New Anticoagulants for Treatment of
`Venous Thromboembolism
`Jeffrey I. Weitz, MD, FRCP(C), FACP, FCCP
`
`Abstract—Treatment of venous thromboembolism (VTE) usually starts with concomitant administration of heparin or
`low-molecular-weight heparin (LMWH) and a vitamin K antagonist. The parenteral anticoagulant, which is given for
`at least 5 days, is stopped once the vitamin K antagonist produces a therapeutic level of anticoagulation. Although the
`introduction of LMWH has simplified the initial treatment of VTE, problems remain. LMWH must be given by daily
`subcutaneous (SC) injection and vitamin K antagonists require routine coagulation monitoring, which is inconvenient
`for patients and physicians. Recently, 3 new anticoagulants have been introduced in an attempt to overcome these
`limitations. These include fondaparinux and idraparinux, synthetic analogs of the pentasaccharide sequence that
`mediates the interaction of heparin and LMWH with antithrombin, and ximelagatran, an orally active inhibitor of
`thrombin. These agents produce a predictable anticoagulant response;
`thus, routine coagulation monitoring is
`unnecessary. Because they do not bind to platelets or platelet factor 4, fondaparinux and idraparinux do not cause
`heparin-induced thrombocytopenia (HIT). Unlike vitamin K antagonists, ximelagatran has a rapid onset of action,
`thereby obviating the need for concomitant administration of a parenteral anticoagulant when starting treatment. The
`lack of an antidote for these new agents is a drawback, particularly for idraparinux, which has a long half-life.
`(Circulation. 2004;110[suppl I]:I-19–I-26.)
`
`Key Words: venous thromboembolism 䡲 pulmonary embolism 䡲 deep venous thrombosis 䡲 anticoagulants
`䡲 coagulation 䡲 pharmacology 䡲 thrombosis
`
`Venous thromboembolism (VTE), which includes deep
`
`vein thrombosis (DVT) and pulmonary embolism (PE),
`occurs in ⬇1 in 1000 white individuals per year.1 The
`primary goal of initial treatment of VTE is to limit thrombus
`extension.2 This not only reduces the risk of PE, a complica-
`tion that can be fatal, but also may minimize postphlebitic
`syndrome, a potentially debilitating long-term sequelae of
`extensive DVT.3
`Anticoagulants remain the cornerstone of treatment of
`VTE. The landmark study by Barritt and Jordan4 established
`the role of anticoagulants in this setting. These investigators
`randomized 35 patients with clinically diagnosed PE to
`treatment with heparin or to no treatment. There were no
`fatalities in the heparin-treated group. In contrast, 25% of
`those untreated died of autopsy-proven PE.
`Rapid anticoagulation is necessary to minimize the risk of
`thrombus extension and PE in patients with VTE. This
`concept
`is supported by the placebo-controlled study of
`Brandjes et al,5 which randomized 120 patients with proximal
`DVT to treatment with heparin plus a vitamin K antagonist or
`to a vitamin K antagonist alone. The study was stopped
`prematurely because the rate of symptomatic recurrent VTE
`was lower in those given heparin plus a vitamin K antagonist
`than in those treated only with a vitamin K antagonist (6.7%
`
`and 20%, respectively; P⫽0.058), as was the rate of VTE
`extension (8.2% and 39.6%, respectively; P⬍0.001).
`With currently available drugs, rapid anticoagulation can
`only be effected with parenteral anticoagulants, such as
`heparin or LMWH. The introduction of LMWH has simpli-
`fied the initial treatment of VTE. Compared with heparin,
`LMWH exhibits greater bioavailability after SC injection, has
`a longer half-life, and produces a more predictable anticoag-
`ulant response.6 Consequently, LMWH can be given subcu-
`taneously once or twice daily without coagulation monitor-
`ing. Meta-analyses of trials comparing SC LMWH with
`continuous intravenous (IV) heparin for initial treatment of
`VTE demonstrate that LMWH is at least as effective and safe
`as heparin.7,8 Because LMWH is more convenient to admin-
`ister, however, it is ideally suited for outpatient treatment of
`VTE,9,10 an approach that reduces health care costs9 –12 and
`improves patient satisfaction.13
`After initial treatment with heparin or LMWH, ongoing
`anticoagulant therapy is needed to prevent recurrent VTE.14,15
`Extended therapy usually involves administration of a vita-
`min K antagonist,2 although long-term LMWH may be a
`better choice in cancer patients with VTE.16 A 3-month
`course of anticoagulant treatment is adequate for patients
`with VTE complicating a transient risk factor, such as
`surgery. In contrast, more extended therapy is needed in
`
`From McMaster University and Henderson Research Centre, Hamilton, Ontario, Canada.
