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Introduction: New treatment strategies for thrombotic disorders
Seminars in
HEMATOLOGY Vol 39, No 3, July 2002
Introduction: New Treatment Strategies for Thrombotic Disorders Barbara M. Alving
T
HIS ISSUE OF Seminars reviews new drugs for thrombotic disorders that have been recently approved or are probably soon to be approved. Several articles also focus on the ways in which commonly used agents such as low molecular weight heparin (LMWH) and warfarin can be employed more safely for those patients who are at high risk for either thrombosis or bleeding. Stephan Moll and Harold Roberts provide the background and rationale for development of antithrombotic agents. They describe the benefits and disadvantages of current drugs and review our newer understanding of hemostasis, which provides the basis on which to develop drugs with specific targets, such as the tissue factor:factor VIIa complex. In addition, these authors provide an excellent summary of the pharmaceuticals that have been recently approved or are in development. Graham Turpie provides a thorough review of the preclinical and clinical trials that led to the recent approval by the Food and Drug Administration (FDA) of fondaparinux sodium (Arixtra, Sanofi-Synthe´labo, Paris, France/Organon, Oss, The Netherlands) for prevention of venous thromboembolism after surgery for hip fracture or for hip or knee replacement. This pentasaccharide, which acts in conjunction with antithrombin to inhibit factor Xa, is synthesized rather than derived from animal origin; its long terminal half-life of 17 to 21 hours allows for once-daily dosing. The drug does not appear to inhibit platelet function or to interact with platelet factor 4, suggesting that it may have potential as alternative therapy in heparin-induced thrombocytopenia. Its disadvantages are that no antidote is available to neutralize its activity and it is cleared by the
renal route, indicating cautious use in patients with any evidence of renal dysfunction. The FDA approval for the use of LMWH as treatment for acute venous thromboembolism has resulted in a revolution in the care of most patients with this disorder, with hospital days either completely eliminated or markedly reduced. However, many of the clinical trials that were designed to show efficacy of LMWH excluded patients with known underlying hypercoagulable states, or who were obese or had renal disease. These patients are now also receiving LMWH. Susan O’Shea and Thomas Ortel review what is known about the use of LMWH in patients who have renal insufficiency, cancer, or who are obese or pregnant. They also discuss the perioperative use of LMWH and the role of protamine in neutralizing the anticoagulant activity. The issues addressed in their article will also need to be considered for pentasaccharide. Jean Chai and Gail Macik discuss several factors that can affect the anticoagulant potency of warfarin. Polymorphisms in the cytochrome P450 CYP2C9 enzyme result in prolonged catabolism of the S enanFrom the National Heart, Lung, and Blood Insitute, Bethesda, MD. This article was written by Dr Alving in her private capacity. The views expressed do not necessarily represent the views of the National Institutes of Health, DHHS, or the US government. Address reprint requests to Barbara Alving, MD, Deputy Director, National Heart, Lung, and Blood Institute, Building 31, Room 5A47, MSC 2490, 31 Center Dr, Bethesda, MD 20892. Copyright 2002, Elsevier Science (USA). All rights reserved. 0037-1963/02/3903-0008$35.00/0 doi:10.1053/shem.2002.34094
Seminars in Hematology, Vol 39, No 3 ( July), 2002: pp 143-144
143
144
Barbara M. Alving
tiomer of warfarin; individuals who have these polymorphisms may have markedly reduced dose requirements. The authors also describe the value of near-site monitoring and the role of self-management with at-home devices. Finally, they review the approaches for the rapid correction of excessive anticoagulation, as determined by the measurement of the international normalized ratio (INR), in clinical situations in which the patient is bleeding or is asymptomatic. An ideal oral anticoagulant would directly inhibit thrombin or other coagulation factors, have a rapid onset of action, demonstrate good predictability in anticoagulation for the dose administered, be monitored by a simple, commonly used assay, and be quickly neutralized by a widely available antidote in situations of excessive anticoagulation. Karen Kaplan and Charles Francis discuss a new oral drug, ximelagatran, now in phase III clinical trials, that has many of these properties. Ximelagatran is an inactive prodrug which, after oral ingestion, is converted to melagatran, a dipeptide that is a competitive inhibitor of thrombin. It has a rapid onset of action (within 1 to 2 hours), can be administered on a weight basis if necessary, and is easily monitored with an activated partial thromboplastin time. The half-life is 2.5 to 3.5 hours and is more prolonged in individuals with renal insufficiency; there is no satisfactory antidote to neutralize activity. Ximelagatran has been studied in the clinical settings of post orthopedic surgery, acute venous thrombosis, and atrial fibrillation. Kaplan and Francis also review the three parenteral thrombin-specific inhibitors that are currently available. Lepirudin (a recombinant form of hirudin) and argatroban (an arginine derivative) are used in heparin-induced thrombocytopenia. An additional thrombin-specific inhibitor known as bivalirudin, a truncated form of hirudin, is approved for use in patients undergoing angioplasty. John Griffin, Berislav Zlokovic, and Jose Fernandez discuss the multiple biologic properties of activated protein C (APC), as demonstrated by both in vitro and preclinical studies. They provide evidence that the anticoagulant action of APC is only one property that accounts for its biologic activity. APC also has anti-inflammatory, profibrinolytic, and antiapoptotic properties. Together, these characteristics may explain its role in significantly reducing mortality in patients with sepsis and associated organ dysfunction who received infusions for 96 hours compared to those who received placebo. This has led to
