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Correspondence to: Jeffrey Weitz, FCCP, 711 Concession St, Hamilton, ON, L8V 1C3 Canada; e-mail: jweitz{at}thrombosis.hhscr.org
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Abstract |
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 TOP Abstract Introduction1.0 Thrombogenesis2.0 Regulation of Coagulation3.0 Pathways for Development...4.0. Conclusions and Future...SummaryReferences |
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Key Words: anticoagulants • antithrombotic drugs • profibrinolytic agents
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Introduction |
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TOPAbstractIntroduction1.0 Thrombogenesis2.0 Regulation of Coagulation3.0 Pathways for Development...4.0. Conclusions and Future...SummaryReferences |
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The limitations of existing oral and parenteral anticoagulants have prompted a search for novel agents. Focusing on new anticoagulant drugs for the prevention and treatment of arterial and venous thrombosis, this article (1) reviews arterial and venous thrombogenesis, (2) discusses the regulation of coagulation, (3) describes the pathways for testing new anticoagulants, (4) describes new anticoagulant strategies focusing primarily on agents that are in phase II or III clinical testing, and (5) provides a clinical perspective as to which of these new strategies is most likely to succeed.
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1.0 Thrombogenesis |
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TOPAbstractIntroduction1.0 Thrombogenesis2.0 Regulation of Coagulation3.0 Pathways for Development...4.0. Conclusions and Future...SummaryReferences |
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Venous thrombi develop under low-flow conditions and usually originate in the muscular veins of the calf or in the valve cusp pockets of the deep calf veins.34 Because the venous valve cusps are avascular, they depend on the circulating blood for their oxygen and nutrient supply. With venous stasis, there is local hypoxemia, which can induce tissue factor expression in the valve cusps. Coagulation in the veins also can be initiated by vascular trauma. Damage to the vessel wall is a particularly important predisposing factor to venous thrombosis after major hip or knee surgery.5 Indwelling central venous catheters also can injure the vein wall, causing deep-vein thrombosis (DVT) in the upper extremities.
Inflammatory cytokines generated after trauma, surgery, or medical illness can contribute to the procoagulant state that occurs with these conditions. Endothelial cells are activated by inflammatory cytokines and express adhesion molecules that tether leukocytes onto their surface. Bound monocytes elaborate tissue factor and express receptors for factor X and fibrinogen, that promote coagulation on their surfaces.67 Tethered neutrophils damage the endothelium by generating oxygen free radicals and releasing hydrolytic enzymes, thereby enhancing local clot formation.89 Finally, tissue factor-containing leukocyte and platelet-derived microparticles also accumulate at sites of vascular damage where they augment coagulation.10 It is through these mechanisms that inflammation is intimately linked with coagulation.
The initiation of coagulation in arteries or veins is triggered by tissue factor (Fig 2 ), a cellular receptor for activated factor VII (factor VIIa).11 Although a small fraction of circulating factor VII is activated, factor VIIa has little or no enzymatic activity until it is bound to tissue factor. Most nonvascular cells express tissue factor in a constitutive fashion, whereas de novo tissue factor synthesis can be induced in monocytes.1213 Injury to the arterial or venous wall exposes nonvascular, tissue factor-expressing cells to blood.11 Lipid-laden macrophages in the core of atherosclerotic plaques are particularly rich in tissue factor,1 thereby explaining the propensity for thrombus formation at sites of plaque disruption.
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The propagation of coagulation is effected by factors IXa and Xa. In the presence of calcium, factor IXa binds to factor VIIIa on the surface of activated platelets to form intrinsic tenase, the complex that activates factor X. Factor Xa then binds to factor Va on the activated platelet surface, a process that also is calcium-dependent, to form the prothrombinase complex. This complex activates prothrombin, and the resultant thrombin then dissociates from the platelet surface and converts fibrinogen to fibrin monomer.1114 Fibrin monomers polymerize to form the fibrin mesh that is stabilized and crosslinked by activated factor XIII (factor XIIIa), a thrombin-activated transglutaminase. Thrombin amplifies its own generation by the feedback activation of factor V and factor VIII, as described above, and by activating platelet-bound factor XI, thereby leading to further factor Xa generation.15
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2.0 Regulation of Coagulation |
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TOPAbstractIntroduction1.0 Thrombogenesis2.0 Regulation of Coagulation3.0 Pathways for Development...4.0. Conclusions and Future...SummaryReferences |
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TFPI
The inhibition of the factor VIIa/tissue factor complex is effected by TFPI.16 A bivalent, Kunitz-type inhibitor, TFPI acts in a two-step manner (Fig 3
). In the first step, TFPI complexes and inactivates factor Xa to form a TFPI/factor Xa complex. The TFPI within this complex then inactivates tissue factor-bound factor VIIa as the second step. Because the formation of the TFPI/factor Xa complex is a prerequisite for the efficient inactivation of factor VIIa, the system ensures that some factor Xa generation occurs before factor VIIa-mediated initiation of the coagulation system is shut down.
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Most circulating TFPI is bound to lipoproteins. TFPI also is found in platelet 
-granules and on the endothelial cell surface.16 TFPI bound to the endothelium is released with therapeutic doses of heparin or low-molecular-weight heparin, suggesting that TFPI binds to endogenous glycosaminoglycans on the endothelial wall surface.16 It is uncertain, however, whether released TFPI contributes to the antithrombotic properties of these agents.
Antithrombin
Antithrombin inhibits thrombin, factor Xa, and other activated clotting factors, but these reactions are slow in the absence of heparin. With heparin, the rate of inhibition is accelerated about 1,000-fold.18 Heparin binds to antithrombin via its high-affinity pentasaccharide sequence and, by altering the conformation of the reactive center loop of antithrombin, renders the protease trap more accessible to target enzymes. Although heparin is not normally found in the blood, the vascular endothelium is rich in heparan sulfate, a glycosaminoglycan that also contains the antithrombin-binding pentasaccharide sequence. Most of the heparan sulfate is located on the abluminal surface of the endothelium and is exposed only when the vessel lining is damaged.19 Nevertheless, the small amounts of proteoglycan located on the luminal surface may help to render intact endothelium nonthrombogenic.
Protein C pathway
In addition to inactivation by antithrombin, thrombin also is inhibited by binding to thrombomodulin, a thrombin receptor found on the endothelium (Fig 4
). Once bound to thrombomodulin, thrombin undergoes a conformational change at its active site that converts it from a procoagulant enzyme into a potent activator of protein C, a vitamin K-dependent protein. Activated protein C serves as an anticoagulant by proteolytically degrading and inactivating factors Va and VIIIa, thereby attenuating thrombin generation.20 This reaction occurs on negatively charged phospholipid surfaces where protein S, another vitamin K-dependent protein, serves as a cofactor.10
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Fibrinolytic system
Designed to remove intravascular fibrin, thereby restoring blood flow, fibrinolysis is initiated by plasminogen activators that convert plasminogen to plasmin (Fig 5
). A trypsin-like protease, plasmin degrades fibrin into soluble fibrin degradation products. The following two immunologically distinct plasminogen activators are found in blood: tissue-type plasminogen activator (tPA); and urokinase-type plasminogen activator (uPA). Both plasminogen activators are synthesized and released from endothelial cells.22
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A protease that links fibrinolysis with coagulation has been identified. Known as factor VII-activating protease (FSAP), this protease not only activates factor VII, as its name implies, but also converts single-chain uPA (prourokinase) into the active two-chain form.24 Genetic analyses have identified common polymorphisms in FSAP, one of which is designated Marburg 1.25 FSAP from subjects with the Marburg 1 polymorphism exhibits reduced capacity to activate prourokinase,25 and an epidemiologic study26 has suggested that there may be an association between this polymorphism and the risk of carotid stenosis secondary to atherosclerosis. Although it is tempting to attribute this association to defective uPA-mediated fibrinolysis in subjects with the Marburg 1 polymorphism, it is as yet unclear whether these individuals also have reduced activation of factor VII. If so, the Marburg 1 polymorphism should offer protection from the thrombotic complication of atherosclerosis. Consequently, additional studies are needed to clarify the role of FSAP in atherosclerosis and thrombosis.