`Correspondence to Dr Jeffrey I. Weitz, Henderson Research Centre, 711 Concession Street, Hamilton, Ontario, Canada, L8V 1C3. E-mail
`jweitz@thrombosis.hhscr.org
`© 2004 American Heart Association, Inc.
`Circulation is available at http://www.circulationaha.org
`
`DOI: 10.1161/01.CIR.0000140901.04538.ae
`
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`I-20
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`Circulation
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`August 31, 2004
`
`patients with unprovoked VTE.17–24 Long-term anticoagula-
`tion therapy is problematic because vitamin K antagonists are
`not easy to administer.25 Routine coagulation monitoring is
`essential to ensure that a therapeutic response is obtained
`because vitamin K antagonists have a narrow therapeutic
`window. Thus, a subtherapeutic response does not effectively
`reduce the risk of thrombosis, whereas excessive anticoagu-
`lation increases the risk of bleeding.25 Furthermore, interac-
`tions with a range of drugs can reduce or enhance the
`anticoagulant effects of vitamin K antagonists, as can variable
`intake of foods containing vitamin K. In addition, genetically
`determined polymorphisms in the cytochrome P4502C9 en-
`zyme influence the metabolism of vitamin K antagonists.26,27
`These phenomena contribute to the need for routine coagu-
`lation monitoring. Even when coagulation monitoring is
`performed, patients using vitamin K antagonists have a
`therapeutic anticoagulant response less than half the time,25 a
`situation that places them at risk for complications.
`Recently, 2 new parenteral and 1 novel oral anticoagulant
`have been evaluated in patients with VTE. Parenteral agents
`with longer half-lives than heparin or LMWH have the
`potential to simplify initial or extended treatment of VTE,
`whereas rapidly acting oral anticoagulants provide an oppor-
`tunity for streamlined therapy by eliminating the need for
`parenteral agents for initial VTE treatment and by obviating
`the requirement for coagulation monitoring and dose adjust-
`ment. Focusing on new drugs that have been evaluated in
`patients with VTE, this article (1) reviews their pharmacol-
`ogy, (2) outlines the potential advantages of these agents over
`existing anticoagulants, (3) describes the results of clinical
`trials evaluating new anticoagulants for treatment of VTE, (4)
`provides perspective as to strengths and potential drawbacks
`of these new agents, and (5) identifies their evolving role in
`VTE management.
`
`Pharmacology of New Anticoagulants
`The new anticoagulants that have been evaluated for the
`treatment of VTE include 2 parenteral antithrombin-
`dependent
`inhibitors of activated factor X (factor Xa),
`fondaparinux and idraparinux, and ximelagatran, the first oral
`direct thrombin inhibitor. By targeting factor Xa, fondapa-
`rinux and idraparinux block thrombin generation. In contrast,
`ximelagatran inhibits thrombin, the enzyme that catalyzes the
`conversion of fibrinogen to fibrin (Figure 1). Thrombin also
`activates platelets and amplifies its own generation by feed-
`back activation of factors VIII and V, key cofactors in factor
`Xa and thrombin generation, respectively. The pharmacology
`of fondaparinux,
`idraparinux, and ximelagatran is briefly
`discussed.
