Review articleA new era for anticoagulants
Introduction
Venous and arterial thromboembolic diseases are still the most frequent cause of death and disability in high-income countries, and their incidence is dramatically increasing also in middle- and low-income countries. Antithrombotic drugs inhibiting coagulation or platelet function play a key role in the management of these patients. This review article deals only with anticoagulants, that currently include unfractionated heparin (UFH), low-molecular-weight heparins (LMWH), vitamin K antagonists (VKA) and the synthetic pentasaccharide fondaparinux [1], [2], [3]. Although the benefit of warfarin, the most commonly used VKA, is well established in a wide spectrum of thromboembolic disorders [4], its use is hampered by numerous limitations, such as delayed onset and offset of action, narrow therapeutic window, genetic variations of metabolism and food and drug interactions that warrant frequent monitoring and dose adjustment [5]. Like warfarin, UFH is highly efficacious but has a number of limitations that restrict its clinical use: its route of administration (mainly intravenous), significant binding to plasma and endothelial proteins, need for laboratory monitoring, risk of osteoporosis and the life-threatening thrombotic complications associated with heparin-induced thrombocytopenia (HIT) [6]. The limitations of UFH and warfarin led to the development of new anticoagulants for the prevention and treatment of venous and arterial thromboembolism. LMWHs, derived from the depolymerization of UFH resulting in shorter chain lengths, have progressively replaced UFH, because they have a similar or greater efficacy and safety coupled with a number of advantages, such as longer half-life and more predictable dose-response that allows weight-adjusted fixed dosages with no need of laboratory monitoring [7]. However, the use of LMWH is still associated with the risk of HIT, although to a much lesser degree than for UFH, and the need for parenteral administration (mainly subcutaneous) renders its use sometimes problematic, especially in the outpatient setting.
Over the past decade, interest in anticoagulants has grown dramatically, as shown by the increasing number of drugs introduced in both preclinical and clinical development. In particular, research was focused on new agents selectively targeting specific steps in the coagulation cascade. For the most recently available among these drugs, the greatest advantage is that they can be administered orally and at fixed dosages.
Section snippets
New anticoagulant drugs
The new anticoagulants target a number of different steps in the coagulation system. However, the most advanced clinical development has been achieved for those inhibiting factor Xa (FXa) (either directly or indirectly via antithrombin) and thrombin (direct thrombin inhibitors) (Fig 1) [8], [9], [10], [11], [12]. They are usually small molecules that inhibit not only these coagulation enzymes when they circulate freely in plasma but also when they are thrombus bound. Of the new anticoagulants
Conclusions
The new anticoagulants, which inhibit thrombin or factor Xa, have the potential to be more effective and are definitely easier to use than such conventional anticoagulants as the heparins and vitamin K antagonists. Clinical studies with parenteral fondaparinux and oral rivaroxaban, apixaban and dabigatran indicate that inhibitors of factor Xa or thrombin are highly effective for the prevention of venous thromboembolism, particularly in the setting of major orthopedic surgery (the first licensed
Learning points
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Currently available anticoagulant drugs, such as heparins and vitamin K antagonists, are effective and inexpensive, but they need laboratory monitoring and/or parenteral administration.
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Newer drugs have the advantage of being given orally at fixed dosages and do not need laboratory monitoring.
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Yet, there are more expensive, have at the moment no antidote to block anticoagulation in case of severe bleeding, and their risk-benefit profile is not known in patients with abnormal renal function.
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