FDA approval for APC (known commercially as drotrecogin alfa [activated]; Xigris, Eli Lilly, Indianapolis, IN) in adult patients with severe sepsis. The authors provide evidence obtained with a mouse model that APC may also be useful in reducing the volume of cerebral tissue that undergoes infarction after a stroke. The concluding article by Victor Marder and Daphne Stewart reviews fibrinolysis induced by tissue plasminogen activator (t-PA) and its commercially produced variant forms in the clinical settings of myocardial infarction, ischemic stroke, peripheral arterial occlusion, and venous thromboembolism. The most serious side effect of t-PA–induced fibrinolysis, intracranial bleeding, has not been reduced by the variant forms, which were, in part, designed to allow for bolus administration. The authors describe in detail a newer approach to enhancing the safety and efficacy of thrombolytic therapy: infusion of plasmin directly to the site of thrombus formation via an intravascular catheter. This route of drug delivery should allow for a much lower level of fibrinolytic activity systemically and also for achievement of a higher local concentration at the site of thrombus. The idea of plasmin as a drug is not new; this agent was used in human clinical studies in the 1950s and 1960s but was abandoned because of the inability to deliver the enzyme directly to the site of the clot. When infused systemically, plasmin is rapidly inhibited by its specific inactivator known as ␣2-plasmin inhibitor. What is novel is the ability to use catheterdirected delivery of the thrombolytic agent. If plasmin is successful in preclinical studies, then large amounts will be needed for clinical studies in humans. One approach is to use recombinant technology to produce stable microplasminogen which can be activated to yield functional microplasmin.1 Although this issue of Seminars focuses on newer agents, the older ones are unlikely to be abandoned. Rather, the novel drugs should expand the therapeutic options for physicians who must balance the dangers of clotting against the risks of excessive hemorrhage in patients who have multiple medical problems. The success of the agents will be determined by their cost and by the value they offer to the treatment regimen in terms of efficacy, safety, and ease of use.
Reference 1. Collen D. Revival of plasmin as a therapeutic agent? Thromb Haemost 86:731-732, 2001
HEMATOLOGY Vol 39, No 3, July 2002
Introduction: New Treatment Strategies for Thrombotic Disorders Barbara M. Alving
T
HIS ISSUE OF Seminars reviews new drugs for thrombotic disorders that have been recently approved or are probably soon to be approved. Several articles also focus on the ways in which commonly used agents such as low molecular weight heparin (LMWH) and warfarin can be employed more safely for those patients who are at high risk for either thrombosis or bleeding. Stephan Moll and Harold Roberts provide the background and rationale for development of antithrombotic agents. They describe the benefits and disadvantages of current drugs and review our newer understanding of hemostasis, which provides the basis on which to develop drugs with specific targets, such as the tissue factor:factor VIIa complex. In addition, these authors provide an excellent summary of the pharmaceuticals that have been recently approved or are in development. Graham Turpie provides a thorough review of the preclinical and clinical trials that led to the recent approval by the Food and Drug Administration (FDA) of fondaparinux sodium (Arixtra, Sanofi-Synthe´labo, Paris, France/Organon, Oss, The Netherlands) for prevention of venous thromboembolism after surgery for hip fracture or for hip or knee replacement. This pentasaccharide, which acts in conjunction with antithrombin to inhibit factor Xa, is synthesized rather than derived from animal origin; its long terminal half-life of 17 to 21 hours allows for once-daily dosing. The drug does not appear to inhibit platelet function or to interact with platelet factor 4, suggesting that it may have potential as alternative therapy in heparin-induced thrombocytopenia. Its disadvantages are that no antidote is available to neutralize its activity and it is cleared by the
renal route, indicating cautious use in patients with any evidence of renal dysfunction. The FDA approval for the use of LMWH as treatment for acute venous thromboembolism has resulted in a revolution in the care of most patients with this disorder, with hospital days either completely eliminated or markedly reduced. However, many of the clinical trials that were designed to show efficacy of LMWH excluded patients with known underlying hypercoagulable states, or who were obese or had renal disease. These patients are now also receiving LMWH. Susan O’Shea and Thomas Ortel review what is known about the use of LMWH in patients who have renal insufficiency, cancer, or who are obese or pregnant. They also discuss the perioperative use of LMWH and the role of protamine in neutralizing the anticoagulant activity. The issues addressed in their article will also need to be considered for pentasaccharide. Jean Chai and Gail Macik discuss several factors that can affect the anticoagulant potency of warfarin. Polymorphisms in the cytochrome P450 CYP2C9 enzyme result in prolonged catabolism of the S enanFrom the National Heart, Lung, and Blood Insitute, Bethesda, MD. This article was written by Dr Alving in her private capacity. The views expressed do not necessarily represent the views of the National Institutes of Health, DHHS, or the US government. Address reprint requests to Barbara Alving, MD, Deputy Director, National Heart, Lung, and Blood Institute, Building 31, Room 5A47, MSC 2490, 31 Center Dr, Bethesda, MD 20892. Copyright 2002, Elsevier Science (USA). All rights reserved. 0037-1963/02/3903-0008$35.00/0 doi:10.1053/shem.2002.34094