`
`Fondaparinux
`A synthetic analog of the antithrombin-binding pentasaccha-
`ride sequence found on heparin or LMWH (Figure 2),
`fondaparinux binds antithrombin with high affinity. Once
`bound, fondaparinux evokes conformational changes in the
`reactive center loop of antithrombin that enhance its reactiv-
`ity with factor Xa.28,29 Fondaparinux is a catalytic inhibitor;
`thus, after promoting the formation of the factor Xa/anti-
`thrombin complex, fondaparinux dissociates from antithrom-
`
`Figure 1. Sites of action of fondaparinux, idraparinux, and
`ximelagatran. Coagulation is initiated by the tissue factor/factor
`VIIa (TF/VIIa) complex, which activates factors IX and X. Acti-
`vated factor X (Xa) converts small amounts of prothrombin (II) to
`thrombin (IIa), which then feeds back to activate factors VIII and
`V, key cofactors in coagulation. The process is propagated by
`activated factor IX (IXa), which together with activated factor VIII
`(VIIIa) assembles on the surface of activated platelets to form
`intrinsic tenase, a complex that efficiently activates factor X. Xa,
`together with activated factor V (Va), assembles on the surface
`of activated platelets to form prothrombinase. This complex
`generates a burst of thrombin that, in the final stage of the
`coagulation process, converts fibrinogen to fibrin. By inhibiting
`factor Xa in an antithrombin-dependent fashion, fondaparinux
`and idraparinux block thrombin generation. In contrast, ximel-
`agatran undergoes biotransformation to melagatran, which then
`blocks thrombin activity by binding directly to the active site of
`the enzyme.
`
`bin and is available to activate additional antithrombin
`molecules.
`With excellent bioavailability after SC administration and
`a plasma half-life of 17 hours,30 fondaparinux is administered
`subcutaneously once daily. Systemic fondaparinux is ex-
`creted unchanged via the kidneys. Therefore, fondaparinux
`must be used with caution in patients with renal
`insufficiency.28,29
`When given SC in fixed doses, fondaparinux produces a
`predictable anticoagulant response. Consequently, routine
`coagulation monitoring is unnecessary. If necessary, fondapa-
`rinux can be monitored with antifactor Xa levels using a
`chromogenic assay.31 Fondaparinux has no effect on routine
`tests of coagulation, such as the activated partial thrombo-
`plastin time or activated clotting time.32
`
`Figure 2. Structures of fondaparinux and idraparinux. Fondapa-
`rinux is a synthetic analog of the natural pentasaccharide found
`in heparin and LMWH heparin. To enhance its affinity for anti-
`thrombin, idraparinux is 0-methylated and 0-sulfated.
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`Weitz
`
`New Anticoagulants for VTE
`
`I-21
`
`Figure 3. Structures of ximelagatran and
`melagatran. Ximelagatran has ester and
`hydroxyl groups added to the carboxyl and
`amidine groups of melagatran. Bioconver-
`sion of ximelagatran to melagatran involves
`hydrolysis of the ester by esterases and
`reduction of the hydroxyl group. Intermedi-
`ates with one or the other of these protect-
`ing groups removed can be found tran-
`siently in the plasma.
`
`ximelagatran ingestion; melagatran circulates with a half-life
`of 3 hours in healthy volunteers and 4 to 5 hours in patients.
`Because melagatran has a relatively short half-life, ximelagat-
`ran is administered orally twice daily.34
`Ximelagatran produces a predictable anticoagulant re-
`sponse after fixed oral dosing. The half-life of melagatran
`does not vary among ethnic groups35 and is not influenced by
`obesity36 or mild to moderate hepatic insufficiency.37 Ximel-
`agatran does not interact with drugs that are metabolized by
`cytochrome P450 isozymes CYP2C19, CYP2C9, or
`CYP3A4.34
`At least 80% of systemic melagatran is eliminated un-
`changed via the kidneys. The half-life of melagatran is
`slightly prolonged in the elderly,
`likely reflecting their
`reduced creatinine clearance.38
`Coagulation monitoring is unnecessary for ximelagatran
`because it produces a predictable anticoagulant response.34
`Like all direct thrombin inhibitors, ximelagatran prolongs the
`activated partial thromboplastin time and international nor-
`malized ratio (INR). However, its effect on these tests is not
`dose-dependent and the extent of prolongation depends on the
`reagent used for testing. If monitoring is required, the ecarin
`clotting time, a test that has yet to be standardized, provides
`the best estimate of drug concentration.
