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Evidence-Based College of Chest Physicians New Antithrombotic Drugs New Antithrombotic Drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Jeffrey I. Weitz, Jack Hirsh and Meyer M. Samama Chest 2008;133;234-256 DOI 10.1378/chest.08-0673 The online version of this article, along with updated information and services can be found online on the World Wide Web at: http://chestjournal.org/cgi/content/abstract/133/6_suppl/234S CHEST is the official journal of the American College of Chest Physicians. It has been published monthly since 1935. Copyright 2007 by the American College of Chest Physicians, 3300 Dundee Road, Northbrook IL 60062. All rights reserved. No part of this article or PDF may be reproduced or distributed without the prior written permission of the copyright holder (http://www.chestjournal.org/misc/reprints.shtml). ISSN: 0012-3692. Downloaded from chestjournal.org on June 25, 2008 Copyright © 2008 by American College of Chest Physicians Supplement ANTITHROMBOTIC AND THROMBOLYTIC THERAPY 8TH ED: ACCP GUIDELINES New Antithrombotic Drugs* American College of Chest Physicians Evidence- Based Clinical Practice Guidelines (8th Edition)* Jeffrey I. Weitz, MD, FCCP; Jack Hirsh, MD, FCCP; and Meyer M. Samama, MD This chapter focuses on new antithrombotic drugs that are in phase II or III clinical testing. Development of these new agents was prompted by limitations of existing antiplatelet, anticoag- ulant, or fibrinolytic drugs. Addressing these unmet needs, this chapter (1) outlines the rationale for development of new antithrombotic agents, (2) describes the new antiplatelet, anticoagulant, and fibrinolytic drugs, and (3) provides clinical perspectives on the opportunities and challenges faced by these novel agents. (CHEST 2008; 133:234S–256S) Key words: anticoagulants; antiplatelet drugs; antithrombotic drug; fibrinolytic agents Abbreviations: ACS ϭ acute coronary syndrome; CYP ϭ cytochrome P450; DVT ϭ deep vein thrombosis; factor VIIai ϭ active site-blocked factor VIIa; LMWH ϭ low-molecular-weight heparin; MI ϭ myocardial infarction; NAPc2 ϭ nematode anticoagulant peptide c2; PAI-1 ϭ type 1 plasminogen activator inhibitor; PAR ϭ protease activated receptor; PCI ϭ percutaneous coronary intervention; PE ϭ pulmonary embolism; PF4 ϭ platelet factor 4; TAFI ϭ thrombin activatable fibrinolysis inhibitor; TIMI ϭ Thrombolysis in Myocardial Infarction; tPA ϭ tissue-type plasminogen activator; TRAP ϭ thrombin receptor agonist peptide; u-PA ϭ urokinase-type plasminogen activator; VTE ϭ venous thromboembolism rterial and venous thrombosis are major causes patients with atrial fibrillation or mechanical heart A of morbidity and mortality. Whereas arterial valves. Fibrinolytic drugs are used for rapid restora- thrombosis is the most common cause of myocardial tion of antegrade blood flow in patients with acute infarction (MI), ischemic stroke and limb gangrene, myocardial infarction who do not undergo a primary deep vein thrombosis (DVT) leads to pulmonary percutaneous coronary intervention (PCI) and for embolism (PE), which can be fatal, and to the post- treatment of acute ischemic stroke. phlebitic syndrome. Arterial thrombi, which form un- Venous thrombi, which form under low shear, are der high shear conditions, consist of platelet aggre- composed mainly of fibrin and trapped red cells, and gates held together by small amounts of fibrin.1 contain relatively few platelets.1 With the predomi- Because of the predominance of platelets, strategies nance of fibrin in venous thrombi, anticoagulants are to inhibit arterial thrombogenesis focus mainly on the agents of choice for the prevention and treatment drugs that block platelet function, but include anti- of venous thromboembolism (VTE). Systemic fibrino- coagulants for prevention of cardioembolic events in lytic therapy is used for treatment of massive PE and for management of selected patients with submassive PE, whereas catheter-directed fibrinolytic therapy is *From the Henderson Research Center (Drs. Weitz and Hirsh), McMaster University, Hamilton, ON, Canada; and Hoˆtel-Dieu used in some patients with extensive iliofemoral DVT. University Hospital (Dr. Samama), Paris, France. Limitations of existing antithrombotic drugs have Manuscript accepted December 20, 2007. prompted a search for novel agents. Focusing on Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. new drugs for the prevention and treatment of org/misc/reprints.shtml). arterial and venous thrombosis, this chapter1 outlines Correspondence to: Jeffrey Weitz, MD, 711 Concession St, the rationale for development of new antithrombotic Hamilton, ON, L8V 1C3, Canada; e-mail: jweitz@thrombosis. 