The fibrinolytic system is regulated at two levels. Plasminogen activator inhibitors, the most important of which is endothelial cell-derived type 1 plasminogen activator inhibitor (PAI-1), block tPA, whereas 2-antiplasmin inhibits plasmin.22 Although 2-antiplasmin rapidly complexes and inactivates free plasmin, fibrin-bound plasmin is relatively protected from inactivation so that fibrinolysis can occur despite physiologic levels of this inhibitor.22
A procarboxypeptidase B that serves as a link between coagulation and fibrinolysis has been identified in plasma (Fig 5).27 Activated by the thrombin/thrombomodulin complex, this enzyme, known as thrombin activatable fibrinolysis inhibitor (TAFI), attenuates fibrinolysis by cleaving carboxyl-terminal lysine residues from fibrin.27 The removal of these lysine residues decreases plasminogen and plasmin binding to fibrin, thereby retarding the lytic process.
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3.0 Pathways for Development of New Anticoagulants |
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TOPAbstractIntroduction1.0 Thrombogenesis2.0 Regulation of Coagulation3.0 Pathways for Development...4.0. Conclusions and Future...SummaryReferences |
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3.1 Inhibitors of initiation of coagulation
Drugs that target the factor VIIa/tissue factor complex inhibit the initiation of coagulation. Agents in this category that have reached phase II clinical testing include recombinant TFPI, recombinant nematode anticoagulant peptide (NAPc2), and active site-blocked factor VIIa (factor VIIai).
3.1.1 TFPI A recombinant form of TFPI (tifacogin; Chiron Corporation; Emeryville, CA) has been evaluated in patients with sepsis. In a phase II trial,28 210 such patients were randomized to receive one of two doses of tifacogin by continuous infusion (25 or 50 µg/kg/h) or placebo for 4 days. Compared with placebo, tifacogin produced a 20% relative reduction in all-cause mortality at 28 days. Major bleeding occurred in 9% of patients treated with tifacogin, and in 6% of those treated with placebo, a difference that was not significant. Building on these results, a phase III trial31 compared tifacogin with placebo in 1,754 patients with severe sepsis. The primary end point, all-cause mortality rate at 28 days, was similar in both groups (tifacogin group, 34.2%; placebo group, 33.9%), and the rate of bleeding was significantly higher with tifacogin than with placebo (6.5% and 4.8%, respectively). With these results, further development of tifacogin for sepsis has been halted.
3.1.2 NAPc2 An 85-amino acid polypeptide that was originally isolated from the canine hookworm, Ancylostoma caninum,32 NAPc2 can be expressed in yeast. NAPc2 binds to a noncatalytic site on factor X or factor Xa.33 Once bound to factor Xa, the NAPc2/factor Xa complex inhibits factor VIIa bound to tissue factor. Because it binds to factor X with high affinity, NAPc2 has a half-life of approximately 50 h after subcutaneous injection.
Initial clinical trials with NAPc2 focused on venous thromboprophylaxis. In a phase II dose-finding study,34 293 patients undergoing elective knee arthroplasty were given subcutaneous NAPc2 on the day of surgery and every second day thereafter to a maximum of four doses. The best results were observed with an NAPc2 dose of 3.0 µg/kg administered 1 h after surgery. With this dose, the overall rate of venographically detected DVT in the operated leg was 12%, while the rate of proximal DVT was 1%. Major bleeding occurred in 2% of these patients. When compared with historical control subjects,5 the efficacy and safety of NAPc2 are similar to those with low-molecular-weight heparin. However, prospective randomized trials are needed to confirm these findings.
Current studies with NAPc2 are focusing on arterial thrombosis. In a series of phase II clinical trials, NAPc2 is being evaluated in patients with unstable angina or non-ST-elevation MI and in those undergoing percutaneous coronary interventions. For each of these indications, NAPc2 is being compared with placebo as an adjunct to antiplatelet therapy (with aspirin, clopidogrel, and, in some cases, a glycoprotein (GP) IIb/IIIa antagonist and an antithrombin [either heparin or low-molecular-weight heparin]).
3.1.3 Factor VIIai By competing with factor VIIa for tissue factor binding, factor VIIai attenuates the initiation of coagulation by the factor VIIa/tissue factor complex. Based on promising results in animal models of thrombosis,3536 treatment with factor VIIai, in doses ranging from 50 to 400 µg/kg with or without adjunctive heparin, was compared with treatment with heparin alone in 491 patients undergoing elective percutaneous coronary interventions.37 Compared with heparin therapy alone, factor VIIai therapy, with or without adjunctive heparin, produced no significant reduction in the primary end point, a composite of death, MI, the need for urgent revascularization, abrupt vessel closure, or bailout use of GPIIb/IIIa antagonists or heparin at day 7 or at hospital discharge. The rates of major bleeding were similar with therapy with factor VIIai and heparin. Because of these disappointing results, factor VIIai has not been developed further.
3.2 Inhibitors of propagation of coagulation
Drugs that block factor IXa, factor Xa or their respective cofactors, factor VIIIa and factor Va, inhibit the propagation of coagulation. Factor IXa inhibitors have yet to reach phase II clinical testing and will not be discussed. New factor Xa inhibitors include agents that block factor Xa indirectly or directly. Indirect inhibitors act by catalyzing factor Xa inhibition by antithrombin. In contrast, direct factor Xa inhibitors bind directly to the active site of factor Xa, thereby blocking its interaction with its substrates. Unlike the heparin/antithrombin complex, direct factor Xa inhibitors not only inhibit free factor Xa, but also inactivate factor Xa bound to platelets within the prothrombinase complex.3839 This property may endow these agents with an advantage over indirect factor Xa inhibitors.
Fondaparinux and idraparinux are two new parenteral indirect factor Xa inhibitors. A parenteral and an orally active direct factor Xa inhibitor, DX9065a and DPC 906, respectively, are currently undergoing phase II clinical testing. The inhibition of factors Va and VIIIa is effected by activated protein C. From a therapeutic standpoint, this can be achieved by directly administering recombinant activated protein C or its precursor, protein C. Recombinant soluble thrombomodulin, another means of generating activated protein C, also is under evaluation.
3.2.1 Fondaparinux A synthetic analog of the antithrombin-binding pentasaccharide sequence found in heparin and low-molecular-weight heparin, fondaparinux binds antithrombin and enhances its reactivity with factor Xa.40 Because it is too short to bridge antithrombin to thrombin, fondaparinux has no activity against thrombin.
