Introduction

This issue of Seminars in Thrombosis and Hemostasis is based on selected manuscripts presented at the 4th annual Antithrombotic Therapy Symposium held in Dearborn, Michigan, in 2003. For the past 5 years, these annual symposia have represented a major yearly event that brings together experts from various disciplines to provide an update on timely topics in antithrombotic therapy. The selected manuscripts provide a state of the art account of the management of thrombotic and cardiovascular disorders with reference to the development and introduction of newer drugs. The information provided herein will be useful to all those interested in antithrombotic drugs.

Anticoagulants and antithrombotic drugs have played a key role in the prophylaxis, treatment, and surgical and interventional management of thrombotic and cardiovascular disorders. There are several newer drugs that are currently developed for these disorders, for both medical and interventional indications. These include the ultra-low-molecular-weight heparins (LMWHs); antithrombin agents such as hirudin, hirulog and argatroban; and indirect and direct anti-Xa drugs, represented by pentasaccharides fondaparinux and DX 9065a, respectively. The oral heparins, anti-IIa and anti-Xa drugs are also in different phases of clinical development. Of these, one oral antithrombin agent, enaxta, is approved in Europe for qualified indications and is under review by the U.S. Food and Drug Administration. Several other agents, such as natural and recombinant anti-Xa drugs and anti-tissue factor agents, are also being developed. New antiplatelet agents include clopidogrel, cilostazol, anplag, and glycoprotein (GP)IIb/IIIa inhibitors. For subcutaneous indications, unfractionated heparin (UFH) is gradually replaced by LMWHs. LMWHs such as enoxaparin and dalteparin are commonly used for the management of acute coronary syndromes and related cardiovascular disorders. These drugs have been approved for the treatment of unstable angina and are currently undergoing rigorous trials for interventional indications. Fondaparinux is also developed for various subcutaneous indications. However, it exhibits lower anticoagulant effects and may not be optimal for intravenous and interventional purposes. At higher dosages, when administered intravenously, the LMWHs produce varying degrees of anticoagulation at relatively shorter activated clotting times (ACT) (150 to 200 seconds). Several studies in vascular and cardiovascular interventions have shown that even at relatively lower anticoagulant levels the LMWHs are as effective as UFH at the recommended dosages, which produce a relatively higher level of anticoagulation (ACT > 200 seconds). Thus, these agents are currently developed for interventional and surgical indications. It should be emphasized that different LMWHs produce different degrees of anticoagulation and should, therefore, be individually optimized for a given interventional or surgical purpose. When combined with such GPIIb/IIIa inhibitors as abciximab, aggrastat, or eptifibratide, these drugs may require dosage adjustment. However, since the introduction of the front loading of clopidogrel, the unqualified use of GPIIb/IIIa is debated.

LMWHs will find expanded indications in both the medical and the surgical management of patients with cardiovascular disorders, including atrial fibrillation and congestive heart failure. The LMWHs are also useful in the management of cancer patients. Recent trials have clearly shown that these drugs reduce mortality in these patients. The only approved anti-Xa drug is represented by a synthetic heparinomimetic, fondaparinux. This drug is given for thromboprophylaxis in orthopedic patients. This agent is undergoing additional clinical trials in the management of coronary artery diseases. Because of the dependence on antithrombin and the sole anti-Xa effects, the drug has a narrow therapeutic index, and its efficacy in this indication may be limited. Additional clinical trials are needed at this time to validate the clinical potential of this drug. The longer-lasting methylated pentasaccharide derivative, idraparinux, is also optimistically developed; however, there is no antidote for this agent.

The antithrombin agents (hirudin, hirulog, and argatroban) were initially developed for arterial indications. However, these agents are approved as a substitute anticoagulant in patients with heparin-induced thrombocytopenia (HIT) and with percutaneous coronary interventions (PCI). Different antithrombin agents produce their therapeutic effects by distinct mechanisms and should be considered equivalent on the basis of their anticoagulant effects. Currently all of these agents are being developed for surgical and interventional use. However, because there is no available antidote at this time, the applicability is somewhat limited. The antithrombin agents may be useful in patients with HIT, but this requires further clinical validation. Many other anti-Xa agents are also developed at this time. Most of these can be given parenterally. However, the clinical data are presently somewhat limited. Similarly, several of the new antiplatelet drugs can be administered parenterally and may be useful in coronary artery diseases. Because most of these newer anticoagulant and antithrombotic drugs are monotherapeutic, their therapeutic index is limited. Only in combination can these agents mimic heparins. At this time it is safe to state that UFH and its LMW derivatives will remain the anticoagulant of choice for the management of thrombosis until these newer agents have been validated in extended clinical trials in polytherapeutic settings.

Polytherapeutic approaches, including the targeting of adhesion molecules and cellular receptors, modulation of inflammatory processes, targeting procoagulant proteins such as the coagulation factors, tissue factor and von Willebrand factor and bifunctional antiplatelet/antiprotease drugs, will be the focus of future targets in this field. Educational forums and publications based on these are, therefore, of value in the appraisal of the development of antithrombotic drugs.

This symposium was hosted by the Henry Ford Hospital Systems with the joint sponsorship by the Detroit Medical Center, Wayne State University, and the Loyola University Medical Center. The past three annual conferences were a testimonial of the largest independent anticoagulant continuing medical education program of its kind in the United States. The faculty represented several national and international leaders covering cutting edge topics, such as cancer and thrombosis, anticoagulation in acute coronary syndromes, practical issues in the dosing and monitoring of antithrombotic agents, and development of newer drugs.

The organizers of this meeting are thankful to the faculty who contributed to this program. We also acknowledge the support from various pharmaceutical companies who contributed to this program.