A nticoagulants are widely used by cardiologists. Unfractionated heparin (UFH) and coumarins were discovered more than 60 years ago, and for more than 40 years, they have been the sole anticoagulant drugs available to clinicians. 1,2 Now, in 2007, several new anticoagulants have been introduced, and many more are under clinical development. Will these new anticoagulants replace the established drugs, and if so, how will these new anticoagulants fit into the therapeutic armamentarium of the

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... icing cardiologist? Both UFH and coumarins were in clinical use long before their mechanism of action was completely understood. Both were also discovered by chance: UFH from extracts of dog liver and coumarins from extracts of vegetable matter (spoiled sweet clover). Low-molecular-weight heparin (LMWH) was also discovered by chance in the late 1970s and early 1980s and was in clinical use for at least a decade before its mechanistic advantages over UFH were identified. 3 In the quest for new anticoagulants, scientists often turned to extracting natural anticoagulants from hemophagic animals and insects and from snake venoms. 4 Defibrinating enzymes, factor Xa inhibitors, and thrombin inhibitors were isolated, purified, and in some cases synthesized by recombinant techniques. Of these anticoagulants, recombinant hirudin (from leeches) and recombinant NAPC2 (from hookworm) have been tested clinically. A few new anticoagulants (thrombomodulin, activated protein C) are synthesized by recombinant techniques, but with advances in structure-based design, most new anticoagulants are small molecules designed specifically to block the activity of coagulation enzymes either by fitting into their catalytic pockets, like a key into a lock, or by interacting with and activating anticoagulant proteins such as antithrombin (AT; eg, fondaparinux). On the basis of these technological advances, it is now possible to modulate the coagulation process at almost every step. The first wave of new anticoagulants was not orally active, thereby limiting their value for long-term treatment. These new parenteral anticoagulants (LMWH, bivalirudin, and fondaparinux) are effective and, because of their advantages over UFH, have replaced or are likely to replace UFH for many acute cardiac indications. As a result, the need for additional parenteral anticoagulants is less pressing than for new oral anticoagulants to replace warfarin. Initially, development of orally active agents was stalled because of tech-nical difficulties; however, with advances in techniques for oral absorption, several new site-specific oral anticoagulants have now been developed and are undergoing clinical testing. Drug developers have focused mainly on 2 key targets: factor Xa and factor IIa (thrombin). The cost of developing a new anticoagulant is high. Added to these development costs, trials evaluating novel anticoagulant therapies for the prevention of major vascular events for cardiac indications are particularly expensive, because the required sample size is large, and the duration of follow-up is long. Consequently, drug development often starts with less expensive studies in the prevention of venous thrombosis, based on the premise that success in this indication predicts success for other indications. Drugs currently under development or recently introduced into clinical practice are listed in Table 1 . In the remainder of the present review, we emphasize those agents that have been or are likely to be introduced into clinical practice in cardiology. Several new parenteral compounds but no new oral agents have been approved clinically. Before discussing the new antithrombotic drugs, we briefly review the limitations and advantages of UFH and LMWH, because it is these limitations that provide opportunities for new parenteral anticoagulants. The limitations of warfarin have been reviewed extensively elsewhere 5 and will not be discussed here. Limitations and Advantages of UFH and LMWH In addition to its well-known bleeding complications, UFH has biological and pharmacokinetic limitations. 3 The biological limitations are immune-mediated platelet activation, which leads to heparin-induced thrombocytopenia (HIT), and an effect on bone cells that leads to heparin-induced osteoporosis. These side effects are chain length-dependent and charge-dependent. Pharmacokinetic limitations are caused by AT-independent binding of UFH to plasma proteins and to proteins released from platelets, which results in the variable anticoagulant response and, therefore, a need for anticoagulant monitoring. Is UFH likely to become obsolete? The answer is not yet. UFH has 3 major advantages over LMWH. 3 The first is that the anticoagulant effects of UFH can be rapidly and completely neutralized by protamine. On the basis of this advantage, UFH remains the anticoagulant of choice during cardio-