`
`Potential Advantages of New Anticoagulants
`Fondaparinux was developed to replace heparin or LMWH
`for initial treatment of VTE, whereas idraparinux and ximel-
`agatran were designed to compete with vitamin K antago-
`nists. Because of their rapid onset of action, however,
`idraparinux and ximelagatran also may be useful for initial
`treatment of VTE, as well as for extended therapy.
`
`TABLE 1. Comparison of Fondaparinux and Idraparinux
`with LMWH
`
`Feature
`
`Target
`
`Fondaparinux
`
`Idraparinux
`
`LMWH
`
`Factor Xa
`
`Factor Xa
`
`Route of administration
`Half-life (h)
`Endothelial cell binding
`Protein binding
`Clearance
`HIT
`Antidote
`
`SC
`17
`None
`None
`Renal
`No
`None
`
`SC
`80
`None
`None
`Renal
`No
`None
`
`LMWH indicates low-molecular-weight heparin; SC, subcutaneous; HIT,
`heparin-induced thrombocytopenia.
`
`Factor Xa and
`thrombin
`SC
`4
`Some
`Some
`Renal
`Rare
`Partial neutralization
`with protamine sulfate
`
`Idraparinux
`A second-generation synthetic pentasaccharide, idraparinux
`is more negatively charged than fondaparinux (Figure 2).
`Consequently,
`idraparinux binds to antithrombin with an
`affinity higher than that of fondaparinux.33 Because it binds
`antithrombin so tightly, idraparinux has a plasma half-life
`similar to that of antithrombin, ⬇80 hours. With this long
`half-life, idraparinux is administered SC on a once-weekly
`basis. Like fondaparinux, idraparinux exhibits excellent bio-
`availability after SC injection and produces a predictable
`anticoagulant response, thereby obviating the need for routine
`coagulation monitoring.33
`
`Ximelagatran
`The first oral, direct thrombin inhibitor, ximelagatran is a
`prodrug of melagatran (Figure 3), a 429-dalton dipeptide that
`fits within the active-site cleft of thrombin and blocks the
`enzyme’s interactions with its substrates.34 Thus, melagatran
`is a stoichiometric inhibitor of thrombin that forms a revers-
`ible 1:1 complex with the enzyme. Melagatran exhibits poor
`bioavailability after oral administration. Ximelagatran, which
`has a molecular mass of 474, was developed to overcome this
`problem. With the addition of an ester and a hydroxyl group
`to the carboxyl and amidine groups of melagatran, respec-
`tively, ximelagatran is more lipophilic than melagatran.
`Consequently, ximelagatran is readily absorbed in the small
`intestine.34 Plasma levels of ximelagatran peak in the blood
`30 minutes after drug ingestion (Figure 4). Although ximel-
`agatran has no intrinsic anticoagulant activity, it is rapidly
`converted to melagatran via 2 intermediates. The bioavail-
`ability of melagatran after administration of oral ximelagatran
`is ⬇20%. Plasma levels of melagatran peak 2 hours after
`
`Figure 4. Plasma levels of ximelagatran and melagatran after
`administration of oral ximelagatran to healthy volunteers. Ximel-
`agatran levels in the blood peak 30 minutes after drug adminis-
`tration, whereas the levels of melagatran peak at 2 hours. Mel-
`agatran has a half-life of 3 hours in young healthy volunteers
`and 4 to 5 hours in patients.