2 hhscr.org drugs, describes the new antithrombotic drugs, DOI: 10.1378/chest.08-0673 focusing primarily on those in Phase II or III clinical 234S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines testing, and3 provides perspective on the unmet problematic in patients undergoing percutaneous needs in antithrombotic therapy. coronary interventions (PCI) where rapid platelet inhibition is required. Administration of loading doses of clopidogrel accelerates its antiplatelet ef- 2.0 Rationale for Development of New fects, but maximum inhibition remains delayed for 11 Antithrombotic Drugs several hours. Not only do the thienopyridines have a slow onset of action, but their offset of action also Better understanding of the molecular mechanisms is delayed for at least 5 days because the active underlying thrombogenesis, advances in recombinant metabolites of these drugs irreversibly inhibit their DNA technology, isolation and characterization of target receptor. This causes problems for patients antithrombotic proteins from hematophagous organ- who require urgent surgery because clopidogrel isms, and improvements in structure-based drug increases the risk of bleeding.12–14 design have accelerated the pace of drug discovery. The limitations of existing antiplatelet drugs pro- With these advances, we now have an array of new vide opportunities for new agents. Attempts to re- antithrombotic drugs. place aspirin with other inhibitors of the thrombox- The established efficacy of aspirin and the thien- ane A2-mediated pathway of platelet aggregation opyridines validates platelet cyclooxygenase-1 and have not yet been successful. Instead, attention has ADP receptors as targets for antiplatelet drugs.2,3 By focused on novel ADP receptor antagonists and on irreversibly acetylating cyclooxygenase-1, aspirin in- drugs that target protease activated receptor (PAR)-1, hibits arachidonate-induced platelet aggregation and the major thrombin receptor on platelets. New Ͼ reduces thromboxane A2 synthesis by 98%. Al- P2Y12 antagonists have been developed to replace though cheap and effective, breakthrough cardiovas- clopidogrel. Drugs that produce more predictable cular events occur despite aspirin therapy. Some inhibition of ADP-induced platelet aggregation may patients are resistant to usual doses of aspirin as overcome clopidogrel resistance, whereas those with manifested by incomplete inhibition of platelet ag- a rapid onset and offset of action may have advan- gregation and/or ongoing thromboxane A2 produc- tages in the PCI setting. Whether a rapid onset and tion. Such patients may be more prone to recurrent offset of action is an advantage for long-term admin- 4–6 cardiovascular events. istration is uncertain. Although new P2Y12 antago- Thromboxane A2 receptor antagonists were devel- nists have the potential to be more efficacious than oped, at least in part, to overcome the limitations of clopidogrel because they produce more profound aspirin. Thromboxane A2 induces platelet aggrega- inhibition of ADP-induced aggregation, there may tion by binding to the thromboxane A2 receptor on be issues with safety. Thus, enhancing the extent of platelets. The thromboxane A2 receptor also binds platelet inhibition by adding clopidogrel to aspirin prostanoids, such as prostaglandin F2␣, which can increases the risk of major bleeding,15,16 and more promote platelet aggregation by causing vasocon- potent ADP receptor antagonists may further in- striction. crease this risk. Finally, clinical development of Thromboxane A2 receptor antagonists block plate- PAR-1 antagonists has started and preliminary re- let aggregation in response to both thromboxane A2 sults are encouraging. Clinical trials with these and prostanoids. In contrast, aspirin has no effect on agents will help define the role of PAR-1 in athero- prostanoid synthesis and incompletely inhibits throm- thrombosis. 4–6 boxane A2 synthesis in some patients. Therefore, Currently available anticoagulants include both thromboxane A2 receptor antagonists have the poten- parenteral and oral agents. Rapidly acting parenteral tial to be more effective than aspirin. anticoagulants are usually used for initial treatment The thienopyridines irreversibly inhibit P2Y12,a of arterial or venous thromboembolism, whereas oral major ADP receptor on the platelet surface. Cur- agents are employed for long-term therapy. For initial rently available thienopyridines include ticlopidine treatment, low-molecular-weight heparin (LMWH) and clopidogrel.7 Clopidogrel has largely replaced has replaced heparin for most indications because ticlopidine because the risk of hematological toxicity LMWH is more convenient to administer and meta- is lower and the drug can be given once daily. When analyses of clinical trials comparing it with heparin given in usual
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