In plasma, fondaparinux binds to antithrombin, and there is no detectable binding to other plasma proteins. With excellent bioavailability after subcutaneous injection and a plasma half-life of about 17 h, fondaparinux can be administered subcutaneously once daily. The drug is excreted unchanged in the urine. Consequently, dose adjustments are necessary in patients with renal insufficiency, and fondaparinux should not be used in those with renal failure.
Fondaparinux does not bind to platelets or platelet factor 4 (PF4). Because it does not induce the formation of heparin/PF4 complexes that serve as the antigenic target for the antibodies that cause heparin-induced thrombocytopenia, heparin-induced thrombocytopenia is unlikely to occur with fondaparinux. However, fondaparinux also fails to interact with protamine sulfate, the antidote for heparin. If uncontrolled bleeding occurs with fondaparinux, a procoagulant such as recombinant factor VIIa might be effective.41 However, recombinant factor VIIa is not available in all hospitals, and the drug is expensive and can cause thrombotic complications.
Fondaparinux has been evaluated for the prevention and treatment of venous thromboembolism, and for the treatment of arterial thrombosis. The results of the venous thrombosis prevention trials are described elsewhere in this supplement and will not be described in detail. Instead, the focus will be on the evaluation of fondaparinux for the treatment of venous or arterial thrombosis.
Venous thromboprophylaxis.
Fondaparinux has been evaluated for thromboprophylaxis in patients undergoing major orthopedic surgery, and in general medical and surgical patients. Based on four large phase III trials comparing fondaparinux with enoxaparin for thromboprophylaxis in patients undergoing surgery for hip fracture or elective hip or knee arthroplasty, fondaparinux has been licensed for this indication.42434445 In these trials, fondaparinux was found to reduce the risk of venous thromboembolism by approximately 55% compared with enoxaparin. Major bleeding occurred more frequently in the fondaparinux-treated group (p = 0.008), but the incidence of bleeding leading to death or reoperation, or occurring in a critical organ was not significantly different between the two groups. It is possible that the increase in major bleeding with fondaparinux relative to enoxaparin reflects the fact that fondaparinux therapy was started 6 h after surgery, whereas enoxaparin therapy was initiated 12 to 24 h after surgery, with or without a dose 12 h prior to surgery. It also is unclear whether the asymmetry in the timing of the initiation of prophylaxis accounts for the superior efficacy of fondaparinux relative to enoxaparin.
A recent phase III trial (Pentasaccharide in Hip-Fracture Surgery Plus)46 evaluated the efficacy of extended fondaparinux thromboprophylaxis in 656 patients undergoing surgery for hip fracture. All patients received 2.5 mg fondaparinux subcutaneously once daily for 7 days. Patients then were randomized to receive fondaparinux on a continuing basis or to receive placebo for an additional 3 weeks. Based on the results of routine venography performed at 1 month, fondaparinux treatment decreased the rate of venous thrombosis from 35 to 1.4%, a highly significant reduction (p < 0.001). More importantly, the rate of symptomatic venous thromboembolic events also was reduced from 2.7 to 0.3% with extended fondaparinux treatment (p = 0.021). This trial adds to a mounting body of evidence indicating that patients remain at risk for several weeks after major orthopedic surgery and that extended anticoagulant prophylaxis can reduce this risk.47484950
Fondaparinux also has been evaluated for thromboprophylaxis in general medical and general surgical patients. In a blinded, placebo-controlled, phase III trial,51 849 medical patients who were 
65 years of age were randomly assigned to receive subcutaneous fondaparinux (2.5 mg once daily) or placebo for 6 to 14 days. The primary end point, a composite of venographically diagnosed DVT, symptomatic DVT, and nonfatal and fatal PE at day 15 occurred in 5.6% of patients randomized to receive fondaparinux, and in 10.5% of those randomized to receive placebo (p = 0.03). Major bleeding while receiving therapy was infrequent and occurred in 0.2% of patients in both groups.
In a blinded, phase III trial,52 2,297 patients undergoing abdominal surgery were randomly assigned to receive subcutaneous fondaparinux (2.5 mg once daily) or dalteparin (2,500 U preoperatively and 2,500 U postoperatively the evening of surgery, and 5,000 U qd thereafter) for 5 to 9 days. Fondaparinux treatment was started 6 h after surgery. The primary end point, a composite of venographically documented DVT, symptomatic DVT, and nonfatal and fatal PE at postoperative day 30, occurred in 4.6% of those patients randomized to receive fondaparinux, and in 6.1% of those randomized to receive dalteparin (p = 0.14). Symptomatic venous thromboembolism occurred in 0.4% of those given fondaparinux and in 0.3% of those given dalteparin, whereas major bleeding occurred in 3.4% and 2.4%, respectively. The differences were not statistically significant. In the subgroup of patients with cancer, fondaparinux therapy reduced the incidence of the composite end point from 7.7 to 4.6% (p = 0.02).
Treatment of venous thromboembolism.
Fondaparinux also has been evaluated for the initial treatment of established venous thromboembolism in two phase III clinical trials. In the MATISSE DVT trial,53 2,205 patients with DVT were randomized, in a blinded fashion, to receive either fondaparinux (weight adjusted < 50 kg 5.0 mg subcutaneously qd; 50 to 100 kg 7.5 mg subcutaneously qd, and > 100 kg 10 mg subcutaneously qd) or enoxaparin (1 mg/kg subcutaneously twice daily) for 5 days followed by a minimum 3-month course of treatment with an oral vitamin K antagonist. At 3 months, the rates of recurrent symptomatic venous thromboembolism with fondaparinux or enoxaparin were 3.9% and 4.1%, respectively, whereas major bleeding rates were 1.1% and 1.2%, respectively. None of these differences were statistically significant.
In the open-label MATISSE PE trial,54 2,213 patients with PE were randomized to receive either fondaparinux (weight adjusted < 50 kg 5.0 mg subcutaneously qd; 50 to 100 kg 7.5 mg subcutaneously qd, and > 100 kg 10 mg subcutaneously qd) or unfractionated heparin (by continuous infusion) for 5 days followed by a minimum 3-month course of therapy with an oral vitamin K antagonist. At 3 months, the rates of recurrent symptomatic venous thromboembolism occurring after therapy with fondaparinux or unfractionated heparin were 3.8% and 5.0%, respectively, whereas major bleeding rates were 1.3% and 1.1%, respectively. Based on these two trials, fondaparinux appears to be at least as effective and safe as low-molecular-weight heparin or unfractionated heparin for the initial treatment of venous thromboembolism.
Treatment of acute coronary syndromes.
On the arterial side, fondaparinux has been evaluated for the treatment of acute coronary syndromes. The Synthetic Pentasaccharide as an Adjunct to Fibrinolysis in ST-Elevation Acute Myocardial Infarction trial55 was an open-label, phase II trial that randomized 326 patients with evolving ST-elevation MI to receive either fondaparinux, in various doses, or unfractionated heparin as adjuncts to therapy with alteplase and aspirin. Using patency of the infarct-related artery as the primary end point, grade 3 Thrombolysis in Myocardial Infarction (TIMI) flow at 90 min ranged from 60 to 68% and was similar in all treatment groups. Bleeding rates also were similar after therapy with fondaparinux and heparin.
The phase II Pentasaccharide in Unstable Angina trial56 randomized 1,134 patients with unstable angina or non-STelevation myocardial infarction to subcutaneous fondaparinux (in once-daily doses ranging from 2.5 to 12 mg) or enoxaparin (1 mg/kg twice daily). Overall, the primary outcome, a composite of death, MI, or recurrent angina at day 9, occurred in 37% of those receiving any dose of fondaparinux and in 40.2% of patients treated with enoxaparin. There was no evidence of a dose response with fondaparinux therapy. In fact, the lowest dose appeared to produce the best results. Bleeding was similar in all treatment groups.