Seminars in Hematology, Vol 39, No 3 ( July), 2002: pp 143-144
143
144
Barbara M. Alving
tiomer of warfarin; individuals who have these polymorphisms may have markedly reduced dose requirements. The authors also describe the value of near-site monitoring and the role of self-management with at-home devices. Finally, they review the approaches for the rapid correction of excessive anticoagulation, as determined by the measurement of the international normalized ratio (INR), in clinical situations in which the patient is bleeding or is asymptomatic. An ideal oral anticoagulant would directly inhibit thrombin or other coagulation factors, have a rapid onset of action, demonstrate good predictability in anticoagulation for the dose administered, be monitored by a simple, commonly used assay, and be quickly neutralized by a widely available antidote in situations of excessive anticoagulation. Karen Kaplan and Charles Francis discuss a new oral drug, ximelagatran, now in phase III clinical trials, that has many of these properties. Ximelagatran is an inactive prodrug which, after oral ingestion, is converted to melagatran, a dipeptide that is a competitive inhibitor of thrombin. It has a rapid onset of action (within 1 to 2 hours), can be administered on a weight basis if necessary, and is easily monitored with an activated partial thromboplastin time. The half-life is 2.5 to 3.5 hours and is more prolonged in individuals with renal insufficiency; there is no satisfactory antidote to neutralize activity. Ximelagatran has been studied in the clinical settings of post orthopedic surgery, acute venous thrombosis, and atrial fibrillation. Kaplan and Francis also review the three parenteral thrombin-specific inhibitors that are currently available. Lepirudin (a recombinant form of hirudin) and argatroban (an arginine derivative) are used in heparin-induced thrombocytopenia. An additional thrombin-specific inhibitor known as bivalirudin, a truncated form of hirudin, is approved for use in patients undergoing angioplasty. John Griffin, Berislav Zlokovic, and Jose Fernandez discuss the multiple biologic properties of activated protein C (APC), as demonstrated by both in vitro and preclinical studies. They provide evidence that the anticoagulant action of APC is only one property that accounts for its biologic activity. APC also has anti-inflammatory, profibrinolytic, and antiapoptotic properties. Together, these characteristics may explain its role in significantly reducing mortality in patients with sepsis and associated organ dysfunction who received infusions for 96 hours compared to those who received placebo. This has led to
FDA approval for APC (known commercially as drotrecogin alfa [activated]; Xigris, Eli Lilly, Indianapolis, IN) in adult patients with severe sepsis. The authors provide evidence obtained with a mouse model that APC may also be useful in reducing the volume of cerebral tissue that undergoes infarction after a stroke. The concluding article by Victor Marder and Daphne Stewart reviews fibrinolysis induced by tissue plasminogen activator (t-PA) and its commercially produced variant forms in the clinical settings of myocardial infarction, ischemic stroke, peripheral arterial occlusion, and venous thromboembolism. The most serious side effect of t-PA–induced fibrinolysis, intracranial bleeding, has not been reduced by the variant forms, which were, in part, designed to allow for bolus administration. The authors describe in detail a newer approach to enhancing the safety and efficacy of thrombolytic therapy: infusion of plasmin directly to the site of thrombus formation via an intravascular catheter. This route of drug delivery should allow for a much lower level of fibrinolytic activity systemically and also for achievement of a higher local concentration at the site of thrombus. The idea of plasmin as a drug is not new; this agent was used in human clinical studies in the 1950s and 1960s but was abandoned because of the inability to deliver the enzyme directly to the site of the clot. When infused systemically, plasmin is rapidly inhibited by its specific inactivator known as ␣2-plasmin inhibitor. What is novel is the ability to use catheterdirected delivery of the thrombolytic agent. If plasmin is successful in preclinical studies, then large amounts will be needed for clinical studies in humans. One approach is to use recombinant technology to produce stable microplasminogen which can be activated to yield functional microplasmin.1 Although this issue of Seminars focuses on newer agents, the older ones are unlikely to be abandoned. Rather, the novel drugs should expand the therapeutic options for physicians who must balance the dangers of clotting against the risks of excessive hemorrhage in patients who have multiple medical problems. The success of the agents will be determined by their cost and by the value they offer to the treatment regimen in terms of efficacy, safety, and ease of use.
Reference 1. Collen D. Revival of plasmin as a therapeutic agent? Thromb Haemost 86:731-732, 2001