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`Circulation
`
`August 31, 2004
`
`TABLE 2. Comparison of Ximelagatran with Vitamin K Antagonists
`
`Feature
`
`Target
`
`Route of administration
`Onset of action (h)
`Food interactions
`Drug interactions
`
`Therapeutic window
`Coagulation monitoring required
`Liver function monitoring required
`Antidote
`
`Ximelagatran
`
`Thrombin
`
`Oral
`2
`None
`None
`
`Wide
`No
`Yes
`None
`
`Vitamin K Antagonists
`
`Vitamin K-dependent clotting factors
`(factor VII, IX, X, and prothrombin)
`Oral
`72 to 96
`Affected by vitamin K content of diet
`Multiple drugs affect pharmacokinetics
`or pharmacodynamics
`Narrow
`Yes
`No
`Vitamin K produces slow reversal
`
`The new anticoagulants have potential advantages over
`existing agents. Focusing first on the parenteral agents, both
`fondaparinux and idraparinux have properties that distinguish
`them from LMWH (Table 1), the anticoagulant that is rapidly
`replacing heparin for initial VTE treatment. Whereas the
`bioavailability of LMWH after SC injection is 80% to 90%,6
`fondaparinux and idraparinux exhibit almost complete bio-
`availability.28,29,33 In addition, there is less between-patient
`variability in the anticoagulant response with fondaparinux
`and idraparinux than with LMWH. These differences reflect
`the fact that fondaparinux and idraparinux are homogeneous
`preparations of synthetic pentasaccharide units that bind only
`to antithrombin.39 In contrast, LMWH preparations are com-
`posed of heparin fragments that range in molecular weight
`from 1000 to 10 000 daltons. Only 15% to 20% of these
`fragments possess a pentasaccharide sequence.6 Longer
`chains can bind nonspecifically to endothelial cells and
`various plasma proteins.40,41 Pentasaccharide-independent
`binding of heparin chains to endothelial cells reduces bio-
`availability because these cellular binding sites must be
`saturated before the LMWH chains can enter the circulation
`and interact with antithrombin. Binding to plasma proteins,
`the levels of which differ between patients, explains the
`between-patient variability in the anticoagulant response to
`LMWH. Although fondaparinux and idraparinux have greater
`bioavailability than LMWH and produce a more predictable
`anticoagulant response, it is unclear whether these properties
`endow the new anticoagulants with clinical advantages over
`LMWH.
`Fondaparinux and idraparinux have half-lives of 17 and 80
`hours, respectively. In contrast, LMWH has a half-life of only
`4 to 5 hours. Despite its relatively short half-life, LMWH is
`effective when given once daily for VTE treatment, although
`uncertainty remains as to whether once-daily LMWH is as
`effective as twice-daily dosing.42 A potential explanation for
`the extended antithrombotic activity of LMWH is its capacity
`to induce the release of tissue factor pathway inhibitor (TFPI)
`from the vasculature.43,44 An endogenous anticoagulant, TFPI
`limits the initiation of coagulation by inhibiting tissue factor-
`bound factor VIIa in a factor Xa-dependent fashion.45 In
`contrast to LMWH, neither fondaparinux nor idraparinux
`induces TFPI
`release. However,
`the long half-lives of
`
`fondaparinux and idraparinux may preclude the need for this
`additional anticoagulant mechanism.
`Although LMWH can induce HIT, the risk of HIT is lower
`with LMWH than with heparin.46 In contrast, fondaparinux
`and idraparinux do not cause HIT because they do not bind to
`platelets or platelet factor 4 (PF4). Thus, HIT is triggered by
`antibodies directed against
`the heparin/PF4 complex.47
`Fondaparinux and idraparinux do not bind to platelets.
`Therefore, they do not cause platelet activation and subse-
`quent PF4 release. Likewise, because these agents do not bind
`to PF4, they do not induce the conformational changes in PF4
`that render it antigenic. These properties endow fondaparinux
`and idraparinux with a safety advantage over heparin and
`LMWH and may render these new agents useful for HIT
`treatment, a possibility that requires evaluation in clinical
`trials.
`Osteoporosis can occur after long-term treatment with
`heparin or LMWH.48,49 The risk of this complication should
`be lower with fondaparinux and idraparinux because shorter
`heparin chains cause less bone loss than longer chains in cell
`culture systems and in laboratory animal models.50,51 For
`extended treatment, therefore, fondaparinux and idraparinux
`may be safer than heparin or LMWH.
`As an orally active anticoagulant, ximelagatran has poten-
`tial advantages over vitamin K antagonists (Table 2). Vitamin
`K antagonists have a delayed onset of action. Thus, these
`agents act as anticoagulants by interfering with vitamin
`K-dependent, post-translational modification of the vitamin
`K-dependent clotting factors, an essential step in the synthesis
`of functional coagulation proteins.25 The antithrombotic ef-
`fect of vitamin K antagonists most probably reflects reduc-
`tions in the functional levels of prothrombin and factor X, a
`process that requires 4 to 5 days of treatment. Because of their
`slow onset of action, initial therapy with vitamin K antago-
`nists is usually supported by overlapping treatment with a
`parenteral anticoagulant in patients with established throm-
`bosis, or in those at high risk for thrombosis.2 In contrast,
`ximelagatran has a rapid onset of action, thereby obviating
`the need for concomitant administration of a parenteral
`anticoagulant when starting treatment.