Summary.
Based on these phase II results, phase III trials with fondaparinux are planned in patients with ST-elevation MI and non-ST-elevation MI. However, the lack of a dose response with fondaparinux therapy in the phase II trials makes it difficult to identify the optimal dose. Consequently, additional dose-finding studies may be necessary before undertaking a large-scale phase III clinical trial program.
3.1.2 Idraparinux A more highly sulfated derivative of fondaparinux, idraparinux binds antithrombin with such high affinity that its plasma half-life of 130 h is similar to that of antithrombin.57 Because of its long half-life, idraparinux can be given subcutaneously on a once-weekly basis. In a phase II trial,58 idraparinux therapy was compared with warfarin therapy in 659 patients with proximal DVT. After 5 to 7 days of initial treatment with enoxaparin, patients were randomized to receive once-weekly subcutaneous doses of idraparinux (2.5, 5.0, 7.5, or 10 mg) or warfarin for 12 weeks. The primary end point, changes in compression ultrasound and perfusion lung scan findings, was similar in all idraparinux groups and did not differ from that in the warfarin group. There was a clear dose response for major bleeding in patients who had received idraparinux with an unacceptably high frequency in those receiving the 10-mg dose. Two patients, both of whom received 5 mg idraparinux once weekly, experienced a fatal bleeding incident. Patients who received the lowest dose of idraparinux had less bleeding than those randomized to receive warfarin (p = 0.029). Based on these results, a once-weekly 2.5-mg dose of idraparinux will be used in phase III clinical trials.
3.1.3 DX-9065a A nonpeptidic arginine derivative, DX-9065a binds reversibly to the active site of factor Xa. Administered as a continuous IV infusion, a small phase II trial59 compared four different doses of DX-9065a with placebo in 73 stable patients with coronary artery disease to assess safety. There were no major bleeding incidents among patients receiving DX-9065a. Additional phase II studies are comparing DX-9065a therapy with heparin therapy in patients undergoing percutaneous coronary interventions.
3.1.4 DPC 906 An orally active agent, DPC 906 must be administered twice daily. In a phase II dose-finding study, DPC 906 was compared with enoxaparin in patients undergoing knee arthroplasty. This study was stopped prematurely, but the results have yet to be published.
3.1.5 Activated protein C Recombinant activated protein C, drotrecogin alfa (activated), was compared with placebo in 1,690 patients with severe sepsis.29 When given as an infusion of 24 µg/kg/h over > 96 h, activated protein C produced a 19% reduction in mortality at 28 days (reduction, 30.8 to 24.7%; p = 0.005). The rate of major bleeding was higher with activated protein C therapy than with placebo (3.5% and 2%, respectively; p = 0.06). Based on these results and economic analyses supporting the benefits of recombinant activated protein C,60 this agent has been licensed in North America for the treatment of patients with severe sepsis.
3.1.6 Protein C Although promising results with protein C concentrates have been reported in patients with meningococcemia,6162 additional studies are needed. For theoretical reasons, activated protein C may be a better choice than protein C in patients with severe sepsis because inflammatory cytokines down-regulate thrombomodulin expression on the endothelial surface. This phenomenon may explain the results of immunohistochemical analyses of skin biopsy specimens from patients with meningococcemia, which revealed reduced thrombomodulin staining.63
3.1.7 Soluble thrombomodulin A recombinant analog of the extracellular domain of thrombomodulin, soluble thrombomodulin binds thrombin and induces a conformation change in the active site of the enzyme that converts it into a potent activator of protein C. In an open-label, dose-escalation study,64 soluble thrombomodulin attenuated coagulation abnormalities in patients with disseminated intravascular coagulation. Soluble thrombomodulin has recently been evaluated in a phase II dose-ranging study65 in patients undergoing elective hip arthroplasty. Patients were given thrombomodulin subcutaneously (dose, 0.3 or 0.45 mg/kg) 2 to 4 h after surgery. Those patients receiving the lower dose of thrombomodulin received a second injection 5 days later. The primary end point, a composite of venographically detected DVT and symptomatic venous thromboembolism, occurred in 4.3% of the 94 patients who received the lower dose of soluble thrombomodulin and in none of the 99 patients receiving the higher dose. Major bleeding occurred in 1.6% and 5.7%, respectively, of patients receiving the low dose or high dose of soluble thrombomodulin. Phase III clinical trials are necessary to compare soluble thrombomodulin with other forms of thromboprophylaxis, such as low-molecular-weight heparin or fondaparinux.
3.2 Inhibitors of fibrin formation
Thrombin, the enzyme that converts fibrinogen to fibrin, can be inhibited indirectly or directly. Indirect thrombin inhibitors act by catalyzing antithrombin and/or heparin cofactor II. In contrast, direct inhibitors bind directly to thrombin and block its interaction with substrates. All of the new agents that block fibrin formation are direct thrombin inhibitors.
Direct thrombin inhibitors have properties that give them potential mechanistic advantages over indirect thrombin inhibitors, such as heparin.6667 First, because direct thrombin inhibitors do not bind to plasma proteins, they produce a more predictable anticoagulant response. Second, unlike heparin, direct thrombin inhibitors do not bind to PF4. Consequently, the anticoagulant activity of direct thrombin inhibitors is unaffected by the large quantities of PF4 released in the vicinity of platelet-rich thrombi. Finally, direct thrombin inhibitors inactivate fibrin-bound thrombin, as well as fluid-phase thrombin.6667
Three parenteral direct thrombin inhibitors (ie, hirudin, argatroban, and bivalirudin) have been licensed in North America for limited indications. Hirudin and argatroban are approved for the treatment of patients with heparin-induced thrombocytopenia, whereas bivalirudin is licensed as an alternative to heparin in patients undergoing percutaneous coronary interventions. Ximelagatran, a prodrug of melagatran, is the first orally available direct thrombin inhibitor.
3.2.2 Hirudin A 65-amino acid polypeptide originally isolated from the salivary glands of the medicinal leech Hirudo medicinalis,6869 hirudin is now available in recombinant form. Hirudin inhibits thrombin in a bivalent fashion. Its globular amino-terminal domain interacts with the active site of thrombin, whereas its anionic carboxy-terminal tail binds to exosite 1 on thrombin, the substrate recognition site.68 The hirudin/thrombin complex is essentially irreversible, which is a potential drawback because there is no specific antidote.
The plasma half-life of hirudin is 60 min after IV injection, and 120 min after subcutaneous injection.70 Hirudin is cleared via the kidneys and should not be used in patients with renal insufficiency.70 The anticoagulant effect of hirudin can be monitored using the activated partial thromboplastin time (APTT).
Recombinant hirudin (lepirudin) is licensed for the treatment of arterial or venous thrombosis complicating heparin-induced thrombocytopenia, and as an alternative for heparin for cardiopulmonary bypass surgery in these patients. Hirudin has been evaluated in acute coronary syndromes and, to a lesser extent, for the prevention and treatment of venous thrombosis. The results for each of these indications will be discussed separately.
Unstable angina.
