antithrombotic Conundrum

Selective and Reversible Inhibition of Clotting Cascade Yields Safer, More Effective Therapies

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    David J. Mazzo, Ph.D.

    The multibillion-dollar worldwide market for injectable antithrombotic drugs (including anticoagulants and antiplatelet agents) will continue to grow as minimally invasive surgical interventions to open blocked coronary vessels become increasingly commonplace.

    Despite the agents available in the clinician’s antithrombotic toolbox today, control of clotting remains suboptimal. Clinicians performing intravascular interventions are still faced with achieving the delicate balance between preventing the formation of ischemia-producing clots while allowing healing clots to form and develop normally to prevent excessive bleeding.

    Antithrombotic technology in the acute and subacute care cardiovascular setting is poised for a paradigm shift and is in need of therapeutic alternatives with improved safety profiles and enhanced effectiveness. New treatment strategies capable of more selective and actively controlled inhibition of critical targets in the coagulation cascade will reduce the risk of adverse events associated with revascularization procedures.

    Novel approaches that give clinicians a greater degree of control over coagulation will concomitantly minimize the risk of ischemia and bleeding and allow for real-time adjustment of the therapeutic effect in individual patients. The result will be optimized safety and efficacy of anticoagulant therapy and a broadly applicable approach to antithrombosis that embraces the principles and advantages of personalized medicine.

  • Optimizing Antithrombotic Control

    Click Image To Enlarge +
    Preventing the formation of ischemia-producing clots while allowing healing clots to form and develop normally to prevent excessive bleeding remains a challenge. [Astoria/Fotolia.com]

    Patients with acute coronary syndromes routinely undergo coronary revascularization procedures such as percutaneous coronary interventions (PCI)—angioplasty with or without intracoronary stent placement—to unblock clogged arteries.

    With the anticoagulant therapies available for use during PCI, patients are at risk of coagulation-related complications such as unwanted thrombus formation that can lead to myocardial infarction, stroke, and/or the need for vessel revascularization, or, at the other end of the spectrum, uncontrolled bleeding resulting in life-threatening exsanguination, the need for transfusion, and/or extensive medical treatment and a prolonged hospital stay.

    Because existing anticoagulants are administered as IV infusions and the infusion is only stopped at the end of the PCI procedure, these drugs persist in the circulation and continue to exert their effects long after it would be desirable to reduce anticoagulation to a level that would minimize the risk of excessive bleeding and maintain homeostasis. The inability to reverse anticoagulant effects with an active control strategy adversely impacts both medical outcomes and the pharmacoeconomics of PCI.

    While it is readily accepted that ischemic events lead to increased costs and grave medical consequences, it is not as well known that excessive bleeding carries a high cost in terms of both mortality and medical expenditures. Patients who experience a major bleed are at least two and a half times more likely to die in the hospital than those who do not.

    The economic toll associated with bleeding complications has been estimated at $1,300 to more than $15,000 per patient. The treatment for bleeding may range from frequent monitoring of anticoagulation to extensive hands-on care, often requiring the use of compression or closure devices. In the instance of a major bleed, blood transfusions, with their associated costs and risks, are often necessary. Thus, the next generation of anticoagulants will need to address the issues of ischemia and bleeding equally well.

    A pivotal characteristic of the optimized antithrombotic agent will be rapid, predictable, real-time control over coagulation. The ability of clinicians to adjust the antithrombotic effect in response to the specific patient and setting would allow them to minimize the risk of ischemia and of bleeding simultaneously without erring on the side of either clotting or anticoagulation. This is a realistic goal that is now within reach due to recent advances in the development of aptamer therapeutics paired with complementary active control agents.

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