`As mentioned earlier, vitamin K antagonists have a narrow
`therapeutic window. Furthermore, genetic differences in me-
`tabolism and multiple drug and food interactions affect the
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`anticoagulant response to vitamin K antagonists.35 These
`factors contribute to the need for routine coagulation moni-
`toring, which is inconvenient for patients and physicians. In
`contrast, ximelagatran, with a wider therapeutic window than
`vitamin K antagonists and no food or drug interactions, can
`be given without coagulation monitoring.34 Building on their
`unique properties, fondaparinux, idraparinux, and ximelagat-
`ran have been compared with conventional anticoagulant
`regimens in VTE patients.
`
`Clinical Trials With New Anticoagulants
`Fondaparinux and ximelagatran have completed phase III
`clinical trials for treatment of VTE. Idraparinux has com-
`pleted phase II evaluation, and phase III clinical trials are
`underway. The results of these trials are discussed.
`
`Fondaparinux
`Fondaparinux has been evaluated for treatment of VTE in 2
`phase III clinical trials. In the MATISSE-DVT study, 2205
`patients with DVT were randomized,
`in a double-blind
`fashion, to receive either fondaparinux (in dosages of 5, 7.5,
`or 10 mg SC once daily depending on body weight) or
`enoxaparin (1 mg/kg SC twice daily) for at least 5 days,
`followed by a minimum of a 3-month course of treatment
`with a vitamin K antagonist.52 At 3 months, rates of recurrent
`symptomatic VTE with fondaparinux or enoxaparin were
`3.9% and 4.1%, respectively, whereas rates of major bleeding
`were 1.1% and 1.2%, respectively.
`In the open-label MATISSE PE trial, 2213 patients with PE
`were randomized to receive either fondaparinux (in dosages
`of 5, 7.5, or 10 mg SC once daily depending on body weight)
`or heparin (by continuous IV infusion) for 5 days, followed
`by a minimum of a 3-month course of therapy with a vitamin
`K antagonist.53 At 3 months, rates of recurrent symptomatic
`VTE with fondaparinux or heparin were 3.8% and 5.0%,
`respectively, whereas rates of major bleeding were 1.3% and
`1.1%, respectively. The results of the MATISSE studies
`suggest
`that fondaparinux is as effective as LMWH or
`unfractionated heparin for initial VTE treatment. Further-
`more, fondaparinux is easier to administer than unfraction-
`ated heparin.
`
`Idraparinux
`In a phase II, dose-finding trial, idraparinux was compared
`with warfarin for treatment of patients with proximal DVT.54
`In this trial, 659 patients were treated for 5 to 7 days with
`enoxaparin and then randomized to receive once-weekly SC
`idraparinux (2.5, 5.0, 7.5, or 10 mg) or warfarin for 12 weeks.
`The primary efficacy 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 given idraparinux with an unacceptably high rate of
`major bleeding in those given the 10-mg dose. Two patients,
`both of whom were in the 5-mg idraparinux group, experi-
`enced fatal bleeds. Patients given the lowest dose of idrapa-
`rinux had less bleeding than those randomized to warfarin
`(P⫽0.029). Based on these data, ongoing phase III trials are
`comparing SC idraparinux monotherapy (at a dose of 2.5 mg
`
`Weitz
`
`New Anticoagulants for VTE
`
`I-23
`
`SC once weekly) with 5 to 7 days of enoxaparin, followed by
`at least 3 months of warfarin therapy for treatment of patients
`with DVT or PE.