The largest phase II study to compare hirudin with heparin, the Organization to Assess Strategies for Ischemic Syndromes (OASIS)-1 pilot trial,71 randomized 909 patients with unstable angina or non-ST-elevation MI to receive a 72-h infusion of hirudin, in either a low dose or medium dose, or to heparin. Doses of hirudin and heparin were adjusted to maintain the APTT between 60 and 100 s. Compared with heparin, hirudin produced a promising reduction in the primary outcome, a composite of cardiovascular death, MI, or refractory angina at 7 days (odds ratio [OR] 0.57; 95% confidence interval [CI], 0.32 to 1.02) and a significant reduction in the secondary outcome, a composite of death, MI, or refractory or severe angina requiring revascularization at 7 days (OR, 0.49; 95% CI, 0.27 to 0.86). Major bleeding occurred in about 1% of patients in both treatment groups and was not significantly higher in those who received hirudin (OR, 0.86; 95% CI, 0.23 to 3.19). Minor bleeding, however, was more frequent in patients given a medium or low dose of hirudin than it was in those treated with heparin (21.3%, 16.2%, and 10.5%, respectively), and the differences were statistically significant (medium-dose or low-dose hirudin, p = 0.033; heparin, p = 0.001).
The results of the OASIS-1 trial prompted the OASIS-2 trial,72 a phase III trial that randomized 10,141 patients with unstable angina or non-ST-elevation MI to receive a 72-h infusion of medium-dose hirudin or heparin. During treatment, hirudin produced a significant reduction in the composite end point of death or MI compared with heparin (2.0% and 2.6%, respectively; OR, 0.76, 95% CI, 0.59–0.99). Although the primary outcomes, a composite of death or MI at 7 days (3.6% and 4.2%, respectively; OR, 0.84; 95% CI, 0.69 to 1.02) and 35 days (6.8% and 7.7%, respectively; OR, 0.87; 95% CI, 0.75 to 1.01) were not significantly different between the two groups, the absolute risk reduction in death or MI produced by hirudin during the 72-h treatment period was maintained at 7 and 35 days. Major bleeding occurred more frequently with hirudin therapy than with heparin therapy (1.2% and 0.7%, respectively; OR, 1.73; 95% CI, 1.13 to 2.63), but the rates of life-threatening bleeding were similar (0.4% in both groups).
When the results of the OASIS-1 and OASIS-2 trials are combined, hirudin therapy produces a significant reduction in the composite outcome of death or MI at 35 days compared with heparin (6.7% and 7.7%, respectively; OR, 0.86; 95% CI, 0.74 to 0.99). Thus, the early treatment benefits of hirudin that were observed in both trials were maintained, at least for 1 month. Despite these results, however, hirudin has not been licensed for the treatment of acute coronary syndromes, reflecting the fact that, compared with heparin, hirudin failed to show a significantreduction in the primary end point in the OASIS-2 trial and produced an increase in major bleeding.
Adjunct to thrombolytic therapy.
Hirudin was compared with heparin as adjuncts to thrombolytic therapy in three trials. The TIMI-9A trial73 and the Hirudin for Improvement of Thrombolysis (HIT)-III trial74 only enrolled patients with acute MI, whereas the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)-IIA trial75 also included patients with unstable angina and those with MI who were ineligible for thrombolytic therapy. The doses of hirudin given in the TIMI-9A study73 and the GUSTO-IIA study74 were higher than that used in the OASIS-2 trial,72 and the TIMI-9A trial73 and GUSTO-IIA trial74 also used higher doses of heparin than that used in the GUSTO-I study.76 Although, the HIT-III trial74 utilized a lower dose hirudin regimen, one that was identical to that used in the OASIS-2 study,72 the heparin doses administered in the HIT-III study74 also were higher than that used in the GUSTO-I study.76
All three initial phase III trials were stopped prematurely because of unacceptably high rates of major hemorrhage. The rate of major bleeding was higher with hirudin therapy than with heparin therapy in the TIMI-9A trial,73 and there was a trend for more intracranial bleeding with hirudin in the GUSTO-IIA trial74 and the HIT-III trial.7576 Consequently, the GUSTO-IIA trial75 and the TIMI-9A trial73 were restarted as the GUSTO-IIB trial7778 and the TIMI-9B trial79 using doses of hirudin that were lower than that used in the OASIS-2 trial.72 The hirudin dose was adjusted to achieve a target APTT of 55 to 85 s in the TIMI-9B trial,79 and 60 to 85 s in the GUSTO-IIB trial.7778 In addition, the dose of heparin also was reduced to more closely match that used in the GUSTO-I trial.76 With lower doses of anticoagulants, both trials completed their planned enrollment.
In the GUSTO-IIB trial,77 hirudin therapy produced a modest reduction in the primary outcome, a composite of death or MI at 30 days, compared with heparin therapy (OR, 0.89; 95% CI, 0.79 to 1.00). During the initial 24 h of treatment, hirudin therapy produced a significant reduction in death or MI compared with heparin therapy (1.3% and 2.1%, respectively; OR, 0.61, 95% CI, 0.46 to 0.81). A retrospective subgroup analysis78 has suggested that when used as an adjunct to streptokinase therapy hirudin produced a greater reduction in death or MI at 30 days than did heparin therapy (9.1% and 14.9%, respectively; OR, 0.57; 95% CI; 0.38 to 0.87). In contrast, hirudin therapy was not superior to heparin therapy in patients receiving tPA.
Hirudin therapy was no better than heparin therapy in the TIMI-9B trial.79 Thus, the primary outcome, a composite of death, MI, cardiac failure, or cardiogenic shock at 30 days, was similar in the hirudin and heparin groups (OR, 1.09; 95% CI, 0.88 to 1.36), as was the composite of death or MI at 30 days (OR, 1.02; 95% CI, 0.80 to 1.31). There was a trend for a reduction in nonfatal MI with hirudin therapy during hospitalization (OR, 0.65; 95% CI, 0.42 to 1.01) and at 30 days (OR, 0.81; 95% CI, 0.56 to 1.18). The rates of major bleeding and intracranial bleeding were similar with hirudin and heparin therapy in both the TIMI-9B trial75 and the GUSTO-IIB trial.77
Taken together, the TIMI-9B trial75 and the GUSTO-IIB trial77 suggest that hirudin therapy is at least as effective as heparin therapy when used as an adjunct to thrombolytic therapy. When the results of these trials are pooled with those of the OASIS-2 study,72 hirudin therapy produced a 10% reduction in the risk of death or MI at 30 to 35 days compared with heparin therapy. However, the lack of a clear benefit of hirudin over heparin at 30 days in the GUSTO-IIB trial77 and TIMI-9B trial75 limits the strength of this conclusion in patients with acute MI. Given the lack of a clear benefit of hirudin over heparin as adjuncts to thrombolytic therapy, hirudin has not been licensed for this indication.
Coronary angioplasty.
Hirudin therapy was compared with heparin therapy for the prevention of restenosis after percutaneous coronary angioplasty in the Hirudin in a European Trial Versus Heparin in the Prevention of Restinosis After PTCA (HELVETICA) study.80 A total of 1,141 patients who were scheduled for coronary angioplasty were randomized to receive either hirudin, administered as a bolus dose plus infusion for 24 h followed by a subcutaneous hirudin injection or placebo for an additional 72 h, or heparin, administered as a bolus dose plus infusion for 24 h followed by subcutaneous placebo injections for 72 h. An additional bolus of placebo (in the hirudin group) or heparin (in those randomized to receive heparin) could be given if the procedure lasted longer than 1 h, but no subsequent dose adjustments were allowed. The primary outcome was event-free survival at 30 weeks, which was defined as the absence of death, MI, coronary artery bypass grafting, or bailout angioplasty with or without coronary stenting at the previous angioplasty site.
At 7 months, event-free survival was similar in those receiving heparin, IV hirudin, or IV hirudin followed by subcutaneous hirudin (67.3%, 63.5%, and 68.0%, respectively). Likewise, on repeat angiography at 6 months, there was no significant differences in the mean luminal diameter of the dilated vessel among the three groups. Compared with heparin therapy, however, hirudin therapy produced a significant reduction in the primary composite outcome at 96 h (OR, 0.61; 95% CI, 0.41 to 0.90) that was preserved at 30 days. The time-to-event curves converged thereafter, possibly reflecting the development of restenosis in both groups. No excess bleeding was seen with hirudin.
Venous thromboprophylaxis.
Hirudin has been compared with unfractionated heparin and low-molecular-weight heparin for thromboprophylaxis in patients undergoing elective hip arthroplasty. In a randomized blinded multicenter phase III trial, Eriksson and colleagues81 compared therapy with subcutaneous unfractionated heparin (5,000 U three times daily) with that using subcutaneous hirudin (15 mg twice daily) in 445 patients undergoing total hip replacement. Hirudin therapy was started preoperatively and was continued for 8 to 11 days. The incidence of venographically detected proximal and total DVT was significantly lower in the hirudin group than in the heparin group. Four patients in the heparin group and none in the hirudin group experienced a PE.
In the largest phase III thromboprophylaxis study performed with hirudin to date, Eriksson and colleagues82 randomized 2,069 patients undergoing elective hip arthroplasty to receive subcutaneous hirudin therapy (15 mg twice daily starting 30 min prior to surgery) or subcutaneous enoxaparin therapy (40 mg once daily starting 12 h prior to surgery). Treatment was administered for 8 to 12 days, and DVT was verified by bilateral venography, which was performed at the end of the treatment period or earlier if symptomatic venous thromboembolism was suspected. The rate of venographically detected proximal DVT was significantly lower in patients treated with hirudin than in those treated with enoxaparin (4.5% and 7.5%, respectively; p = 0.01), as was the overall rate of DVT (18.4% and 25.5%, respectively; p = 0.001) based on data from 1,587 analyzed patients. The rates of major bleeding were similar in the two treatment groups.
Based on these two studies, hirudin therapy appears to be more effective than therapy with heparin or low-molecular-weight heparin for thromboprophylaxis after hip arthroplasty. Despite these data, however, hirudin has not been approved for this indication.
Treatment of venous thromboembolism.
In a phase II trial, Schiele et al83 randomized patients with DVT to receive one of three doses of subcutaneous hirudin (ie, 0.75, 1.25, or 2.0 mg/kg twice daily) or unfractionated heparin administered by continuous IV infusion. All patients underwent venography and ventilation/perfusion lung scanning on days 1 and 5 so that changes in these tests could be evaluated. When the results with the two higher hirudin doses were combined, thrombus extension occurred more frequently in patients treated with unfractionated heparin than in those treated with hirudin (10% and 3%, respectively). In addition, new perfusion abnormalities seen on lung scans were more frequent in the heparin group (26%) than the hirudin groups (< 10% in each group). Major bleeding was seen only in those patients receiving the highest dose of hirudin and in those receiving heparin, occurring in 3% of patients in both groups. Despite these promising early results, no further work in this area has been performed.
Summary.
Hirudin is at least as effective as heparin in treating patients with unstable angina, non-ST-elevation MI, and ST-elevation MI, and is more effective than low-molecular-weight heparin and unfractionated heparin for the prevention of venous thrombosis in patients undergoing elective hip arthroplasty. Because of its narrow therapeutic window and the associated bleeding risk, however, it is unlikely that hirudin will ever be approved for the treatment of acute coronary syndromes. Although hirudin appears promising for the prevention and treatment of venous thrombosis, the clinical development of the drug for these indications has not been pursued.
3.2.2 Bivalirudin A 20-amino acid synthetic polypeptide, bivalirudin is an analog of hirudin.84 The amino-terminal D-Phe-Pro-Arg-Pro sequence, which binds to the active site of thrombin, is connected via four Gly residues to a carboxy-terminal dodecapeptide that interacts with exosite 1 on thrombin.85 Like hirudin, bivalirudin forms a 1:1 stoichiometric complex with thrombin. However, once bound, thrombin cleaves the Pro-Arg bond within the amino terminal of bivalirudin, thereby allowing the recovery of thrombin activity.86 This phenomenon may render bivalirudin safer than hirudin. Bivalirudin has a plasma half-life of 25 min after IV injection,87 and only a fraction is excreted via the kidneys.88 Bivalirudin has been evaluated in patients undergoing percutaneous coronary interventions and as an adjunct to streptokinase therapy in patients with acute MI.
Coronary angioplasty.
Bivalirudin is licensed as an alternative therapy to heparin in patients undergoing percutaneous coronary angioplasty. It was approved for this indication based on the results of a phase III study89 that compared bivalirudin with heparin in 4,098 patients undergoing coronary angioplasty for unstable or postinfarction angina. The primary end point, a composite of in-hospital death, MI, abrupt vessel closure, or rapid clinical deterioration of cardiac origin, occurred in a similar percentage of patients in the two treatment groups (bivalirudin group, 11.4%; heparin group, 12.2%). However, in the prospectively stratified, high-risk subgroup of 704 patients with postinfarction angina, bivalirudin therapy significantly reduced the incidence of the primary outcome compared with heparin therapy (9.1% and 14.2%, respectively; p = 0.04). Overall, the rate of major bleeding was significantly lower with bivalirudin therapy than with heparin therapy (3.8% and 9.8%, respectively; p < 0.001).
In 2001, the results of this trial90 were reanalyzed according to intention-to-treat principles and using a more contemporary definition of MI. The reanalysis demonstrated that, compared with heparin therapy, bivalirudin therapy significantly reduced the combined end point of death, MI, or repeat revascularization at 7 days from 7.9 to 6.2% (p = 0.04), a difference that persisted at 90 days. As in the original report, the rate of major bleeding was significantly lower with bivalirudin therapy than with heparin therapy (3.5% and 9.3%, respectively; p < 0.001).
More contemporary studies have evaluated the utility of bivalirudin in patients undergoing coronary stenting. The Comparison of Abciximab Complications with Hirulog for Ischemic Events Trial91 was a pilot study performed in 268 patients undergoing percutaneous coronary intervention. In three sequential phases, patients received (1) bivalirudin (1.0 mg/kg bolus followed by an infusion of 2.5 mg/kg/h) plus abciximab, (2) bivalirudin (0.5 mg/kg bolus followed by an infusion of 1.75 mg/kg/h) plus provisional abciximab, (3) bivalirudin (0.75 mg/kg bolus followed by an infusion of 1.75 mg/kg/h) plus provisional abciximab, or (4) the control regimen. For each phase, the control regimen consisted of low-dose, weight-adjusted heparin plus abciximab. The rates of the primary end point, a composite of death, MI, repeat revascularization, and major bleeding at 7 days, ranged from 0 to 6% in the bivalirudin groups compared with 10.6% in the heparin-plus-abciximab group, which was a significant difference (p = 0.02). Provisional abciximab therapy was required in 24% of the bivalirudin-treated patients. The rates of major bleeding were lower in patients who received bivalirudin plus abciximab than in those who received heparin plus abciximab (4.7% and 6.3%, respectively), but this difference was not statistically significant.