`
`Ximelagatran
`The double-blind, phase III THRIVE treatment study ran-
`domized 2491 patients with acute DVT to receive either oral
`ximelagatran (36 mg twice daily) alone for 6 months or
`enoxaparin (1 mg/kg SC twice daily for a minimum of 5
`days), followed by warfarin (target INR of 2.0 to 3.0) for 6
`months.55 The primary end point, objectively documented
`recurrent VTE, occurred in 2.1% and 2.0% of patients given
`ximelagatran and enoxaparin/warfarin, respectively. Rates of
`major bleeding were similar in the ximelagatran and enox-
`aparin/warfarin groups (1.3% and 2.2%, respectively), as
`were the all-cause mortality rates (2.3% and 3.4%, respec-
`tively; P⫽NS). These results suggest that oral ximelagatran is
`as effective as conventional anticoagulant
`treatment with
`enoxaparin followed by warfarin in preventing recurrent VTE
`in patients with acute DVT. However, unlike enoxaparin or
`dalteparin, ximelagatran can be given orally, and in contrast
`to warfarin, ximelagatran does not require coagulation mon-
`itoring or dose adjustment. Consequently, ximelagatran has
`the potential to streamline treatment.
`Ximelagatran also has been evaluated for the long-term
`secondary prevention of recurrent thrombosis in patients with
`VTE. An open-label, phase III study (THRIVE III) random-
`ized 1233 patients who had completed a 6-month course of
`anticoagulant therapy for treatment of VTE to oral ximelagat-
`ran (24 mg twice daily) or placebo for an additional 18
`months.56 The primary end point, objectively documented
`recurrent VTE, occurred in 2.8% of patients given ximelagat-
`ran and in 12.6% of those randomized to placebo (hazard
`ratio 0.16; P⬍0.001). Major bleeding rates were similar
`between the ximelagatran and placebo groups (1.1% versus
`1.3%, respectively; hazard ratio 1.16), and there were no fatal
`or intracranial bleeds. Hence, data from this study indicate
`that
`lower-dosage ximelagatran (24 mg twice daily) can
`effectively prevent recurrent VTE.
`
`Potential Role of New Anticoagulants in
`VTE Treatment
`The introduction of LMWH provided a major advance in
`initial VTE treatment. With once- or twice-daily SC admin-
`istration and no need for coagulation monitoring, LMWH
`paved the way for out-of-hospital treatment. New anticoagu-
`lants have the potential to further streamline VTE treatment
`and to offer potential safety advantages over existing agents.
`Based on the results of
`the MATISSE-DVT and
`MATISSE-PE trials,52,53 fondaparinux can be used in place of
`LMWH or heparin for initial treatment of VTE. Although
`more convenient to administer than heparin, like LMWH,
`fondaparinux must be given daily by SC injection. However,
`fondaparinux may be safer than heparin or LMWH because it
`does not cause HIT.
`Idraparinux and ximelagatran have the potential to be used
`as sole therapy for VTE treatment. In the case of idraparinux,
`a single SC injection at the time of VTE diagnosis circum-
`vents the need for daily SC injections of LMWH for the initial
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`I-24
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`Circulation
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`August 31, 2004
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`5 to 7 days of treatment. Thereafter, once-weekly SC idrapa-
`rinux can be used in place of a vitamin K antagonist. With no
`need for routine coagulation monitoring and dose adjustment,
`idraparinux is more convenient to administer than vitamin K
`antagonists. Although promising, the efficacy and safety of
`idraparinux for VTE treatment remains to be established in
`the ongoing phase III trials.
`Like idraparinux, ximelagatran also can be used for both
`initial and extended VTE treatment. Ximelagatran has the
`advantage of oral bioavailability, thereby obviating the need
`for SC injections, and in contrast to vitamin K antagonists,
`ximelagatran does not require coagulation monitoring or
`dosage adjustment. Based on the results of the THRIVE
`treatment trial,55 ximelagatran alone (at a dosage of 36 mg
`twice daily) appears to be as effective and safe as conven-
`tional treatment with LMWH followed by warfarin for DVT
`treatment.