Building on these promising results, the Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial,92 a large phase III clinical trial, randomized 6,010 patients undergoing percutaneous coronary interventions to receive bivalirudin (0.75 mg/kg bolus followed by an infusion of 1.75 mg/kg/h) plus a provisional GPIIb/IIIa antagonist (ie, abciximab and eptifibatide) or heparin plus a GPIIb/IIIa antagonist (eg, abciximab or eptifibatide). The primary end point, a composite of death, MI urgent revascularization, or major bleeding at 30 days, occurred in 9.2% of the patients treated with bivalirudin and in 10% of those treated with heparin (p = 0.32). A GPIIb/IIIa antagonist was required in only 7% of patients randomized to receive bivalirudin. The rates of major bleeding were significantly lower in patients treated with bivalirudin than in those treated with heparin (2.4% and 4.1%, respectively; p < 0.001).
Adjunct to thrombolysis.
Bivalirudin has been compared with heparin as an adjunct to thrombolytic therapy. The Hirulog and Early Reperfusion or Occlusion-2 trial93 randomized 17,073 patients with acute ST-elevation MI to receive an IV bolus followed by a 48-h infusion of either bivalirudin (8,516 patients) or heparin (8,557 patients) in conjunction with streptokinase. The doses of bivalirudin were not adjusted, whereas the doses of heparin were adjusted based on the results of coagulation testing. The primary end point was 30-day mortality, and the secondary end points included reinfarction within 96 h and bleeding. Mortality at 30 days was similar in patients who were randomized to receive bivalirudin or heparin (10.8% and 10.9%, respectively; p = 0.85). Significantly fewer reinfarctions occurred with bivalirudin therapy compared with heparin therapy (OR, 0.70; 95% CI, 0.56 to 0.87; p = 0.001). Severe bleeding occurred in 0.7% and 0.5%, respectively, of patients randomized to receive bivalirudin or heparin (p = 0.07), whereas intracerebral bleeding occurred in 0.6% and 0.4%, respectively, of those treated with bivalirudin or heparin (p = 0.09). The incidence of moderate and mild bleeding was significantly higher in the bivalirudin group than in the heparin group (OR, 1.32; 95% CI, 1.34 to 1.62; p < 0.0001). A post hoc analysis suggested that the increased bleeding with bivalirudin therapy relative to that with heparin therapy could be accounted for by bivalirudin-induced excessive anticoagulation, as reflected by the APTT.
Summary.
With its predictable anticoagulant response and short half-life, bivalirudin is a convenient drug to use in treating patients who are undergoing percutaneous coronary interventions. In this setting, bivalirudin appears to be at least as effective as heparin and produces less bleeding. For patients with a low-to-moderate risk of bleeding who are undergoing percutaneous coronary interventions without receiving an adjunctive GPIIb/IIIa antagonist, bivalirudin may be a better choice than heparin.
Based on the results of the Hirulog and Early Reperfusion or Occlusion-2 study,93 bivalirudin can be used in place of heparin as an adjunct to streptokinase for the treatment of patients with acute ST-elevation MI. In this setting, bivalirudin may reduce the risk of reinfarction compared with heparin. However, bivalirudin therapy requires monitoring, and a dose adjustment may be necessary to reduce the risk of bleeding.
3.2.3 Argatroban A competitive inhibitor of thrombin, argatroban binds noncovalently to the active site of thrombin to form a reversible complex.949596 The plasma half-life of argatroban is 45 min. It is metabolized in the liver94 and must be used with caution in patients with hepatic dysfunction.96 Argatroban is licensed for the treatment of heparin-induced thrombocytopenia. Although phase II trials have evaluated argatroban for the treatment of unstable angina,97 as an adjunct to thrombolysis98 and as an alternative therapy to heparin in patients undergoing coronary angioplasty,99 the studies are small, and none has shown definitive advantages of argatroban over heparin.
3.2.4 Ximelagatran A prodrug of the active site-directed thrombin inhibitor, melagatran, ximelagatran is absorbed from the small intestine.100 Once absorbed, ximelagatran undergoes rapid biotransformation to melagatran via two intermediate metabolites, labeled H338/57 and H415/04, respectively. Ximelagatran has a plasma half-life of 3 to 4 h and is administered orally twice daily. To date, no foods or drugs have been documented to influence its absorption. Because ximelagatran produces such a predictable anticoagulant response, coagulation monitoring is unnecessary. Melagatran, the active agent, is eliminated via the kidneys. Consequently, dose adjustments may be needed in the elderly and in patients with renal insufficiency.100
Ximelagatran is being evaluated for thromboprophylaxis in high-risk orthopedic patients, for the treatment of venous thromboembolism, for the prevention of cardioembolic events in patients with nonvalvular atrial fibrillation, and for the prevention of recurrent ischemia in patients who have recently experienced MIs. Studies for each of these indications will be briefly described.
Venous thromboprophylaxis.
For thromboprophylaxis, ximelagatran, in combination with subcutaneous melagatran or as monotherapy, has been compared with low-molecular-weight heparin or warfarin. In the Melagatran for Thrombin Inhibition in Orthopaedic Surgery II study,101 subcutaneous melagatran (administered preoperatively and twice daily for 1 to 3 days postoperatively) followed by oral ximelagatran therapy (in various doses) was compared with subcutaneous dalteparin therapy (5,000 U once daily started the evening before surgery) in patients undergoing elective hip or knee arthroplasty. A highly significant dose response for both effectiveness and safety was seen with the ximelagatran/melagatran combination.
Because of a trend for excess bleeding at the operative site, an attempt was made to omit the preoperative melagatran dose in the subsequent phase III trial. Consequently, the Melagatran for Thrombin Inhibition in Orthopaedic Surgery III trial102 randomized 2,788 patients undergoing hip or knee arthroplasty to receive either subcutaneous melagatran (3 mg) postoperatively followed by oral ximelagatran (24 mg twice daily) or subcutaneous enoxaparin (40 mg once daily) starting 12 h before surgery. Although the rates of venographically detected proximal DVT and symptomatic PE were similar in patients treated with melagatran/ximelagatran or enoxaparin (5.7% and 6.2%, respectively), the rates of total venous thromboembolism were slightly higher in the melagatran/ximelagatran group (31% and 27.3%, respectively). The rates of bleeding did not differ between the two groups. Based on these unfavorable results, a subsequent phase III trial again started melagatran treatment preoperatively.
The EXPRESS study,103 which was completed in 2002, randomized 2,764 patients undergoing hip or knee arthroplasty to receive melagatran/ximelagatran or enoxaparin. Subcutaneous melagatran (2 mg) was administered immediately prior to surgery with a subsequent 3-mg subcutaneous dose administered on the evening after surgery. This was followed by the oral administration of ximelagatran (24 mg twice daily). In the enoxaparin group, subcutaneous enoxaparin (40 mg) was given once daily starting the evening before surgery. The primary end point, a composite of venographically detected proximal DVT and symptomatic PE, occurred in 2.3% and 6.3%, respectively, of patients treated with melagatran/ximelagatran and enoxaparin (p < 0.001). Symptomatic venous thrombosis was rare, occurring in 8 patients in the melagatran/ximelagatran group and 12 in the enoxaparin group. Although bleeding was more common with ximelagatran/melagatran therapy than with enoxaparin therapy (3.3% and 1.2%, respectively), there was no difference in the rates of fatal bleeding, critical organ bleeding, or bleeding requiring reoperation. Thus, melagatran therapy that is started immediately prior to surgery followed by postoperative ximelagatran therapy reduces the incidence of proximal DVT and PE by 63% compared with enoxaparin therapy.