`The data from the THRIVE III study56 indicate that a
`lower-dosage ximelagatran regimen (24 mg twice daily)
`prevents recurrent VTE. This study highlights the fact that
`patients with unprovoked VTE have a rate of recurrent VTE
`of 7% to 10% per year when anticoagulant
`therapy is
`stopped.17–24 When given in dosages sufficient to produce a
`target INR of 2.0 to 3.0, warfarin reduces this risk by ⬎90%,
`but is associated with an average rate of major bleeding of 2%
`per year, of which 10% are fatal.17–24 A lower-intensity
`warfarin regimen (target INR 1.5 to 1.9) is less effective at
`preventing recurrent VTE than usual-intensity warfarin (tar-
`get INR 2.0 to 3.0) in this setting and does not appear to
`reduce the risk of bleeding.57 Although effective, warfarin is
`inconvenient because of the need for routine coagulation
`monitoring and dosage adjustment. Ximelagatran has the
`potential to overcome this barrier.
`
`Potential Limitations of New Anticoagulants
`What are the drawbacks of these new anticoagulants? Like all
`anticoagulants, the major side effect of these new drugs is
`bleeding. To counteract this problem, a safe rapidly-acting
`antidote is desirable. Unfortunately, none of these new agents
`has an antidote. When rapid reversal is required because of
`major bleeding or the need for urgent surgery, the lack of an
`antidote is more problematic for agents with a long half-life,
`such as idraparinux, than for those with a short half-life, such
`as ximelagatran. Although procoagulants, including recombi-
`nant factor VIIa, may reverse the anticoagulant effects of
`fondaparinux,
`idraparinux, or ximelagatran in animals or
`healthy volunteers,58 – 61
`the effect of
`these agents on
`anticoagulant-induced bleeding has yet
`to be addressed.
`Furthermore, recombinant factor VIIa is not available in all
`hospitals and the drug is expensive, particularly if repeated
`doses are needed. Although not well studied, dialysis is likely
`to clear melagatran, but not fondaparinux or idraparinux.
`A side effect unique to ximelagatran is elevation of liver
`enzymes. Overall, ⬇6% (range, 5% to 10%) of patients
`treated with long-term ximelagatran have a transient increase
`in alanine aminotransferase levels to over 3 times the upper
`limit of normal. Typically, this occurs between 1 and 6
`months after the start of treatment. Concomitant elevation of
`bilirubin levels is found in only 0.4% of patients. The
`
`increase in serum alanine aminotransferase is generally
`asymptomatic and reversible, regardless of whether ximel-
`agatran treatment is continued or stopped. Although this
`phenomenon appears to be benign, more data on patients
`treated long-term are needed. Until this information is avail-
`able, ximelagatran will need to be restricted to patients with
`normal or near normal hepatic function at baseline. Further-
`more, it is likely that testing of liver function will need to be
`performed when initiating ximelagatran treatment and during
`the first 6 months of therapy. Although less problematic than
`the routine coagulation monitoring and dosage adjustments
`needed with vitamin K antagonists, the requirement for liver
`function test monitoring may limit
`the convenience of
`ximelagatran.
`Cost is a consideration with any new drug. Fondaparinux is
`more expensive than LMWH, and idraparinux and ximelagat-
`ran are likely to cost more than vitamin K antagonists, even
`with their attendant cost of coagulation monitoring. There-
`fore, cost-effectiveness analyses will be required to determine
`the extent to which these new treatments reduce health care
`costs. Patient convenience also deserves consideration. By
`obviating the need for routine coagulation monitoring, agents
`such as idraparinux or ximelagatran can improve the quality
`of life for individuals with limited access to anticoagulation
`clinics.
`Finally, compliance with these new drugs may be difficult
`to assess in the absence of coagulation monitoring. Attention
`to packaging and ongoing supervision of patients will help
`minimize this problem.
`
`Conclusions and Future Directions
`New anticoagulants have the potential to further refine VTE
`treatment. Still unknown, however, is the role of these agents
`in selected high-risk VTE patients, such as those with cancer,
`and their safety in pregnancy. With its short half-life and oral
`bioavailability, ximelagatran could prove more convenient
`than LMWH in cancer patients with VTE, provided that its
`safety can be established in those with hepatic metastases and
`abnormal liver function tests. Fondaparinux also may prove
`useful
`in this setting, although its longer half-life may
`complicate timing of invasive procedures.
`The safety of these n