In North America, thromboprophylaxis is started postoperatively in orthopedic patients because many patients have spinal anesthesia. To evaluate the utility of ximelagatran therapy in this setting, the Platinum-Hip trial104 randomized patients but analysis was based on 1,557 patients with adequate venography undergoing total hip arthroplasty to receive oral ximelagatran (24 mg twice daily) or enoxaparin (30 mg twice daily) for 7 to 12 days. Therapy with both drugs was started on the morning after surgery. The overall rates of venographically detected DVT in the operated leg and symptomatic PE by day 12 were 7.9% and 4.6%, respectively, in patients treated with ximelagatran and enoxaparin (p < 0.05), whereas the rates of proximal DVT were 3.6% and 1.2%, respectively (p < 0.05). The rates of major bleeding were similar in the two treatment groups (0.8% and 0.9%, respectively). Thus, when started postoperatively, a 24-mg twice-daily dose of ximelagatran is less effective than enoxaparin in patients who are undergoing total hip arthroplasty.
The same dose of ximelagatran also has been compared with warfarin for thromboprophylaxis in patients undergoing elective knee arthroplasty. The Platinum-Knee trial104 randomized 680 such patients to receive postoperative ximelagatran (24 mg twice daily) or warfarin (in doses sufficient to produce an international normalized ratio (INR) of 2.0 to 3.0). The rates of total DVT with ximelagatran and warfarin were 19.2% and 25.7%, respectively (p = 0.07), whereas the rates of proximal DVT or symptomatic PE were 3.3% and 5.0%, respectively (p > 0.2). There was no significant difference in the rate of major bleeding in the ximelagatran and warfarin groups (1.7% and 0.9%, respectively).
To determine whether the 24-mg twice-daily dose of ximelagatran is optimal for postoperative thromboprophylaxis, the first phase of the Exanta Used to Lessen Thrombosis trial105 randomized 2,301 patients undergoing elective knee arthroplasty to receive one of two doses of unmonitored ximelagatran (ie, 24 or 36 mg twice daily) or to receive warfarin (in doses sufficient to produce an INR of 2.0 to 3.0). Ximelagatran therapy was started the morning after surgery, whereas the first dose of warfarin was given on the evening of the day of surgery. The primary end point, a composite of total venous thromboembolism and all-cause mortality, was significantly lower with the 36-mg dose of ximelagatran than with warfarin (20.3% and 27.6%, respectively; p = 0.003). Likewise, the point estimate for proximal venous thrombosis and all-cause mortality also was lower (2.7% and 4.1%, respectively), although this difference did not reach statistical significance. Major bleeding occurred in 4.8% and 5.3%, respectively, of patients treated with low-dose or high-dose ximelagatran and in 4.5% of those treated with warfarin, differences that were not statistically significant. Based on these data, the second phase of the Exanta Used to Lessen Thrombosis trial will randomize an additional 2,300 patients to receive ximelagatran (36 mg twice daily) or warfarin.
The data available to date suggest that (1) the combination therapy of subcutaneous melagatran started prior to surgery followed by oral ximelagatran postoperatively is more effective than enoxaparin therapy for thromboprophylaxis after hip or knee arthroplasty, but may cause more bleeding, and (2) postoperative ximelagatran therapy, at a dose of 36 mg twice daily, is likely to be at least as effective as warfarin therapy for thromboprophylaxis after knee arthroplasty. Unlike warfarin, however, ximelagatran does not require coagulation monitoring. Consequently, ximelagatran may be particularly useful for extended out-of-hospital prophylaxis in high-risk patients, a concept that will require testing in future studies.
Treatment of venous thrombosis.
Thrombin Inhibition in Venous Thromboembolism (THRIVE) I, a phase II dose-ranging study,106 randomized 350 patients with venous thrombosis to receive monotherapy with ximelagatran (in doses ranging from 24 to 60 mg twice daily) or subcutaneous dalteparin followed by warfarin for 2 weeks. Based on follow-up venograms, the rate of thrombus regression plus changes in clinical symptoms were similar in both groups. There was a trend for more thrombus progression with ximelagatran than with dalteparin (8% and 3%, respectively), but this difference was not statistically significant. The rates of bleeding were similar in both treatment groups. Building on this information, a phase III placebo-controlled, blinded trial107 comparing oral ximelagatran monotherapy (36 mg twice daily) for 6 months with enoxaparin therapy (1 mg/kg subcutaneously twice daily) followed by warfarin therapy (in doses sufficient to produce an INR of 2 to 3) for 6 months has recently been completed. A total of 2,489 patients with venous thromboembolism were entered into the trial, with 1,249 randomized to receive ximelagatran and 1,249 randomized to receive enoxaparin followed by warfarin. The primary end point, objectively documented recurrent venous thromboembolism, occurred in 2.1% and 2.0%, respectively, of those randomized to receive ximelagatran or enoxaparin/warfarin, a difference that was not statistically significant. Major bleeding occurred in 1.3% and 2.2% of those patients randomized to receive ximelagatran or enoxaparin/warfarin, respectively, a difference that was not statistically significant. The all-cause mortality rates were 2.3% and 3.4%, respectively, in the ximelagatran and enoxaparin/warfarin groups.
This study suggests that therapy with oral ximelagatran is as effective and safe as conventional anticoagulation therapy with low-molecular-weight heparin followed by warfarin for the initial treatment of patients with venous thromboembolism. Unlike low-molecular-weight heparin, ximelagatran can be given orally, and, in contrast to warfarin, ximelagatran does not require anticoagulation monitoring. Consequently, ximelagatran is more convenient to administer than conventional treatment.
Ximelagatran also has been evaluated for the prevention of recurrent thrombosis in patients with venous thromboembolism. The THRIVE III trial108 randomized 1,233 patients who had completed a 6-month course of anticoagulant therapy for the treatment of venous thromboembolism to receive ximelagatran (24 mg twice daily) or placebo for an additional 18 months. Recurrent venous thromboembolism, the primary end point, occurred in 12 patients who had been randomized to receive ximelagatran and 71 who had been randomized to receive placebo (hazard ratio, 0.16; p < 0.001). Major bleeding occurred in six patients who had been treated with ximelagatran and five patients who had been treated with placebo, and there were no incidents of fatal or intracranial bleeding.
Atrial fibrillation.
Ximelagatran has been compared with warfarin in the treatment of patients with nonvalvular atrial fibrillation. In the Stroke Prevention Using Oral Thrombin Inhibition in Atrial Fibrillation (SPORTIF) II trial,109 257 patients were randomized to receive one of three doses of ximelagatran (20, 40, or 60 mg twice daily) or warfarin (in doses sufficient to produce an INR of 2.0 to 3.0). Ximelagatran was administered without coagulation monitoring. At 12 weeks, fewer patients in the ximelagatran group had experienced transient ischemic attacks (0.5% and 3%, respectively), and one patient in the ximelagatran group had an ischemic stroke compared with none in the warfarin group. There were
